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Archive for the ‘Stem Cell Negative’ Category

Oklahoma 10-year-old in remission after being diagnosed with rare form of leukemia 2 years ago – KFOR Oklahoma City

Wednesday, July 21st, 2021

EDMOND, Okla. (KFOR) Edmond 10-year-old, Miller Hines enjoys soccer, his scooter, constructing Legos, and playing with his younger brother.

Miller is a lover of life, I like to say that hes a world shaker and game changer, says his mother, Miranda.

Two years ago, Miranda remembers the cascade of bad news that started with swollen lymph nodes.

He was swollen in his neck area which was concerning but Id also seen that with him when hed had strep throat, she recalls.

But when Miller went to the doctor, the strep test came back negative. Thats when they ran blood tests which revealed alarming results.

Miranda remembers, I did somethingyoure not supposed to do, which is google what this means.

Miller had AML leukemia with an added genetic mutation which made it even more dangerous.

He had a very aggressive form of leukemia. I knew Miller was really, really sick, Miranda recalls. Preparing for his bone marrow transplant and then having the transplant was really brutal.

In the middle of the pandemic, mother and son leaned on each other for dear life.

Miller is such a sweet boy. He made me a mom, and were buddies, and he would often encourage me by saying Mom, Im OK,' Miranda shakes her head as she remembers his efforts to ease her fears.

Holding them both up with medical support and emotional encouragement was their medical team at OU Childrens Hospital, and Jimmy Everest Cancer Center.

Miranda doesnt hold back the tears as she expresses her gratitude, We absolutely adore them. Theres no doubt that they saved Miller.

His treatments included a stem cell transplant, chemotherapy, and gene therapy.

Working in tandem, his treatment plan proved to be successful.

His blood work shows hes free of cancer 17 months after his transplant.

Despite the pain, and even boredom that comes from months of treatment, Miller has happy memories of playing with therapy dogs at the clinic and joking around with the nurses.

Miranda says, We miss them, but we are happiest to run into them outside of the clinic!

Miller wants to get on with the hobbies he had to put on the sidelines.

Hes getting to be a 10-year-old. Hes playing soccer again.And the best thing thats ever happened in my whole life is Miller, so for him to be here and be healthy is incredible, says Miranda.

Its been almost a three-year roller coaster ride the Hines are happy to step off, grateful for a new chapter of childhood ahead.

If youd like to help children like Miller fight cancer, consider donating to JECFriends.org.

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Covid: There’s a serious problem with how we are testing people for the virus Neale Hanvey MP – The Scotsman

Wednesday, July 21st, 2021

This gives Scotland an opportunity, and a pressing need, to chart a different course. This is not political hyperbole. It is based on an NHS career in cancer care where infection prevention and control are a daily struggle for patients with suppressed immune systems.

Having led bone marrow and stem cell transplantation services at both University College Hospital and the Royal Marsden, I have a strong grasp of the systematic approach needed for effective infection protection, control, and treatment.

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While most people are not as vulnerable as transplant patients, with a novel virus like Covid we simply cannot predict how and when the virus will mutate or how this could impact the general population.

There are three interdependent strands to consider: controls such as mask wearing, social distancing and hand hygiene; surveillance testing and genomic studies that chart the progress and development of the virus; and treatment the use of dexamethasone and vaccination programmes.

Get one element wrong and the whole approach could fail.

Until now weve diligently been following guidance across a range of control measures, and the vaccination programme delivered by the ever-valiant NHS workforce has been a great success but weve still seen a sharp rise in Delta-variant cases. This brings me to surveillance.

The problem is the UK and devolved governments have relied on Innova lateral-flow devices (LFDs) as the method of rapid-test surveillance.

This means taxpayers money is being spent to prop up Chinese imports that are being used in a potentially dangerous way, while our domestic diagnostics industrys superior tests have been cast adrift.

As a result, we are now at a perilous crossroads. Failure to use effective controls or robust surveillance risks the Delta variant spreading ever more rapidly, presenting a significant risk of further mutation.

I am already seeing this in my constituency where people have received repeated negative results with Innova LFD tests, only to insist on a PCR test and discover they are Covid positive and at the centre of a new cluster of infections.

To be blunt, the Prime Ministers desire to appease some Tory backbenchers with cries of Freedom Day has endangered all the advances made to date.

Thats why the Scottish government must chart an independent course. Maintain all the sensible controls, continue the vaccination roll-out, but abandon the inappropriate use of these Chinese tests in favour of superior tests made here in Scotland.

There is no good reason to follow Boris over the cliff on his Covid surrender strategy.

Neale Hanvey is the Alba Party MP for Kirkcaldy and Cowdenbeath

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Profilin 1 Protein and Its Implications for Cancers – Cancer Network

Wednesday, July 21st, 2021

Introduction

Profilin 1 (PFN1) is a ubiquitous small-molecule protein that exists in all eukaryotes.1 PFN1 was first identified as a G-actin sequestering molecule,2 and subsequently, its true functions in actin polymerization and F-actin dynamics were revealed.3 In the following decades, the structure of PFN1 was recognized to have 3 domains: an actin-binding domain,4 a poly-L-proline (PLP)-binding domain,5 and a phosphoinositide-binding domain.6

PFN1 plays a vital role in many cell functions, including membrane trafficking, endocytosis, cell cycle, motility, proliferation, cell survival, transcription, stemness, and autophagy (Figure 1). Abnormal expression or deletion of PFN1 can affect the normal physiological activity of cells and lead to disease development. PFN1 has been deeply studied in a variety of diseases, some genetic (eg, amyotrophic lateral sclerosis)7 and some chronic (eg, hypertension).8

In the past 10 years, PFN1s role in cancer has received increasing attention. In this review, we summarize the studies of PFN1 in cancer that have been completed in recent years, discuss the roles of PFN1 in cancer, and discuss the implications for tumor diagnosis and therapy in the future.

Early diagnosis of cancers is still a major challenge worldwide, and early detection can notably reduce their associated morbidity and mortality.9 PFN1, a critical actin-binding protein, is found to be dysregulated in many cancers, which makes it possible to use it as a biomarker for diagnosis and prognosis. PFN1 mainly plays a role in the cytoplasm, but it can also be found in the nucleus and can even be secreted into the extracellular space. The rich knowledge in the proteomics field makes the detection of proteins for new diagnostic markers and targets for therapy possible.10

In some tumor types (such as renal cell carcinoma [RCC], gastric cancer, and others), high expression of PFN1 indicates later stage and worse prognosis. Via differential proteomics, PFN1 has been identified in metastatic and primary RCC, and further analysis indicated that high PFN1 expression was associated with poor outcome and that PFN1 could be used as a potential prognostic marker in RCC.11 In clear-cell RCC (ccRCC), the expression of PFN1 was decreased in early-stage tumors compared with normal tissues. However, its expression in stage IV ccRCC was significantly increased. PFN1 was selected as a candidate marker of late-stage ccRCC.12 Results of a recent study determined that the vast majority of ccRCC tumors tend to be selectively PFN1-positive in stromal cells only; dramatic transcriptional upregulation of PFN1 was found in tumor-associated vascular endothelial cells in clinical specimens of ccRCC.13 Tissue microarray results also showed that PFN1 was increased in metastatic ccRCC compared with primary tumors. Univariate analysis suggested that higher PFN1 expression was associated with shorter disease-free survival (HR, 7.36; P = .047) and lower overall survival.14

In gastric cancer, Tanaka et al found that PFN1 was highly expressed in fetal rat stomach. Additionally, PFN1 was overexpressed in some human and rat gastric cancers.15 The results of later studies indicated that PFN1 expression was higher in gastric cancer tissues than in adjacent normal tissues. High PFN1 expression was correlated with tumor infiltration, lymph node metastasis, and tumor-node-metastases (TNM) stage. Functional assays confirmed that silencing PFN1 could inhibit the invasion and migration of gastric cancer cell lines.16

In addition, PFN1 expression was higher in nonsmall cell lung cancer (NSCLC). Lower expression of PFN1 was associated with better prognosis and a higher survival rate in NSCLC.17 Proteomic analysis revealed that PFN1 was differentially expressed in laryngeal carcinoma tissues compared with adjacent normal tissues. Further study results revealed that PFN1 was increased in laryngeal carcinoma tissues compared with adjacent normal tissues, indicating that PFN1 was a novel potential biomarker for the diagnosis of laryngeal carcinoma.18

However, in some other tumors (such as colorectal cancer [CRC], oral carcinoma, and others), the opposite is true. PFN1 was downregulated in pancreatic cancer.19-20 Lower expression of PFN1 was significantly associated with a shorter survival period.20 In late-stage oral squamous cell carcinoma, PFN1 expression was lower than that in normal oral epithelium, and loss of PFN1 expression was related to invasion into and metastasis of lymph nodes.21 PFN1 was also decreased in late advanced hepatocellular carcinoma (HCC) and was associated with a poor survival rate of patients.22-23 In addition, PFN1 was found to be downregulated in nasopharyngeal carcinoma24 and breast cancer.25 Combined with another 4 actin-binding proteins, PFN1 could be used to construct a model for predicting poor prognosis of esophageal squamous cell carcinoma.26

Under normal physiological conditions, PFN1 is involved in multiple cellular functions, such as cell motility, migration, adhesion, and transduction signaling pathways.27 PFN1 is differentially expressed in various types of tissues and cells, which may explain its variable tumorigenic mechanisms in different tumors, even in different stages of the same cancer (Figure 2). Because PFN1 plays important roles in tumorigenesis and progression, targeting PFN1 dysregulation could to some extent influence the prognosis of patients with cancer. Determining the expression of PFN1 could thus be used to distinguish high-risk disease from lower-risk disease. Combination with other indices could further improve the diagnostic and prognostic value of PFN1.

In addition to dysregulation in tumor tissues, PFN1 was also found to bedifferentially expressed in the serum, urine, and extracellular vesicles of patients with cancer, which makes it possible to utilize PFN1 in liquid biopsy analysis of tumors. Compared with tumor tissue biopsy, liquid biopsy is a more practical method for real-time monitoring of patients with cancer.28 In addition, PFN1 was detected in the supernatants of cultured cells.

It has been shown that PFN1 gene expression is increased in peripheral blood cells of patients with HCC compared with healthy controls.29 A 9-gene expression system (including PFN1) was used to discriminate patients with HCC from healthy people.30 Proteomic analysis of serum proteins showed that PFN1 was increased in patients with gallbladder cancer. The expression difference between these patients and healthy controls was more than 2-fold.31 PFN1 was differentially expressed in the urine of patients with invasive and noninvasive bladder cancer. Further studies confirmed that PFN1 was notably decreased in the epithelium of invasive bladder tumors compared with noninvasive tumors, which was associated with the clinical outcomes of bladder cancer.32 In in vitro pancreatic cancer cell lines, PFN1 was downregulated in secretomes compared with nonneoplastic pancreatic ductal cells.33 In invitro cultured RCC cell lines, PFN1 was differentially regulated in the supernatant. Further studies revealed that PFN1 was upregulated in RCC tissues.34 Apart from its dysregulation in serum and urine, PFN1 was found to be downregulated in the circulating leukocytes of patients with breast cancer compared with healthy controls, which provides a new paradigm for highly sensitive and less invasive approaches for the diagnosis of breast cancer.35 Studies have already revealed that PFN1 can be secreted via exosomes or other secretory pathways.36-38

Extracellular PFN1 in the tumor microenvironment can be taken up by recipient cells and execute its function in recipient cells, which in turn may influence the biological behavior of cells in the microenvironment, ultimately affecting tumorigenesis and progression of cancers. As mentioned above, PFN1 is expressed differentially in the serum and urine of patients with cancer, which enables its application as a biomarker for diagnosis and prognosis in liquid biopsy (Table 1).

Cell motility involves membrane protrusion, cell matrix adhesion, cell body translocation, and rear detachment. Many of these processes require the actin cytoskeleton and its regulators. By facilitating the exchange of ATP for ADP on G-actin, PFN1 plays a major role in actin polymerization, thus influencing motility in numerous cells.39 PFN1 also participates in cell motility by regulating actin polymerization and interactions with other regulators of actin cytoskeletons, such as ARP3, VASP, and proteins of cell signaling pathways. Cell-cell adhesion and cell-matrix adhesion are critical contributors to maintaining tissue architecture. Dysregulation of cell-cell adhesion is an important sign in tumor initiation and progression of malignancy. PFN1 can modulate cell adhesion and epithelial-to-mesenchymal transition (EMT) in cancer cells. However, the mechanisms by which PFN1 regulates cell adhesion are still not very clear. Undoubtedly, learning more about the roles of PFN1 in cell adhesion and motility will help us better understand its roles in modulating tumor invasion and migration.

Since PFN1 plays a critical role in actin polymerization, it is an indispensable regulator of cell motility. PFN1 participates in the invasion and metastasis of multiple cancers. However, the roles of PFN1 in regulating cell motility are context specific.27 Exogenous PFN1 with intact actin-binding abilities can ameliorate the adherence and spreading capabilities of cancer cells and exert tumor-suppressive effects in breast cancer.40 Consistent with the results of the study by Wittenmayer et al, Zou et al found that PFN1 overexpression could revert MDA MB-231 cells to an epithelioid phenotype, with restored adherence junctions.41 In addition, PFN1 overexpression could promote AMPK activation and p27 phosphorylation, which in turn induces epithelial morphological reversion of mesenchymal breast cancer through restoration of adherens junctions.42 These studies highlighted the involvement of PFN1 in epithelial adhesion and differentiation, which helped us better understand its roles in cancer cell motility.

Invadopodia are actin-driven membrane protrusions that can deliver matrix metalloproteinases to degrade the matrix and support invasion and dissemination of tumor cells. Any dysregulation of the actin cytoskeleton can impair the formation and maturation of invadopodia.43-46 PFN1 can regulate PI(3,4)P2, which in turn negatively regulates lamellipodin at the leading edge of breast cancer cells and thus inhibits those cells motility.47 The depletion of PFN1 leads to an increase in the level of PI(3,4)P2 in invadopodia and its interacting adaptor Tks5. The interaction of PI(3,4)P2-Tks5 has been shown to promote the anchorage, maturation, and turnover of invadopodia, which in turn enhances the invasiveness and motility of breast cancer.48 Breast cancer is an invasive adenocarcinoma, and numerous studies have found that PFN1 is downregulated in breast cancer tissues.49-54 Overexpression of PFN1 reduces the invasion and migration of breast cancer cells, while loss of PFN1 significantly enhances breast cancer cell motility and invasion. Mechanisms involved in PFN1s negative roles in breast cancer metastasis include Enabled (Ena)/vasodilator stimulated phosphoprotein (VASP)-dependent lamellipodial protrusion,51 miRNA-182 regulation,52 and regulation of PFN1 degradation.53 Mouneimne et al found that PFN1 knockdown (KD) could increase F-actin bundles and enhance stress fiber formation. In that study, the numbers of protrusions in PFN1-KD cells were markedly decreased, and PFN1-KD could inhibit the motility of breast cancer.55 Moreover, Liu et al indicated that the interaction of LMO2-PFN1 and LMO2-ARP3 could promote the formation of lamellipodia/filopodia in basal-type breast cancer cells.56 Ena/VASP is a critical regulator of the actin cytoskeleton at the leading edge of cells, which controls membrane protrusions and cell motility. Cell-substrate adhesion and downregulation of Protein Kinase A (PKA) promote interactions of PFN1 with VASP, which is another mechanism by which PFN1 regulates cell motility.57-58 Knockdown of PFN-1 has been shown to abrogate the inhibitory effect of tyrphostin A9, suggesting that modulating PFN1 expression could have therapeutic potential in the treatment of metastatic breast cancer.59

As in breast cancer, PFN1 was found to be a suppressor of migration in HCC.22,23,60 All-trans retinoic acid60 and guttiferone K22 could inhibit hepatocellular cell migration and proliferation by upregulating the expression of PFN1. In prostate cancer, cathepsin X can inactivate PFN1, thus promoting adhesion, invasion, and migration of cancer cells.61 In CRC, elevated expression of PFN1 obviously inhibited invasion and migration. PFN1 was suppressed by the HLA-F-AS1/miRNA-330-3p/PFN1 or HCP5/miRNA-299-3p/PFN1/AKT axis.62-63

Interestingly, Ding et al showed that in the early stages of metastasis, breast cancer cells exhibit a hyperinvasive phenotype characterized by upregulation of MMP-9 and by faster invasion when PFN1 expression is downregulated. However, in the late stages of metastasis, loss of PFN1 markedly inhibits the growth of metastatic colonies of breast cancer cells.54 Rizwani et al reported that PFN1 expression was elevated in breast cancer tissues and that overexpression of PFN1 could inhibit the migration of breast cancer cells. The phosphorylation of S137 mutants abrogated PFN1s promotion of migration. These studies provided a different vision of PFN1s role in breast cancer metastasis.64

In gastric cancer, silencing PFN1 inhibited the invasion and migration of cells, and the PFN1 expression level in cancer tissue was positively correlated with tumor infiltration and lymph node metastasis.16 However, different conclusions were drawn from the study of Ma et al. The authors found that PFN1 expression was inversely correlated with lymph node metastasis.65 In the lung cancer cell line A549, downregulation of PFN1 inhibited migration.17 In addition, in vitro studies support the importance of PFN1 in the proliferation and migration of RCC cells, and treatment with a novel computationally designed PFN1-actin interaction inhibitor reduced the proliferation and migration of RCC cells in vitro and RCC tumor growth in vivo.13 Additional studies have demonstrated that downregulation of PFN1 can also suppress the migration of laryngeal cancer18 and bladder cancer.66

Although more studies on PFN1 have been completed recently, its roles in cancer metastasis are still unclear. The concentrations of actin and PFN1 are time- and space-specific, and so is the regulation of the actin cytoskeleton (Table 2). Additional thorough studies are needed to comprehend the mechanisms and laws regulating the actin cytoskeleton. More importantly, in addition to actin dependence, PFN1 affects cell migration in an actin-independent manner by interacting with proteins with PIP2 or PLP domains. Furthermore, lncRNAs and microRNAs also modulate the functions of PFN1. All of these proteins and RNAs interact with PFN1 and indirectly influence the functions of cancer cells, which makes understanding the roles of PFN1 in cancer metastasis and other functions more complicated (Table 3).

In yeast, the gene encoding PFN1 is essential for cytokinesis.67 Early studies revealed that PFN1/ embryos died as early as the 2-cell stage, while PFN1/+ embryos displayed reduced survival during embryogenesis compared with wild-type embryos; this indicates that PFN1 is essential for cell division and survival during embryogenesis.68 PFN1 silencing in endothelial cells inhibits proliferation.69 In addition, homozygous deletion of PFN1 in chondrocytes failed to complete abscission at late-stage cytokinesis.70 The results of all these studies imply that PFN1 plays a role in cell proliferation. In breast cancer, PFN1 overexpression (PFN1-OE) has been shown to inhibit cell growth and exert an inhibitory effect on tumorigenesis,25,40,52,71-75 and PFN1-OE suppresses the activation of AKT, which in turn inhibits the growth of tumor cells.71 PFN1-OE cells arrested at the G1 phase, which was partly attributed to the upregulation of P27kip1.72 miRNA-182 could downregulate PFN1 expression and promote triple-negative breast cancer cell proliferation.52 However, Yap et al put forward opposite views. The authors research results revealed that silencing PFN1 resulted in a multinucleation phenotype of breast cancer cells, thus inhibiting proliferation.76 Recent studies from Chakraborty et al also reported that PFN1 knockdown could upregulate SMAD3 and inhibit the proliferation of breast cancer.77 Results of single-cell studies on the extracellular matrix revealed that stiff extracellular matrix led to upregulation of PFN1, possibly promoting the proliferation of breast cancer.78 Apart from breast cancer, PFN1 was also found to suppress proliferation in pancreatic adenocarcinoma,20 endometrial cancer,79 and HCC.23,60 In gastric cancer, silencing PFN1 caused cell cycle arrest at G0/G1 phase, thus restraining cell proliferation.16 Knockdown of PFN1 could also inhibit the proliferation of laryngeal cancer.18 Our previous studies found that overexpression of PFN1 could promote the proliferation of multiple myeloma cells by accelerating the cell cycle from G1 to S phase.80 PFN1 is indispensable for cytokinesis. Nevertheless, PFN1 is involved in regulating cell proliferation not only by impacting cytokinesis but also by modulating cell cyclerelated proteins. Otherwise, PFN1 could also interact with cell signaling pathways and indirectly influence cell proliferation.

Tumor growth is not only about uncontrolled proliferation but also resistance to apoptosis.81 Actin dynamics have notable impacts on multiple stages of apoptosis.82 PFN1, as a critical actin-binding protein, is an indispensable regulator of actin dynamics, through which PFN1 participates in regulating apoptosis. PFN1 overexpression could upregulate the most common tumor-associated hotspot mutation of p53p53R273Hthus sensitizing cancer cells to apoptosis via the intrinsic apoptotic pathway.83 PFN1 has been shown to facilitate apoptosis of breast cancer cells, thus exerting a suppressive effect on tumorigenesis.73,75,83,84 By inducing apoptosis and reducing autophagy, PFN1 has also been shown to sensitize pancreatic cancer cells to irradiation. Additionally, overexpression of PFN1 can significantly elevate apoptotic markers such as cleaved caspase-3 and cleaved PARP after irradiation, suggesting that PFN1 can modulate radiosensitivity partly by regulating apoptosis.85

Given that PFN1 is involved in cell proliferation and apoptosis, it is not difficult to understand its roles in the drug resistance of tumor cells. PFN1 was found to be downregulated in butyrate-treated CRC cells,86 and proteomics studies revealed that PFN1 was differentially expressed in erinacine Atreated CRC cells,87 which suggested the roles of PFN1 in drug-mediated cell death and inhibition of proliferation. In addition, proteomics showed that PFN1 was differentially expressed in mitotane-treated adrenocortical carcinoma,88 and PFN1 was found to be increased in tocotrienol-treated MDA-MB-231 cells,89 indicating its roles in predicting the response to anticancer therapies. Compared with temozolomide (TMZ)-treated glioblastoma cells, PFN1 was downregulated in OKN-007 combined with TMZ-treated glioblastoma cells. Further study results revealed that PFN1 is involved in TMZ resistance.90 Results of our previous studies showed that PFN1 could interact with the Beclin 1 complex and participate in bortezomib resistance in multiple myeloma.80 Since PFN1 is involved in multiple cell processes, including proliferation, apoptosis, and proteomics, it was recognized as a biomarker for therapy sensitivity, and it is worth further exploring its roles in drug resistance. In addition, PFN1 was found to participate in angiogenesis,91-92 initiation of tumors,93 and autophagy.80 Loss of PFN1 in A549 cell lines resulted in fewer early apoptotic cells after treatment with piperlongumine, and PFN1 sensitized A549 cells to anticancer agents.17 PFN1 serves as a bridge for actin-cytoskeleton and cell signaling pathways and is involved in multiple biological and physiological processes. Dysregulation of PFN1 in cancer cells has a notable impact on sensitivity to chemotherapy or radiotherapy and may be a new target for the treatment of drug-resistant or radioresistant patients.

Studies have already confirmed that PFN1 is essential for cell survival in early embryos, as PFN1-KN could induce Drosophila embryos to die at the 2-cell stage.94 For further investigation of PFN1s roles in tissue-specific stem cells, Zheng et al established PFN1flox/flox mice that inducibly delete PFN1 in HSCs. Results showed that PFN1 was essential for the retention and metabolism of mouse hematopoietic stem cells in bone marrow partially through the axis of PFN1/G13/EGR1.95 These study results implied important roles of PFN1 in stem cell function, which were still unclear and deserved further research. Later study results have found that both overexpression and depletion of PFN1 could reduce the stem-like phenotype of MDA-MB-231 (MDA-231) triple-negative breast cancer cells, suggesting that a balanced expression of PFN1 was required for maintenance of optimal stemness and tumor-initiating ability of breast cancer cells.93 Considering that tumor heterogeneity is still an ongoing challenge for cancer treatment and that cancer stem cells (CSC) are considered to be a determining factor of tumor heterogeneity,96 intensive studies on PFN1s roles in CSC may provide us new insight into tumor initiation.

As mentioned above, PFN1 has been shown to be a critical participator of actin dynamics and to play important roles in cell migration. For cytotoxic T lymphocytes (CTLs), migration abilities are essential for patrolling tissues and locating targeted cells.97-98 Schoppmeyer et al thus studied PFN1s roles in CTL functions. The authors found that PFN1 negatively regulated CTL-mediated elimination of target cells and that PFN1 downregulation promoted CTL invasion into a 3D matrix in vitro. In patients with pancreatic cancer, PFN1 expression was substantially decreased in peripheral CD8+ T cells.99 However, considering the complexity of immune responses in vivo, the exact roles of PFN1 in tumor immunity remain unclear and need to be further explored.

Based on previous studies, we found that PFN1participates in multiple biological processes of tumor development and progression. Meanwhile, it is noteworthy that PFN1 plays opposite roles in different tumors and at different periods of tumor, potentially leading to the conclusion that PFN1s function in tumor has spatial and temporal specificity. Future studies on PFN1 should take this into account. PFN1 was shown to be of great significance for diagnosis and prognosis prediction and for monitoring the therapeutic effect of anticancer drugs, and PFN1s roles in tumor stemness and immunity may provide a new avenue for cancer therapy. Although much research has been done on PFN1 and cancer, puzzles still need to be solved. With deepening research, the function of PFN1 in cancer would be further clarified and its clinical value would be more prominent.

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Conflicts of Interest: Authors declare no conflicts of interest for this article.

Acknowledgment: The authors are thankful for financial support from the Doctoral Fund Project of Hunan Provincial Peoples Hospital (program number BSJJ201812).

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26. Peng Z-M, Yu W, Xie Y, et al. A four actin-binding protein signature model for poor prognosis of patients with esophageal squamous cell carcinoma. Int J Clin Exp Pathol. 2014;7(9):5950-5959.

27. Ding Z, Bae YH, Roy P. Molecular insights on context-specific role of profilin-1 in cell migration. Cell Adh Migr. 2012;6(5):442-449. doi:10.4161/cam.21832

28. Vaidyanathan R, Soon RH, Zhang P, Jiang K, Lim CT. Cancer diagnosis: from tumor to liquid biopsy and beyond. Lab Chip. 2019;19(1):11. doi:10.1039/c8lc00684a

29. Zhang P-J, Wei R, Wen X-Y, et al. Genes expression profiling of peripheral blood cells of patients with hepatocellular carcinoma. Cell Biol Int. 2012;36(9):803-809. doi:10.1042/CBI20100920

30. Xie H, Xue Y-Q, Liu P, et al. Multi-parameter gene expression profiling of peripheral blood for early detection of hepatocellular carcinoma. World J Gastroenterol. 2018;24(3):371-378. doi:10.3748/wjg.v24.i3.371

31. Tan Y, Ma S-Y, Wang F-Q, et al. Proteomic-based analysis for identification of potential serum biomarkers in gallbladder cancer. Oncol Rep. 2011;26(4):853-859. doi:10.3892/or.2011.1353

32. Zoidakis J, Makridakis M, Zerefos PG, et al. Profilin 1 is a potential biomarker for bladder cancer aggressiveness. Mol Cell Proteomics. 2012;11(4):M111.009449. doi:10.1074/mcp.M111.009449

33. Grnborg M, Zakarias Kristiansen T, Iwahori A, et al. Biomarker discovery from pancreatic cancer secretome using a differential proteomic approach. Mol Cell Proteomics. 2006;5(1):157-171. doi:10.1074/mcp.M500178-MCP200

34. Minamida S, Iwamura M, Kodera Y, et al. Profilin 1 overexpression in renal cell carcinoma. Int J Urol. 2011;18(1):63-71. doi:10.1111/j.1442-2042.2010.02670.x

35. Braun M, Fountoulakis M, Papadopoulou A, et al. Down-regulation of microfilamental network-associated proteins in leukocytes of breast cancer patients: potential application to predictive diagnosis. Cancer Genomics Proteomics. 2009;6(1):31-40.

36. Ji H, Greening DW, Kapp EA, Moritz RL, impson RJ. Secretome-based proteomics reveals sulindac-modulated proteins released from colon cancer cells. Proteomics Clin Appl. 2009;3(4):433-451.doi:10.1002/prca.200800077

37. Makridakis M, Vlahou A. Secretome proteomics for discovery of cancer biomarkers. J Proteomics. 2010;73(12):2291-2305. doi:10.1016/j.jprot.2010.07.001

38. Pavlou MP, Diamandis EP. The cancer cell secretome: a good source for discovering biomarkers? J Proteomics. 2010;73(10):1896-1906. doi:10.1016/j.jprot.2010.04.003

39. Small JV, Stradal T, Vignal E, Rottner K. The lamellipodium: where motility begins. Trends Cell Biol.2002;12(3):112-120. doi:10.1016/s0962-8924(01)02237-1

40. Wittenmayer N, Jandrig B, Rothkegel M, et al. Tumor suppressor activity of profilin requires a functional actin binding site. Mol Biol Cell. 2004;15(4):1600-1608. doi:10.1091/mbc.e03-12-0873

41. Zou L, Hazan R, Roy P. Profilin-1 overexpression restores adherens junctions in MDA-MB-231 breast cancer cells in R-cadherin-dependent manner. Cell Motil Cytoskeleton. 2009;66(12):1048-1056. doi:10.1002/cm.20407

42. Jiang C, Veon W, Li H, Hallows KR, Roy P. Epithelial morphological reversion drives Profilin-1-induced elevation of p27(kip1) in mesenchymal triple-negative human breast cancer cells through AMP-activated protein kinase activation. Cell Cycle. 2015;14(18):2914-2923. doi:10.1080/15384101.2015.1069929

43. Beaty BT, Wang Y, Bravo-Cordero JJ, et al. Talin regulates moesinNHE-1 recruitment to invadopodia and promotes mammary tumor metastasis. J Cell Biol. 2014;205(5):737-751. doi:10.1083/jcb.201312046

44. Beaty BT, Sharma VP, Bravo-Cordero JJ, et al. 1 integrin regulates Arg to promote invadopodial maturation and matrix degradation. Mol Biol Cell. 2013;24(11):1661-1675,S1-S11. doi:10.1091/mbc.E12-12-0908

45. Mader CC, Oser M, Magalhaes MAO, et al. An EGFRSrcArgcortactin pathway mediates functional maturation of invadopodia and breast cancer cell invasion. Cancer Res. 2011;71(5):1730-1741. doi:10.1158/0008-5472.CAN-10-1432

46. Oser M, Yamaguchi H, Mader CC, et al. Cortactin regulates cofilin and N-WASp activities to control the stages of invadopodium assembly and maturation. J Cell Biol. 2009;186(4):571-587. doi:10.1083/jcb.200812176

47. Baea YH, Dinga ZJ, Das T, Wells A, Gertler F, Roy P. Profilin1 regulates PI(3,4)P2 and lamellipodin accumulation at the leading edge thus influencing motility of MDA-MB-231 cells. Proc Natl Acad Sci U S A.2010;107(50):21547-21552. doi:10.1073/pnas.1002309107

48. Valenzuela-Iglesias A, Sharma VP, Beaty BT, et al. Profilin1 regulates invadopodium maturation in human breast cancer cells. Eur J Cell Biol. 2015;94(2):78-89. doi:10.1016/j.ejcb.2014.12.002

49. Roy P, Jacobson K. Overexpression of profilin reduces the migration of invasive breast cancer cells. Cell Motil Cytoskeleton. 2004;57(2):84-95. doi:10.1002/cm.10160

50. Zou L, Jaramillo M, Whaley D, et al. Profilin-1 is a negative regulator of mammary carcinoma aggressiveness. Br J Cancer. 2007;97(10):1361-1371. doi:10.1038/sj.bjc.6604038

51. Bae YH, Ding Z, Zou L, Wells A, Gertler F, Roy P. Loss of profilin-1 expression enhances breast cancer cell motility by Ena/VASP proteins. J Cell Physiol. 2009;219(2):354-364. doi:10.1002/jcp.21677

52. Liu H, Wang Y, Li X, et al. Expression and regulatory function of miRNA-182 in triple-negative breast cancer cells through its targeting of profilin 1. Tumour Biol. 2013;34(3):1713-1722. doi:10.1007/s13277-013-0708-0

53. Choi YN, Lee SK, Seo TW, Lee JS, Yoo SJ. C-terminus of Hsc70-interacting protein regulates profilin1 and breast cancer cell migration. Biochem Biophys Res Commun. 2014;446(4):1060-1066.doi:10.1016/j.bbrc.2014.03.061

54. Ding Z, Joy M, Bhargava R, et al. Profilin-1 downregulation has contrasting effects on early vs late steps of breast cancer metastasis. Oncogene. 2014;33(16):2065-2074. doi:10.1038/onc.2013.166

55. Mouneimne G, Hansen SD, Selfors LM, et al. Differential remodeling of actin cytoskeleton architecture by profilin isoforms leads to distinct effects on cell migration and invasion. Cancer Cell. 2012;22(5):615-630.doi:10.1016/j.ccr.2012.09.027

56. Liu Y, Wu C, Zhu T, Sun W. LMO2 enhances lamellipodia/filopodia formation in basal-type breast cancer cells by mediating ARP3-profilin1 interaction. Med Sci Monit. 2017;23:695-703. doi:10.12659/msm.903261

57. Gau D, Veon W, Shroff SG, Roy P. The VASPprofilin1 (Pfn1) interaction is critical for efficient cell migration and is regulated by cellsubstrate adhesion in a PKA-dependent manner. J Biol Chem.2019;294(17):6972-6985. doi:10.1074/jbc.RA118.005255

58. Gau D, Ding ZJ, Baty C, Roy P. Fluorescence resonance energy transfer (FRET)-based detection of profilinVASP interaction. Cell Mol Bioeng. 2011;4(1):1-8. doi:10.1007/s12195-010-0133-z

59. Joy ME, Vollmer LL, Hulkower K, et al. A high-content, multiplexed screen in human breast cancer cells identifies profilin-1 inducers with anti-migratory activities. PLoS One. 2014;9(2):e88350.doi:10.1371/journal.pone.0088350

60. Wu N, Zhang W, Yang Y, et al. Profilin 1 obtained by proteomic analysis in all-trans retinoic acidtreated hepatocarcinoma cell lines is involved in inhibition of cell proliferation and migration. Proteomics.2006;6(22):6095-6106. doi:10.1002/pmic.200500321

61. Pear Fonovi U, Jevnikar Z, Rojnik M, et al. Profilin 1 as a target for cathepsin X activity in tumor cells. PLoS One. 2013;8(1):e53918. doi:10.1371/journal.pone.0053918

62. Huang Y, Sun H, Ma X, et al. HLA-F-AS1/miR-330-3p/PFN1 axis promotes colorectal cancer progression. Life Sci. 2019;254:117180. doi:10.1016/j.lfs.2019.117180

63. Bai N, Ma Y, Zhao J, Li B. Knockdown of lncRNA HCP5 suppresses the progression of colorectal cancer by miR-299-3p/PFN1/AKT axis. Cancer Manag Res. 2020;12:4747-4758. doi:10.2147/CMAR.S255866

64. Rizwani W, Fasim A, Sharma D, Reddy DJ, Bin Omar NAM, Singh SS. S137 phosphorylation of profilin 1 is an important signaling event in breast cancer progression. PLoS One. 2014;9(8):e103868.doi:10.1371/journal.pone.0103868

65. Ma Y, Li Y-F, Wang T, Pang R, Xue Y-W, Zhao S-P. Identification of proteins associated with lymph node metastasis of gastric cancer. J Cancer Res Clin Oncol. 2014;140(10):1739-1749. doi:10.1007/s00432-014-1679-2

66. Frantzi M, Klimou Z, Makridakis M, et al. Silencing of Profilin-1 suppresses cell adhesion and tumor growth via predicted alterations in integrin and Ca2+ signaling in T24M-based bladder cancer models. Oncotarget.2016;7(43):70750-70758. doi:10.18632/oncotarget.12218

67. Balasubramanian MK, Hirani BR, Burke JD, Gould KL. The Schizosaccharomyces pombe cdc3+ gene encodes a profilin essential for cytokinesis. J Cell Biol. 1994;125(6):1289-1301. doi:10.1083/jcb.125.6.1289

68. Witke W, Sutherland JD, Sharpe A, Arai M, Kwiatkowski DJ. Profilin I is essential for cell survival and cell division in early mouse development. Proc Natl Acad Sci U S A. 2001;98(7):3832-3836.doi:10.1073/pnas.051515498

69. Ding Z, Lambrechts A, Parepally M, Roy P. Silencing profilin-1 inhibits endothelial cell proliferation, migration and cord morphogenesis. J Cell Sci. 2006;119(Pt 19):4127-4137. doi:10.1242/jcs.03178

70. Bttcher RT, Wiesner S, Braun A, et al. Profilin 1 is required for abscission during late cytokinesis of chondrocytes. EMBO J. 2009;28(8):1157-1169. doi:10.1038/emboj.2009.58

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Profilin 1 Protein and Its Implications for Cancers - Cancer Network

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Homing Technology Delivers Therapy to Cancerous Bone – The Scientist

Wednesday, July 21st, 2021

Han Xiao, a protein chemist at Rice University, and Shawn Zhang, a cancer biologist at Baylor College of Medicine, received an email with a big question: When will your drug go to clinical trials? The question came from a patient eager to try out a drug for breast cancer that had metastasized to the bone. When cancer spreads beyond the tissue where it developed, especially to bone, patients outcomes become less optimistic. More than hope hung on the patients email.

Xiao and Zhang developed an innovative therapeutic technology that sends medicine right to cancerous bone tissue by combining two drugs the U.S. Food and Drug Administration (FDA) has already approved. By delivering therapy to tissues such as bone that are notoriously difficult for medicines to access, the new technology, dubbed BonTarg, could be a game changer for patients with metastasized breast cancers and other cancers and bone diseases.

Its quite exciting, particularly because bone metastasis is such a huge problem in breast cancer, said Alana Welm, a breast cancer biologist at the University of Utahs Huntsman Cancer Institute, who was not involved with the new research.

A new technology targets an FDA-approved antibody therapy to cancer in the bone.

Baylor College of Medicine and Rice University

Metastasis to Metastasis

Bone is often the first site of metastasis. Once cancer spreads to bone it will almost inevitably spread to other organs such as the lung, liver, and brain. Metastasis makes cancer difficult or impossible to cure. Metastatic breast cancer, for example, is incurable.

Most metastases originate from other metastases, not the primary tissue. Zhangs group recently showed that bone can act as a launchpad for further metastases.1 They seeded invasive and less aggressive human breast and prostate cancer cell lines in the hind limbs of mice. Within four to eight weeks, they saw metastases in the rodents lungs, livers, kidneys, brains, and additional bones.

Follow-up experiments revealed that once cancer cells are growing in the bone microenvironment, they become more plastic and take on stem cell-like properties. These features allow cancer cells to better adapt to new environments. They leave the bone and spread to other organs, which further advances the disease. Zhang and his team also found that primary metastases in bone can remain small, indicating that further metastases could spread to other organs before the first ones are detectable.

Anything we can do to keep the disease either not going to bones, or to really treat it well once its in the bones, could actually have outcomes for overall survival, Welm said. Treating bone metastases could also alleviate bone pain, spinal compression, and fractures that can make patients lives quite awful, Welm said. To intervene when cancer has only spread to bone represents a huge therapeutic opportunity.

Bone Barriers

To get ahead of the metastatic launchpad in the bone, Zhang and Xiao planned to specifically target breast cancer-derived bone metastases. They started with a proven drug called trastuzumab. Commonly referred to by its brand name Herceptin, trastuzumab is an antibody therapy that targets human epidermal growth factor 2 (HER2), a protein that cells make too much of in about a quarter of breast cancers. The antibody prevents HER2-expressing cancer cells from initiating a cascade of events that leads to proliferation, and may also induce cytotoxicity by attracting the immune systems natural killer cells.

Trastuzumab is a proven therapy that, when given in combination with chemotherapy, has extended overall survival in metastatic breast cancer patients to nearly five years.2 But the drug is not a cure. For many patients, their cancer continues to progress while they are under treatment, and for most, remission rarely lasts.

Bone metastases do not kill patients as often as metastases to internal organs such as the lung or liver, so they do not receive a lot of attention in research. But according to Zhang, Targeting bone metastasis not just kills cancer cells in the bone, it has the potential to prevent cancer cells from going other places in the body.

One difficulty lies in getting drugs to the bone. Despite making billions of blood cells every day, bone tissue holds few blood vessels. Where it does have vasculature, a bone marrow-blood barrier makes it hard for therapies delivered through the circulatory system to arrive at their destination. In addition, antibodies are big molecules. The mineralized matrix structure of bone prevents big molecules from gaining access to the tissue, limiting how effective a drug can be.

In the past, patients were given high doses of antibody therapies to overcome hurdles of getting them to bone. But then the drug ended up in tissues besides the bone, leading to unwanted and sometimes systemic side effects.

People think of antibody drugs as magic bullets that only target cancer cells while missing healthy cells, Xiao said. But research in the clinic has shown that not to be true.

That discrepancy drove Xiao to increase the specificity of the bullet so that it goes to the cancer, but not the healthy tissues. In the new research, he equipped the antibody therapy with a homing device.

Targeting Tumors

Alendronate is a bisphosphonate drug with high affinity for the highly mineralized bone matrix. It has been used to selectively deliver imaging probes, nuclear medicines, and nanoparticles to the bone, and the FDA has approved it to treat bone maladies such as osteoporosis. Xiao joined alendronate to the monoclonal antibody trastuzumab to target the therapy to bone.

Next, Zhang and his team injected the modified drug into the intra-iliac artery, a branch of a major artery in the lower abdomen, of mice with tumors in the hind limb bone derived from a breast cancer cell line.

Within 24 hours, the drug accumulated in the bone and remained there for a week. In contrast, injection with unmodified antibody did not remain in bone past the first day of treatment. The bone-targeted drug also accumulated much more substantially in cancerous bone compared with healthy bone, thanks in part to alendronates affinity for the highly acidic environment of bone metastatic sites.

The conjugated antibody therapy also prevented the development of secondary metastases in most other organs. Zhang and his team let the bone tumors grow for about eight to 12 weeks. Mice treated with trastuzumab harbored metastases in the heart, liver, spleen, lungs, kidney, and brain. Mice treated with alendronate conjugated trastuzumab, however, were mostly devoid of secondary tumors, Zhang and Xiao reported in Science Advances.3

Scans of rodents treated with alendronate-conjugated trastuzumab, individual components, or a salt solution.

Baylor College of Medicine and Rice University

Translatable Technology

The work that theyve done here is quite translatable [to the clinic], Welm said. She added that a trial will likely be straightforward as long as Xiao and Zhang can create a clinical grade version of the compound. The next step is to see whether the therapy works in models with cells derived from patients rather than established cell lines.

She is curious whether the technology could be used with other breast cancer therapies. The FDA recently approved another antibody therapy called Sacituzumab govitecan to treat triple-negative breast cancer. Theoretically, the chemistry Xiao and his team developed to attach alendronate to trastuzumab should work with Sacituzumab govitecan.

For these antibody drugs, even though [trastuzumab] is an older drug, people can modify the antibody, like what we are doingand get more potential from this drug, he said.

The technology allows scientists like Xiao and Zhang to come one step closer to the magic bullet that will take out cancer cells while leaving healthy cells alone. This conjugated antibody is one of the most perfect, best solutions in my mind, to help us gather the bullets to where they need to be, Zhang said.

The team hopes to be ready in time to help the patient who emailed them. This drug can be the next wave of drugs for this patient, Xiao said. We can get a better outcome for her. We want to push this drug to clinical trials as soon as possible, and hopefully this patient can benefit from it.

References

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Developmental Interest in Allogeneic PlacentaDerived Cell Therapies Expands – OncLive

Wednesday, July 21st, 2021

After closing a merger with GX Acquisition Corp., Celularity Inc., a clinical-stage cellular medicine company, is taking the next step in its evolution to enable further development of novel, off-the-shelf allogeneic placentaderived cellular therapies.1

Celularity aims to transform the way we approach the treatment of cancer and other diseases by harnessing the versatility, unique immune biology, and innate stemness of placental-derived cells, Robert J. Hariri, MD, PhD, found, chairperson, and chief executive officer of Celularity, stated in a press release. We are immensely proud of our clinical development results so far as well as the state-of-the-art manufacturing capabilities we built to support rapid scaling and a competitive cost structure for our placental-derived cell therapeutics. We believe off-the-shelf, allogeneic cell therapies will drive a paradigm shift in how clinicians approach the treatment of cancer and other serious diseases.

CYNK-001, the companys lead product candidate, is the only cryopreserved, allogeneic, off-the-shelf natural killer (NK) cell therapy to be developed from placental hematopoietic stem cells. The agent expresses perforin and granzyme B, has showcased cytotoxic activity against hematological tumors and solid tumor cell lines, and can secrete immunomodulatory cytokines in the presence of tumor cells.

The novel therapy is under investigation as a potential option in multiple myeloma, acute myeloid leukemia (AML), and glioblastoma multiforme; it is also being evaluated in infectious diseases like COVID-19 (NCT04365101).

An ongoing, open-label, multi-dose, phase 1 trial (NCT04310592) is examining the maximum-tolerated dose (MTD) or maximum planned dose of CYNK-001 in an estimated 22 patients with acute myeloid leukemia (AML).2 To participate, patients need to have primary or secondary AML and be in first or second morphological clinical response (CR), morphological CR with incomplete hematologic recovery, or a morphologic leukemia-free state per European LeukemiaNet recommendations for AML Response Criteria.

Patients also need to have MRD positivity, be aged between 18 and 80 years old, have an ECOG performance status of 0 to 2, and be able to be off immunosuppressive therapy for at least 3 days before infusion with the therapy. Patients who previously had central nervous system involvement are allowed to enroll if they had been treated and their cerebral spinal fluid is clear for at least 2 weeks before undergoing lymphodepletion.

Exclusion criteria include significant medical conditions, laboratory abnormalities, bi-phenotypic acute leukemia, acute promyelocytic leukemia, unacceptable organ function, autoimmune disease, uncontrolled graft-vs-host disease (GVHD), and GVHD that requires corticosteroids.

Participants are first given cyclophosphamide plus fludarabine. Then, they are administered CYNK-001 at 3 varying dose levels1.8 billion, 3.6 billion, and 5.4 billion CYNK-001 cellson days 0, 7, and 14. The primary objectives of the research include dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and frequency and severity of adverse effects. Important secondary objectives include the number of patients who convert from MRD-positive to -negative status; time to, and duration of, MRD response; progression-free survival; time to progression; duration of morphologic complete remission; and overall survival.

In June 2021, the study was expanded to include patients with relapsed/refractory AML following a case of conversion to MRD negativity, when the therapy was delivered at its highest dose level.3

The decision to expand the trial followed observations of a patient with NPM-1positive, FLT3-negative AML and good-risk cytogenetics who had been administered 5.4 billion CYNK-001 cells. The patient converted from MRD-positive to -negative status, without experiencing any DLTs.

For this patient, primary induction treatment with 7+3 chemotherapy had failed, and so they had gone on to receive second induction therapy followed by high-dose cytarabine consolidation. At this time point, the patient achieved a complete CR, but MRD was found to be persistent; it did not clear following 4 months of treatment with azacitidine. MRD positivity was confirmed on a marrow biopsy.

The patient went on to enter the phase 1 trial, where they received lymphodepletion, and then received 1.8 billion CYNK-001 cells on days 0, 7, and 14 in the outpatient setting, which totaled to 5.4 billion CYNK-001 cells. On day 28, the patient had converted from MRD positivity to negativity. CYNK-001 cells were present in both the peripheral blood and bone marrow.

Notably, no DLTs have been observed with the therapy at any of the dose levels examined thus far.

The company also shared plans to continue dose escalation with the therapy in the MRD indication up to 9.0 billion CYNK-001 cells. To strengthen the persistence of the treatment, the expansion arms of MRD and relapsed/refractory AML will include an augmented lymphodepletion protocol comprised of cyclophosphamide at 3600 mg and fludarabine at 120 mg over 4 days vs cyclophosphamide at 900 mg plus fludarabine at 75 mg over 3 days.

In April 2021, the FDA granted an orphan drug designation to CYNK-001 as a potential therapeutic option for patients with malignant gliomas.4 As such, the therapy is also under investigation in patients with glioblastoma multiforme as part of another phase 1 trial (NCT04489420).5

To be eligible for enrollment, patients need to have historically confirmed disease at first or second relapse, measurable disease, a Karnofsky performance status of 60 or higher, and acceptable organ function, among other criteria.

Patients who previously received radiation within 12 weeks of their screening MRI; those who were on growth factors with less than 4 weeks of a washout period; those treated with radiotherapy, chemotherapy, or other investigational drugs within 4 weeks; those who received prior cellular or gene therapy; and those with active autoimmune disease, were excluded.

Cohort 1A of the trial will enroll up to 6 patients with recurrent glioblastoma multiforme who will receive intravenous CYNK-001 at a dose of 1.2 x 109 cells on days 0, 7, and 14. From the initial infusion of therapy, patients will be followed for a 42-day DLT period. No other interventions are planned between the last day of treatment.

If DLTs are experienced, cohort 1C, the de-escalation cohort, will include up to 6 patients with recurrent glioblastoma multiforme who will receive the therapy at a dose of 600 x 106 cells on days 0, 7, and 14. These patients will also be followed for DLTs for 42 days post infusion. Cohort 1B, the surgical cohort, will also enroll up to 6 patients, who will be given CYNK-001 at a maximum safe dose of either 1.2 x 109 cells or 600 x 106 cells at days 0, 7, and 14. Patients in this cohort will undergo resection following the last dose of the therapy in the DLT period.

Treatment of cohorts 2A or 2C will only begin after the safety data from cohorts 1A or 1C are determined to be acceptable. Here, patients will first have the Ommaya catheter placement in accordance with institutional policy within 1 week before CYNK-001 infusion on day 0. Cohort 2A will enroll up to 6 patients with recurrent glioblastoma multiforme who will be given the therapy at a dose of 200 x 106 cells +/- 50 x 106 cells intratumorally on day 0, 7, and 14.

Cohort 2C will also include up to 6 patients with recurrent disease who will receive the product at a dose of 200 x 106 cells +/- 50 x 106 cells intratumorally on day 0 and day 7. Lastly, cohort 2B, the surgical intratumoral cohort, will include 6 patients with glioblastoma multiforme who will receive the cellular therapy at a maximum safe dose of either 200 x 106 cells +/- 50 x 106 cells on day 0 and 7.

The primary objectives of the trial are to examine the number of patients who report DLTs with the therapy and toxicities. Important secondary objectives are to evaluate the overall response rate, duration of response, progression-free survival, time to progression, and overall survival.

The safety and efficacy of the cell therapy is also being explored in newly diagnosed patients with multiple myeloma after autologous stem cell transplant, as part of another phase 1 trial (NCT04309084).6 The objective of the program is to achieve durable responses with the therapy in these patients with multiple myeloma who are eligible for transplant in the first-line setting.

Another novel agent in the pipeline is CYNK-101, which is manufactured from NK cells extracted from postpartum placentas. The cells are then genetically engineered to boost cell-killing activity when given with a monoclonal antibody.7 Preclinical data with the product in combination with an antibody showed that the regimen resulted in cell-killing activity when administered to lymphoma cells in vitro.

Additionally, CYNK-CAR products are being developed as allogeneic, off-the-shelf strategies by modifying genes of the human placental hematopoietic stem cellderived NK cells. Several CAR constructs that are designed to target hematologic and solid tumor indications are currently under investigation.

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Developmental Interest in Allogeneic PlacentaDerived Cell Therapies Expands - OncLive

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Triple negative breast cancer and non-small cell lung cancer: Clinical challenges and nano-formulation approaches – DocWire News

Wednesday, July 21st, 2021

This article was originally published here

J Control Release. 2021 Jul 14:S0168-3659(21)00357-6. doi: 10.1016/j.jconrel.2021.07.014. Online ahead of print.

ABSTRACT

Triple negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC) are amongst the most aggressive forms of solid tumors. TNBC is highlighted by absence of genetic components of progesterone receptor, HER2/neu and estrogen receptor in breast cancer. NSCLC is characterized by integration of malignant carcinoma into respiratory system. Both cancers are associated with poor median and overall survival rates with low progression free survival with high incidences of relapse. These cancers are characterized by tumor heterogeneity, genetic mutations, generation of cancer-stem cells, immune-resistance and chemoresistance. Further, these neoplasms have been reported for tumor cross-talk into second primary cancers for each other. Current chemotherapeutic regimens include usage of multiple agents in tandem to affect tumor cells through multiple mechanisms with various such combinations being clinically tested. However, lack of controlled delivery and effective temporospatial presence of chemotherapeutics has resulted in suboptimal therapeutic response. Consequently, passive targeted albumin bound paclitaxel and PEGylated liposomal doxorubicin have been clinically used and tested with newer drugs for improved therapeutic efficacy in these cancers. Active targeting of nanocarriers against surface overexpressed proteins in both neoplasms have been explored. However, use of single agent nanoparticulate formulations against both cancers have failed to elicit desired outcomes. This review aims to identify clinical unmet need in these cancers while establishing a correlation with tested nano-formulation approaches and issues with preclinical to clinical translation. Lipid and polymer-based drug-drug and drug-gene combinatorial nanocarriers delivering multiple chemotherapeutics simultaneously to desired site of action have been detailed. Finally, emerging opportunities such as pharmacological targets (immune check point and epigentic modulators) as well as gene-based modulation (siRNA/CRISPR/Cas9) and the nano-formulation challenges for effective treatment of both cancers have been explored.

PMID:34273417 | DOI:10.1016/j.jconrel.2021.07.014

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Triple negative breast cancer and non-small cell lung cancer: Clinical challenges and nano-formulation approaches - DocWire News

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The World’s First Lab-Grown Foie Gras Could Solve This Major Concern – Mashed

Wednesday, July 21st, 2021

Gourmey uses stem cells taken from a fertilized duck egg which are isolated and then fed on a diet of proteins, amino acids, and fats. "The cells multiply as if they are in the egg, then you adjust the nutrients to trigger the cell type that you want," company CEO and cofounder Nicolas Morin-Forest tellsSifted."So if you want liver cells, or muscle cells, you adjust the inputs and the cells react to that. We then harvest muscle cells, fat cells, or liver cells and craft our products."The company says its end product is so successful that an unnamed Michelin-star chef has not been able to tell the lab grown foie gras from its natural counterpart, and that he would cook with the synthesized meat product.

Morin-Forest says their company began with foie gras because it is complex, hard to find due to bans, and it carries premium pricing. But the company wants to do more with what they've created. "Foie gras is just the first application of our current know-how," says Morin-Forest. "With the same starting cells, we can create any type of poultry meat product."

Gourmey's product has been so convincing it's been able to pull together $10 million in additional funding. Fortune notes that with this money, this specialty lab-meat maker expects to begin selling its foie gras before the end of 2022 at the earliest, and by 2023 at the latest.

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The World's First Lab-Grown Foie Gras Could Solve This Major Concern - Mashed

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KEYTRUDA (pembrolizumab) Plus Chemotherapy Before Surgery and Continued as a Single Agent After Surgery Showed Statistically Significant Event-Free…

Wednesday, July 21st, 2021

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced positive event-free survival (EFS) data from the pivotal neoadjuvant/adjuvant Phase 3 study KEYNOTE-522. The trial investigated neoadjuvant KEYTRUDA, Mercks anti-PD-1 therapy, plus chemotherapy followed by adjuvant KEYTRUDA as monotherapy (the KEYTRUDA regimen) compared with neoadjuvant chemotherapy followed by adjuvant placebo (the chemotherapy-placebo regimen) in patients with high-risk early-stage triple-negative breast cancer (TNBC). This is the first time an anti-PD-1/L1 therapy has demonstrated a statistically significant EFS result as combined neoadjuvant and adjuvant therapy for these patients. These results are being presented today during a European Society for Medical Oncology (ESMO) Virtual Plenary.

After a median follow-up of 39 months, the KEYTRUDA regimen reduced the risk of EFS events by 37% (HR=0.63 [95% CI, 0.48-0.82]; p=0.00031) versus the chemotherapy-placebo regimen a statistically significant and clinically meaningful EFS result. EFS was defined as the time from randomization to the first occurrence of either disease progression that precluded definitive surgery, a local/distant recurrence, a second primary cancer, or death from any cause. As previously announced, KEYNOTE-522 met the dual primary endpoint of pathological complete response (pCR) at the first interim analysis. The trial is continuing to allow for additional follow-up of overall survival (OS), a key secondary endpoint. At this fourth interim analysis, although these data have not crossed the boundary for statistical significance, there was a 28% reduction in the risk of death with the KEYTRUDA regimen versus the chemotherapy-placebo regimen (HR=0.72 [95% CI, 0.51-1.02]; p=0.03214). The safety profile of the KEYTRUDA regimen was consistent with the known profiles of each regimen, and no new safety concerns were identified.

Given the high rates of recurrence within the first five years of diagnosis, patients with high-risk early-stage TNBC need new treatment options, said Dr. Peter Schmid, lead, Centre for Experimental Cancer Medicine, Barts Cancer Institute in London, England. KEYNOTE-522 was designed to study whether the combined neoadjuvant and adjuvant regimen with KEYTRUDA could help treat the cancer earlier. Now, with more than three years of follow-up, we see the potential of this approach. These event-free survival data are very encouraging for patients and show that this combination of KEYTRUDA plus chemotherapy as neoadjuvant therapy, followed by single-agent KEYTRUDA as adjuvant therapy, may offer women with high-risk early-stage TNBC a new treatment option for this aggressive disease.

These highly anticipated event-free survival results in this TNBC population build upon earlier findings from the KEYNOTE-522 trial and further support the potential use of KEYTRUDA in these patients, said Dr. Vicki Goodman, vice president, clinical research, Merck Research Laboratories. KEYNOTE-522 is the first large randomized Phase 3 study to report a statistically significant and clinically meaningful EFS result among patients with stage II and stage III TNBC. We have submitted these data to the FDA and are working closely with the agency on its review of our application.

KEYTRUDA is currently approved under accelerated approval in the U.S. in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (Combined Positive Score [CPS] 10) as determined by an FDA-approved test.

Merck is rapidly advancing a broad portfolio in womens cancers with an extensive clinical development program for KEYTRUDA and several other investigational and approved medicines across multiple gynecologic and breast cancers. The KEYTRUDA clinical development program for TNBC encompasses several internal studies and external collaborative trials, including the ongoing studies KEYNOTE-242 and KEYNOTE-355.

Study Design and Additional Data From KEYNOTE-522

KEYNOTE-522 is a Phase 3, randomized, double-blind trial (ClinicalTrials.gov, NCT03036488). The dual primary endpoints are pCR, defined as pathological stage ypT0/Tis ypN0 at the time of definitive surgery, and EFS, defined as the time from randomization to the first occurrence of either disease progression that precluded definitive surgery, a local/distant recurrence, a second primary cancer, or death from any cause in all patients randomized. Secondary endpoints include pCR rate using alternative definitions, OS in all patients randomized, pCR rate according to all definitions, EFS and OS in patients whose tumors express PD-L1 (CPS 1), safety and health-related quality of life assessments. The study enrolled 1,174 patients who were randomized 2:1 to receive either:

As previously announced, KEYNOTE-522 met the success criterion for the dual primary endpoint of pCR at the first interim analysis; pCR was observed in 64.8% of patients treated with KEYTRUDA plus chemotherapy (n=401), an increase of 13.6% (p=0.00055) from 51.2% in patients treated with placebo plus chemotherapy (n=201). At the fourth interim analysis, KEYNOTE-522 met the success criterion for the dual primary endpoint of EFS. The study is continuing to allow for additional follow-up of OS.

At three years, 84.5% of patients treated with the KEYTRUDA regimen were alive and did not experience an EFS event compared to 76.8% of patients treated with the chemotherapy-placebo regimen.

In pre-specified exploratory subgroup analyses of EFS, the EFS benefit seen with the KEYTRUDA regimen was independent of PD-L1 expression. In the PD-L1-positive subgroup (n=973), defined as CPS 1, treatment with the KEYTRUDA regimen reduced the risk of EFS events by 33% (HR=0.67 [95% CI, 0.49-0.92]) versus the chemotherapy-placebo regimen. In the PD-L1-negative subgroup (n=197), defined as CPS <1, treatment with the KEYTRUDA regimen reduced the risk of EFS events by 52% (HR=0.48 [95% CI, 0.28-0.85]) versus the chemotherapy-placebo regimen.

In a pre-specified but non-randomized exploratory analysis of EFS by pCR outcome, the reduction in EFS events with the KEYTRUDA regimen was observed independent of pCR outcome at definitive surgery.

Treatment-related adverse events (TRAEs) were examined in the neoadjuvant phase, the adjuvant phase and the combined phases. TRAEs in the neoadjuvant phase have been previously reported. At the time of this data cutoff, no patients were still receiving protocol treatment. For the combined neoadjuvant and adjuvant phases, TRAEs occurred in 98.9% of patients receiving the KEYTRUDA regimen (n=783) and 99.7% of patients receiving the chemotherapy-placebo regimen (n=389); Grade 3-5 TRAEs occurred in 77.1% versus 73.3%, respectively. TRAEs led to death in 0.5% of patients receiving the KEYTRUDA regimen (n=4) and 0.3% of patients receiving the chemotherapy-placebo regimen (n=1). No new safety concerns were identified. In the adjuvant phase, TRAEs occurred in 53.7% of patients receiving adjuvant KEYTRUDA (n=588) and 48.6% of patients receiving adjuvant placebo (n=331), including 6.3% and 2.7%, respectively, who had at least one Grade 3 event.

Immune-mediated adverse events (AEs) and infusion reactions of any grade in the combined neoadjuvant and adjuvant phases occurred in 43.6% of patients receiving the KEYTRUDA regimen and 21.9% of patients receiving the chemotherapy-placebo regimen. The most common of these events (occurring in 10% of patients) were infusion reactions (18.0%) and hypothyroidism (15.1%) in patients receiving the KEYTRUDA regimen and infusion reactions (11.6%) in patients receiving the chemotherapy-placebo regimen. Immune-mediated AEs led to death in 0.3% of patients receiving the KEYTRUDA regimen (n=2) and no patients receiving the chemotherapy-placebo regimen. In the adjuvant phase, immune-mediated AEs and infusion reactions occurred in 10.2% of patients receiving adjuvant KEYTRUDA and 6.0% of patients receiving adjuvant placebo, including 2.9% and 0.3%, respectively, who had at least one Grade 3 event.

About Triple-Negative Breast Cancer (TNBC)

Triple-negative breast cancer is an aggressive type of breast cancer that characteristically has a high recurrence rate within the first five years after diagnosis. While some breast cancers may test positive for estrogen receptors, progesterone receptors or overexpression of human epidermal growth factor receptor 2 (HER2), TNBC tests negative for all three. Approximately 10-15% of patients with breast cancer are diagnosed with TNBC. TNBC tends to be more common in people who are younger than 40 years of age, who are African American or who have a BRCA1 mutation.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,500 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is:

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or mUC who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma.

Tumor Mutational Burden-High Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDASevere and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen, at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other antiPD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after antiPD-1/PD-L1 treatment. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between antiPD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using antiPD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an antiPD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials.

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The latest business intelligence report analyzes the Human Mesenchymal Stem Cells (hMSC) market in terms of market reach and customer base in key geographic market regions. The Human Mesenchymal Stem Cells (hMSC) market can be geographically divided into North America, Asia Pacific, Europe, Latin America, the Middle East, and Africa. This section of the report provides an accurate assessment of the Human Mesenchymal Stem Cells (hMSC) market presence in the major regions. It defines the market share, market size, sales, distribution network and distribution channels for each regional segment.

Key Points of theGeographical Analysis:

** Data and information on consumption in each region** The estimated increase in consumption rate** Proposed growth in market share for each region** Geographic contribution to market income** Expected growth rates of the regional markets

Key Highlights of the Human Mesenchymal Stem Cells (hMSC)Market Report:

** Analysis of location factors** Raw material procurement strategy** Product mix matrix** Analysis to optimize the supply chain** Patent analysis** R&D analysis** Analysis of the carbon footprint** Price volatility before commodities** Benefit and cost analysis** Assessment and forecast of regional demand** Competitive analysis** Supplier management** Mergers and acquisitions** Technological advances

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[Full text] An Update on the Molecular Pathology of Metaplastic Breast Cancer | BCTT – Dove Medical Press

Wednesday, March 3rd, 2021

Introduction

Metaplastic breast cancer (MpBC) is a unique histologic subtype of breast cancer, defined by characteristic intra-tumoural heterogeneity. Although rare, MpBC accounts for significant morbidity and mortality, and has a poor prognosis. MpBC tend not to respond well to systemic chemotherapies, and together with emerging data on the genomic landscape of MpBC, there is scope for applying precision oncology in the management strategies of MpBC. We focus herein on the molecular pathology of MpBC and the current status and potential of targeted therapies to manage MpBC.

The clinical features of MpBC are similar to other high-grade cancers of no special type (NST), however, they often present at amore advanced stage. They tend to be large in size, with dimensions ranging from 1.2 to >10 cm and often present as a palpable breast mass, with ill-defined borders on mammography, ultrasonography, and magnetic resonance imaging. MpBC represents 0.21% of all breast cancers the rates vary due to the differing definitions and classification systems used over time.

MpBC do not have any distinctive macroscopic features, with the tumor varying from well-circumscribed to having an irregular border. Microscopically, they comprise a heterogenous group with differing outcomes. In the absence of sufficient molecular and outcome data, the current WHO Classification of Tumours of the Breast1,2 has maintained a descriptive morphological classification system, based on the type of the metaplastic elements present. MpBC are classified monophasic (when there is only one metaplastic component) or biphasic (with two or more metaplastic components such as squamous and spindle, or mixed metaplastic and non-metaplastic components such as spindle and invasive carcinoma NST). Further, MpBC can also be classified into epithelial-only carcinomas (with low-grade adenosquamous carcinoma or pure squamous cell carcinoma), pure (monophasic) sarcomatoid (spindle cell or matrix-producing) carcinomas, and biphasic epithelial and sarcomatoid carcinomas.

The current WHO classification includes (i) adenosquamous carcinoma mostly low grade but can be high grade rarely and (ii) pure squamous cell carcinomas (iii) pure spindle cell carcinoma (iv) fibromatosis-like metaplastic carcinoma, (iv) metaplastic carcinoma with mesenchymal differentiation that includes chondroid (myxoid/cartilaginous), osseous (bone), rhabdomyoid (muscle) and neuroglial, and (v) mixed metaplastic carcinoma where the mix may be multiple metaplastic elements or a mixture of epithelial and mesenchymal elements. Examples of the heterologous elements are shown in Figure 1. The detailed morphology of the subtypes is beyond the scope of this review and the reader is directed to the WHO Tumour Classification of the Breast 5th Ed (2019).2

Figure 1 Examples of Metaplastic breast cancer morphologies. (A) High-grade, pleomorphic de-differentiated carcinoma (IBC-NST). (B) High-grade carcinoma with focal squamous differentiation. (C) Osteoid differentiation. (D) Chondroid differentiation. (E) Spindle differentiation. Scale bar is 100 m.

MpBC are typically, though not invariably triple-negative (TN), lacking expression of estrogen and progesterone receptors (ER/PR), and HER2. Analysis of the SEER data showed that HER2 positive MpBC had an improved overall survival compared to TN, and other MpBC including ER+/PR+/HER2-cases, which accounted for 20% of the cohort.3 Conversely, HER2-positive metaplastic squamous cell carcinomas were recently demonstrated to have a poorer prognosis than the TN metaplastic squamous variants.4 MpBC fit into the claudin-low and/or basal breast cancer intrinsic subtypes,5,6 although whether or not claudin low represents an intrinsic subtype or phenotype has recently come into question.7 A recent large meta-analysis reported that approximately three quarters of all MpBC stain positively for pan-cytokeratin biomarkers (AE1/3, MNF116) and basal cytokeratin biomarkers (34E12, CK5/6, CK14 and CK17). GATA3, a common diagnostic marker used to identify tumours of breast origin, is expressed by only 21% of MpBC, while a novel breast marker, TRPS1, was shown to be highly expressed in 86% of MpBC, as well as non-metaplastic TNBC and BC more broadly.8 Frequent expression of p63 was also noted, as was an absence of staining for CD34.9 Those cases lacking cytokeratin expression were studied in more detail, and determined to be carcinomatous rather than true primary sarcomas in most cases, further evidencing the inter-tumor heterogeneity of breast cancer broadly, and MpBC specifically.10 Indeed, a pure sarcoma of the breast is rare and is a diagnosis of exclusion, requiring extensive sampling; negative stains for p63 and a range of cytokeratins; and, a morphological examination for any evidence of epithelial differentiation.

For the adenosquamous and fibromatosis-like variants of MpBC, the grade is implicitly low, and prognostic outcome is better than for the majority of MpBC which are typically classified as high grade (grade 3) tumors. Although high histologic grading is a relatively consistent finding, its prognostic value is still uncertain.11 A subset of MpBC tumors with extreme, bizarre cytologic pleomorphisms has been reported,11 with a noted enrichment in the spindle phenotype.

With respect to the TNM classification system of cancer stage, MpBC present with a larger tumor size (TNM), with reports indicating that ~60% of MpBC have tumors between 2 and 5 cm (T2;12). As for triple-negative breast cancers more broadly, lymph node (LN; the N of TNM) positivity is not a prominent feature, with LN metastasis documented in about 24% of patients. Distant metastasis (TNM) occurs with or without LN spread in MpBC, and spread to the lungs and brain has been reported.13

The innate plasticity of MpBC has led to suggestions that it is a stem-cell like breast cancer, and a wealth of data show that MpBC express classic stem cell markers. It is presently considered that there exist three categories of breast cancer stem cell (CSC): an ALDH+ epithelial-like CSC; CD44+/CD24 mesenchymal-like CSCs; and, a hybrid epithelial/mesenchymal-like ALDH+/CD44+/CD24 (reviewed in detail in14). The work of Zhang et al15 demonstrated the increased expression of classic stem cell markers ALDH1 and CD44/CD24 ratios in a series of MpBC, much like the above-noted hybrid CSC state, and also expression of characteristic epithelial to mesenchymal transition (EMT) markers (increased ZEB1 and loss of E-cadherin). This expression of stem-like markers was also supported by Gerhard et al,16 with most of their series showing positivity for CD44 and loss of CD24, as well as an enrichment for vimentin and loss of the claudins and E-cadherin. Given that cancer stem cells have well-documented chemoresistance,17 it is unsurprising that MpBC, with their enrichment of both stem-like markers and the hallmarks of EMT,5,18 also respond poorly to chemotherapeutics. Notably, MpBC have a high frequency of PIK3CA mutations (see below) and these mutations correlate with poor response to neoadjuvant chemotherapy in breast cancer subtypes broadly,19 and this holds true in the metastatic setting.20 Drugs targeting the PI3K/AKT axis are emerging in the clinic, may be appropriate for MpBC, and are discussed further below.

As shown in Table 1, the research community has yet to robustly elucidate a molecular landscape for MpBC, most likely due to the extensive sample heterogeneity. There is limited concordance between studies on the mutations present, however this is likely influenced by the sequencing platform (exome vs panel), and also the subtype composition of the cohorts.

Table 1 Genetic Alterations Identified Across MpBC Cohorts and Morphologies

PI-3 Kinase and Ras signaling pathway mutations have been shown to be early events in MpBC pathogenesis.21 Mutation frequencies reported for MpBC range from 26%-75% for TP53, and 23%-70% for PIK3CA (Table 1) and this is supported by a recent meta-analysis of 14 studies encompassing 539 cases.22 Other than TP53 and PIK3CA, the most frequently identified mutations across multiple cohorts occur in PTEN, NF1, HRAS, PIK3R1. Emerging data support that the various morphologic elements feature subtly different mutation profiles, with for example, a lack of PIK3CA mutations found in those MpBC with chondroid differentiation.23 Chondroid tumors were also shown to lack mutations in TERT promoters.21 TERT promoter mutations were enriched in the spindle and squamous type tumors, while TP53 mutations were less likely to be in spindled tumors than other MpBC types.21 An increase in mutations in Wnt pathway genes has been reported for MpBCs,23 with WISP3/CCN6 mutations more frequently seen in the epithelial components, and 3/7 CTNNB1 mutations present only in the spindle compartment of the tumor.24

In spite of the private mutations in the different morphological components as noted above, evidence supports that the different histologies have a shared origin, and following a detailed exome sequencing study, Avigdor et al postulated that methylation and/or non-coding changes may also regulate the phenotypic differentiation.25 To clarify the outstanding elements of the genomic landscape of MpBC, a concerted effort must be made to standardize sequencing approaches on an adequately powered cohort of well-annotated MpBC.

Uterine carcinosarcoma (UCS) are considered the metaplastic cancers of the gynaecological tract, and a recent study performed a comparative analysis of 57 UCS with 35 MpBC.26 Genetic differences unique to the UCS were reported, with a significant enrichment for mutations in FBXW7 and PPP2R1A, and HER2 amplifications, while shared genomic features included alterations in TP53, PIK3CA, PTEN and EMT-related Wnt and Notch signalling components. Interestingly, unlike the UCS, almost half of the profiled MpBC had a dominant homologous recombination deficiency (HRD; signature 3) signature, and these same cases showed other features of a HRD including large scale transitions, and allelic imbalance extending to the telomeres.

In the absence of indications for hormone and anti-HER2 therapies, and given their typically large size at presentation, MpBC are managed with chemotherapeutics in addition to surgery (with/without radiation). However, early studies showed that systemic therapy was less effective in MpBC12 and this data has held true over time and is supported by the overall poor outcomes of MpBC patients.27 In fact, while 90% of diagnoses of MpBC are for localized disease, half of these patients will progress to advanced BC over time.28,29 Treatment in the neoadjuvant setting appears to afford little advantage, with a 1017% pathological complete response rate reported3033 for American studies, while studies in Japan and Turkey reported no complete responders.34,35 It is clear that efficacious treatments for MpBC are an unmet clinical need, and while some clinical trials specifically for MpBC are being initiated, the potential for novel therapeutic interventions must be capitalized upon.

MpBC are characteristically triple-negative BC, thus eliminating these patients from current tailored therapeutic options of hormone therapy and anti-HER2 therapy. This triple-negativity, does however make them eligible for a multitude of trials currently recruiting, including those assessing benefit of immune checkpoint inhibitors; a non-exhaustive list of open trials is presented in Table 2.

Table 2 Active Trials Open to Metaplastic Breast Cancer Patients

MpBC show frequent alterations in the PI3K/AKT/mTOR pathway making them candidates for targeted therapies such as everolimus, temsirolimus, and alpelisib. In a Phase I intervention, a 42% rate of partial/complete remission was reported for a combination of temsirolimus and bevacizumab (HIF inhibitor).36 A 25% response rate (complete/partial response) was achieved in MpBC treated with temsirolimus/everolimus in combination with standard chemotherapy and a 21% objective response rate was also reported for the regimen of doxorubicin, bevacizumab and temsirolimus/everolimus,37 however genetic analysis showed that while PI3K pathway alterations were associated with a significant improvement in objective response rate (31% vs 0%) they were not associated with an improved clinical benefit rate (44% vs 45%). Detailed analysis of this trial data showed an improvement in overall survival for the MpBC patients, and suggests that MpBC histology is an indicator for doxorubicin with bevacizumab and everolimus/temsirolimus.38 A lone MpBC participant in the BELLE-4 Phase II/III trial responded well to a combined therapy of paclitaxel and the PI3K inhibitor buparlisib39 although toxicity was noted, and indeed buparlisib was subsequently discontinued from development, with a significantly higher burden of adverse effects noted for buparlisib than alpelisb in the B-YOND (hormone receptor positive, phase Ib) trial.40 Pre-clinical data in MpBC patient derived xenograft models suggest that a combination of PI3K and MAPK inhibitors may be a potential avenue for therapy in PIK3CA mutated MpBC patients.41

CDK4/6 inhibitors (eg, ribociclib, palbociclib, abemaciclib) are now approved as standard of care for advanced, hormone receptor positive breast cancers, however this proliferation check-point may also be a useful target in TNBC, and trials are underway to determine the efficacy of this approach (reviewed in42), including in combination with immune checkpoint inhibitors (PAveMenT: NCT04360941). A recent case report demonstrated a dramatic but short-term benefit from combined dabrafenib and trametinib in an advanced MpBC patient.43 Dabrafenib and trametinib target BRAF and MEK signalling, respectively, and their application in MpBC has not previously been reported.

Although a pre-clinical study did not support the efficacy of PARP inhibitor olaparib in an MpBC-like mouse model,44 given the recent evidence of a dominant HRD signature in almost 50% of the MpBC profiled,26 the suggestion by Tray et al45 that PARP inhibition for MpBC needs further study is certainly warranted. These studies together support further investigations into a range of targeted therapies and highlight their potential value in MpBC.

The potential benefit of therapeutic modulation of the immune system in breast cancer is becoming increasingly clear for TNBC, as well as MpBC. A case report of a remarkable, durable response to pembrolizumab (anti-PD-1) in combination with nab-Paclitaxel in advanced, pre-treated spindled MpBC was reported in 2017.46 A similar combination of durvalumab (anti-PD-L1) and paclitaxel was also shown to provide a sustained, complete response in a second case report of advanced MpBC, this time with squamous features.47 In this case, 20% of tumor cells stained with medium intensity (clone SP142), and there was an absence of staining in the TILS; while in the former case, 100% of tumor cells stained positively for PD-L1 using the 22C3 clone. Indeed, there is no standardized definition criteria for PD-L1 staining at this stage, and the characterization of expression of this and other immune checkpoint markers across TNBC and MpBC has only recently emerged. As shown in Table 3, heterogeneity in percentage positivity of PD-L1 in tumor cells is reported across TNBC, with a higher rate of positivity consistently reported for MpBC. MpBC tumor cells show a range of PD-L1 expression from 17% to 80%, recording both cytoplasmic and membranous staining, and in the immune cells from 48% to 69%. Combinations of immune-checkpoint inhibitors are also being evaluated, with the DART (Dual Anti-CTLA-4 and Anti-PD-1 blockade in Rare Tumors, Table 2) trial facilitating an MpBC specific assessment.48 Primary endpoint data confirmed clinical activity of ipilimumab combined with nivolumab and resulted in 3 cases of 17 showing a durable response, which supports further investigation. It is hoped that trials such as the Morpheus-TNBC Phase 1/1b umbrella trial (Table 2, NCT03424005), will provide insights to further our understanding of the biomarkers and patient indicators for a range of immunotherapeutic interventions.

Table 3 PD-L1 Expression in Metaplastic Breast Cancer

The morphologically diverse metaplastic breast cancers account for significant global morbidity and mortality, in spite of their relatively rare frequency, due to their aggressive clinical course. As more molecular pathology data emerges on the genomic underpinnings of this intriguing tumor type, we are increasingly better placed to consider MpBC for targeted therapies and immunotherapies.

We apologize to those authors whose work we could not include due to space restrictions.

The authors report no conflicts of interest in this work.

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59. Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res. 2014;2(4):361370.

60. Beckers RK, Selinger CI, Vilain R, et al. Programmed death ligand 1 expression in triple-negative breast cancer is associated with tumour-infiltrating lymphocytes and improved outcome. Histopathology. 2016;69(1):2534.

61. Dogukan R, Ucak R, Dogukan FM, Tanik C, Citgez B, Kabukcuoglu F. Correlation between the Expression of PD-L1 and Clinicopathological parameters in triple negative breast cancer patients. Eur J Breast Health. 2019;15(4):235241.

62. Morgan E, Suresh A, Ganju A, et al. Assessment of outcomes and novel immune biomarkers in metaplastic breast cancer: a single institution retrospective study. World J Surg Oncol. 2020;18(1):11.

63. Lien HC, Lee YH, Chen IC, et al. Tumor-infiltrating lymphocyte abundance and programmed death-ligand 1 expression in metaplastic breast carcinoma: implications for distinct immune microenvironments in different metaplastic components. Virchows Arch. 2020;24.

64. Kalaw E, Lim M, Kutasovic JR, et al. Metaplastic breast cancers frequently express immune checkpoint markers FOXP3 and PD-L1. Br J Cancer. 2020.

65. Chao X, Liu L, Sun P, et al. Immune parameters associated with survival in metaplastic breast cancer. Breast Cancer Res. 2020;22(1):92.

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[Full text] An Update on the Molecular Pathology of Metaplastic Breast Cancer | BCTT - Dove Medical Press

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4D Pharma Appointments Paul Maier to the Board as Non-Executive Director – Business Wire

Wednesday, March 3rd, 2021

LEEDS, England--(BUSINESS WIRE)--4D pharma plc (AIM: DDDD), a pharmaceutical company leading the development of Live Biotherapeutic products (LBPs) - a novel class of drug derived from the microbiome, today announces the appointment of Paul Maier as Non-Executive Director of the Board. Mr Maier will also be a member of 4D's Audit and Risk Committee and will serve as the Companys audit committee financial expert under SEC and Nasdaq rules.

With over 25 years of extensive senior operational, international and financial management experience in the pharmaceutical and biotechnology industry, Paul will be able to provide 4D pharma with invaluable insights as we continue to execute across our business both clinically and operationally, said Duncan Peyton, Chief Executive Officer of 4D pharma. Pauls strong track record will support our Board with additional perspective and expertise.

I am excited to join 4D pharmas Board and support its goals to establish a larger global presence while working to bring its differentiated approach and pipeline of Live Biotherapeutics to patients in need, said Paul Maier, Non-Executive Director of 4D pharma. I look forward to working with 4D and offering my experiences in transactional and operational strategy as the company continues to grow, catalyzed by 4Ds upcoming NASDAQ listing.

Mr. Maier has over 25 years of investor and public relations, operational, regulatory, and finance expertise in the healthcare industry. Mr. Maier was previously the Chief Financial Officer of Sequenom Inc., where he was responsible for raising over $360 million in equity and debt financings, expanding institutional sell side research analyst coverage, as well as overseeing and establishing internal financial infrastructure. Previously, he was Senior Vice President and Chief Financial Officer of Ligand Pharmaceuticals (NASDAQ: LGND) where he helped build Ligand from a venture stage company to a commercial, integrated biopharmaceutical organization, raising over $1 billion in equity and debt financings including a successful IPO, and helped negotiate multiple R&D and commercial partnerships and transactions. He has also acted as an independent financial consultant to life sciences companies. Mr. Maier is currently a Board member of Eton Pharmaceuticals, Inc, Biological Dynamics and International Stem Cell Corporation (OTCQB: ISCO). He holds an MBA from Harvard University and a BS in Business Logistics from the Pennsylvania State University.

Additional Disclosures Required under the AIM Rules for Companies

In accordance with Schedule 2(g) of the AIM Rules, Paul Victor Maier (aged 73) currently holds the following directorships:Eton Pharmaceuticals, IncBiological Dynamics, IncInternational Stem Cell Corp.

Previous directorships held in the past five years:Ritter Pharmaceuticals, Inc (Mar 2015 May 2020)Apricus Biosciences, Inc (May 2012 Jan 2019)Mabvax, Inc (June 2014 July 2018)

Paul Maier does not currently hold any ordinary shares in the Company.

Save as set out above there are no further disclosures pursuant to Rule 17 or Schedule Two paragraph (g) of the AIM Rules for Companies in respect of the appointment of Paul Maier.

About 4D pharma

Founded in February 2014, 4D pharma is a world leader in the development of Live Biotherapeutics, a novel and emerging class of drugs, defined by the FDA as biological products that contain a live organism, such as a bacterium, that is applicable to the prevention, treatment or cure of a disease. 4D has developed a proprietary platform, MicroRx, that rationally identifies Live Biotherapeutics based on a deep understanding of function and mechanism.

4D pharma's Live Biotherapeutic products (LBPs) are orally delivered single strains of bacteria that are naturally found in the healthy human gut. The Company has six clinical programs, namely a Phase I/II study of MRx0518 in combination with KEYTRUDA (pembrolizumab) in solid tumors, a Phase I study of MRx0518 in a neoadjuvant setting for patients with solid tumors, a Phase I study of MRx0518 in patients with pancreatic cancer, a Phase I/II study of MRx-4DP0004 in asthma (NCT03851250), a Phase II study of MRx-4DP0004 in patients hospitalized with COVID-19 (NCT04363372), and Blautix in Irritable Bowel Syndrome (IBS) (NCT03721107) which has completed a successful Phase II trial. Preclinical-stage programs include candidates for CNS disease such as Parkinson's disease and other neurodegenerative conditions. The Company has a research collaboration with MSD, a tradename of Merck & Co., Inc., Kenilworth, NJ, USA, to discover and develop Live Biotherapeutics for vaccines.

For more information, refer to http://www.4dpharmaplc.com.

Forward-Looking Statements

This press release contains "forward-looking statements." All statements other than statements of historical fact contained in this announcement, including without limitation statements regarding timing of the clinical trial are forward-looking statements within the meaning of Section 27A of the United States Securities Act of 1933, as amended (the "Securities Act"), and Section 21E of the United States Securities Exchange Act of 1934, as amended (the "Exchange Act"). Forward-looking statements are often identified by the words "believe," "expect," "anticipate," "plan," "intend," "foresee," "should," "would," "could," "may," "estimate," "outlook" and similar expressions, including the negative thereof. The absence of these words, however, does not mean that the statements are not forward-looking. These forward-looking statements are based on the Company's current expectations, beliefs and assumptions concerning future developments and business conditions and their potential effect on the Company. While management believes that these forward-looking statements are reasonable as and when made, there can be no assurance that future developments affecting the Company will be those that it anticipates.

All of the Company's forward-looking statements involve known and unknown risks and uncertainties, some of which are significant or beyond its control, and assumptions that could cause actual results to differ materially from the Company's historical experience and its present expectations or projections. The foregoing factors and the other risks and uncertainties that affect the Company's business, including the risks of delays in the commencement of the clinical trial and those additional risks and uncertainties described the documents filed by the Company with the US Securities and Exchange Commission (SEC), should be carefully considered. The Company wishes to caution you not to place undue reliance on any forward-looking statements, which speak only as of the date hereof. The Company undertakes no obligation to publicly update or revise any of its forward-looking statements after the date they are made, whether as a result of new information, future events or otherwise, except to the extent required by law.

Additional Information about the Transaction and Where to Find it

This press release is being made in respect of a proposed business combination involving 4D and Longevity. Following the announcement of the proposed business combination, 4D filed a registration statement on Form F-4 (the Registration Statement) with the SEC which was declared effective on February 25, 2021. This press release does not constitute an offer to sell or the solicitation of an offer to buy or subscribe for any securities or a solicitation of any vote or approval nor shall there be any sale, issuance or transfer of securities in any jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such jurisdiction. The Registration Statement includes a prospectus with respect to 4Ds ordinary shares and ADSs to be issued in the proposed transaction and a proxy statement of Longevity in connection with the merger. The proxy statement/prospectus has been mailed to the Longevity shareholders on or about February 26, 2021. 4D and Longevity also plan to file other documents with the SEC regarding the proposed transaction.

This press release is not a substitute for any prospectus, proxy statement or any other document that 4D or Longevity may file with the SEC in connection with the proposed transaction. Investors and security holders are urged to read the Registration Statement and, when they become available, any other relevant documents that will be filed with the SEC carefully and in their entirety because they will contain important information about the proposed transaction.

You may obtain copies of all documents filed with the SEC regarding this transaction, free of charge, at the SECs website (www.sec.gov). In addition, investors and security holders will be able to obtain free copies of the Registration Statement and other documents filed with the SEC without charge, at the SECs website (www.sec.gov) or by calling +1-800-SEC-0330.

Participants in the Solicitation

Longevity and its directors and executive officers and other persons may be deemed to be participants in the solicitation of proxies from Longevitys shareholders with respect to the proposed transaction. Information regarding Longevitys directors and executive officers is available in its annual report on Form 10-K for the fiscal year ended February 29, 2020, filed with the SEC on April 30, 2020. Additional information regarding the participants in the proxy solicitation relating to the proposed transaction and a description of their direct and indirect interests is contained in the Registration Statement.

4D and its directors and executive officers may also be deemed to be participants in the solicitation of proxies from the shareholders of Longevity in connection with the proposed transaction. A list of the names of such directors and executive officers and information regarding their interests in the proposed transaction is included in the Registration Statement.

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4D Pharma Appointments Paul Maier to the Board as Non-Executive Director - Business Wire

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Investigative Interventions Gain Ground in GVHD – OncLive

Wednesday, March 3rd, 2021

With an increased understanding of disease biology, several approaches are under examination to optimize the management of patients with graft-versus-host disease (GVHD), Corey Cutler, MD, MPH FRCP, who added that novel combinations with steroids are gaining ground in the frontline setting, while novel agents such as JAK inhibitors are raising the bar in the steroid-refractory setting.1

When treating patients with GVHD, it is important to differentiate on a clinical level whether a patient has chronic or acute disease, as the pathobiological differences between the 2 differ greatly. Acute GVHD (aGVHD) can develop into chronic GVHD (cGVHD) and is thought to represent T-cell mediated disease that targets specific organs, such as the skin, the gastrointestinal tract, and the liver. cGVHD is a more complex disease, with several T-cell subsets, as well as involvement of the B-cell pathway and the monocyte macrophage lineage.2

[This is] particularly relevant in terminal stages of cGVHD, where we see lots of fibrosis scarring and sclerosis, Cutler, the medical director of Stem Cell Transplantation at the Dana Farber Cancer Institute, and an associate professor of medicine at Harvard Medical School, explained during a presentation at the 25th Annual International Congress on Hematologic Malignancies.

It has become clear that the gut microbiome can play a role in the development of aGVHD, according to Cutler. Some inflammatory markers can be elucidated by the microbiome, and in the absence of conditioning-related injury, can activate the immune system; this is partially responsible for the upregulation of alloantigen presentation at the level of lamina propria, as well as the recruitment of donor T cells, added Cutler.3

Not only have we learned a lot about how to treat [patients with] GVHD, but were also learning how to prevent it through modulation of the gut microbiome, Cutler said.

Treatment goals in aGVHD are focused on improving or stabilizing organ manifestations, limiting long-term treatment-associated adverse effects, improving the functional capacity or quality of life of patients, and ultimately, improving overall survival (OS), according to Cutler.

Frontline treatment for patients with aGVHD often includes the use of corticosteroids, such as solumedrol (methylprednisolone), which is generally administered at a daily dose of 1 mg/kg to 2 mg/kg.4 Many patients will respond to this treatment but up to 20% will be steroid refractory, and another 20% to 25% will relapse, according to Cutler. Notably, until recently, no standard of care for second-line setting was available.

Several studies have been conducted to improve initial therapy for patients for aGVHD; however, many have yielded negative results, Cutler said. A significant phase 3 study (NCT01002742) evaluated the addition of mycophenolate mofetil to steroids (n = 116) vs steroids alone (n = 119) as frontline treatment in patients with aGVHD. Results showed that survival probability after 360 days with steroids plus mycophenolate mofetil was 57.8% (95% CI, 48.2%-66.3%) vs 64.7% (95% CI, 55.2%-72.6%) with steroids/placebo.5

[The addition of mycophenolate mofetil] added nothing. In fact, [the combination did] even worse than steroids alone for [patients with] aGVHD, Cutler said. We need more targets.

To this end, investigators have set out to target cytokines in aGVHD by focusing on the JAK-STAT signaling pathway, according to Cutler. Many of the inflammatory cytokines that are important in the disease, like interleukin-6 or interferon-g (INF-g), signal through JAK-STAT pathways through independent receptors.6 The assemblies of different monomers can result in varied processes, which can be targeted with agents like ruxolitinib (Jakafi), Cutler explained.

Recently, the phase 3 GRAVITAS-301 trial (NCT03139604) examined a newer JAK inhibitor itacitinib with or without steroids in the initial treatment of 436 patients with aGVHD. Participants were randomized 1:1 to receive itacitinib at a daily dose of 200 mg plus corticosteroids, or placebo plus corticosteroids. The primary end point of the trial was overall response rate (ORR) at 28 days, while the secondary end point was non-relapse mortality (NRM) at 6 months. Top-line results showed that the ORR at day 28 was slightly better in the itacitinib arm at 74.0%, compared with 66.4% in the placebo arm (P = .08); however, this was not determined to be statistically significant and so, the trial was halted.7

This was unfortunate, because the control group actually did significantly better than what we anticipated and what we had planned for, Cutler explained. This was a negative trial, although it certainly tells us that the incorporation of JAK inhibitors in the frontline might be promising.

The phase 2 BMT CTN 1501 trial (NCT02806947) enrolled a total of 127 patients with standard-risk aGVHD per the Minnesota risk criteria who were randomized 1:1 to receive either sirolimus (Rapamune; n = 58) or prednisone (n = 64). Results showed that complete response (CR) and partial response (PR) rates at day 28 were similar in the sirolimus and prednisone arms, at 64.8% (90% CI, 53.8%-75.8%) and 73.0% (90% CI, 63.6%-82.4%), respectively. Additionally, no change in OS was observed.

Subjects who had a slightly lower response rate with sirolimus ended up being salvaged very well with corticosteroids, and this did not lead to a reduction in OS, Cutler noted.

In patients with steroid-refractory aGVHD, JAK inhibition was once again examined in the phase 2 REACH-1 study (NCT02953678). To be eligible for enrollment, patients had to be at least 12 years of age with grade 2 to 4 corticosteroid-refractory aGVHD per MAGIC criteria. Here, patients were treated with ruxolitinib at a daily dose of 5 mg until treatment failure, intolerable toxicity, or death. The primary end point of the trial was ORR at day 28, while secondary end points included 6-month duration of response, NRM, malignancy relapse rate, OS, and safety.

Results indicated that the ORR with this approach was 54.9% in all patients (n = 71), while those with grade 2 disease (n = 23) experienced the highest ORR, at 82.6%. Additionally, the median time to response was 7 days. However, although response rates were high, approximately one-third of responders still experienced 1-year NRM.9

That was significantly better but still lacking in terms of a great number, in comparison with the subjects who were non-responders, of whom 85% died at 1 year, Cutlet said.

Notably, the data from this trial led to the May 2019 FDA approval of ruxolitinib for the treatment of patients with aGVHD.

This trial was followed by the phase 3 REACH-2 trial (NCT02913261), which was mostly conducted in Europe. A total of 308 patients were enrolled in this trial and they were randomized to receive either ruxolitinib at a slightly higher dose of 10 mg twice daily, or best available care per the treating physician. Several regimens were allowed in this trial, although most would not typically be considered to be standard therapy in North America, noted Cutler.

Results for this trial showed that the ORR at day 28 was 62.3% in the ruxolitinib arm (n = 154) vs 39.4% in the control arm (n = 155; P <.001). However, at day 56 of treatment, only 39.6% of patients in the ruxolitinib arm maintained their response.10

As such, we still have a long way to go in [the treatment] of [patients with] steroid-refractory aGVHD, Cutlet said.

To this end, many efforts are being made to develop other agents to treat patients with steroid-refractory aGVHD. For example, one compound under evaluation is Alpha-1 Antitrypsin; this agent prevents effector cell cytotoxic cell killing, noted Cutler. Additional agents under investigation include the CD6 T-cell inhibitor EQ001 and T-Guard, a CD3/CD7-ricin conjugated monoclonal antibody cocktail. Additionally, several efforts are being made to examine mesenchymal stromal cells and costimulation blockades, according to Cutler.

It is understood that there are 3 distinct phases of cGVHD: phase 1 is acute inflammation and tissue injury, phase 2 is chronic inflammation and dysregulated immunity, and phase 3 is aberrant tissue repair and fibrosis.11

The majority of patients will cycle through multiple lines of therapy when they are initially treated for cGVHD, noted Cutler. After 4 years, only 11% of patients have not moved on to receive second-, third-, or fourth-line therapy.12 However, several agents can now be used in the second-line setting for these patients, such as extracorporeal photopheresis, rituximab, imatinib (Gleevec), and pentostatin.

In terms of mechanistic interventions for prevention and treatment of patients with cGVHD, 2 major pathways should be focused on, according to Cutler. The first is a reduction in the alloreactive T-cell pathway, by augmenting regulatory T cells. The second pathway is one that inhibits B cells and their role in initiating cGVHD, explained Cutler.13 Several agents are able to block those individual pathways.

Ibrutinib (Imbruvica), a B-cell inhibiting compound that targets the BTK pathway, is under examination in patients with steroid-refractory cGVHD. In a phase 1/2 study (NCT02195869), investigators examined the agent in 42 patients, at a dose of 420 mg. Patients received treatment until disease progression or intolerable toxicity. Results showed that 79% of patients had responded at the time of the first assessment, and 71% had a response that extended past 5 months.14 Data from the study led to the September 2017 FDA approval of ibrutinib for patients with steroid-refractory cGVHD.

This was the first drug that was approved in cGVHD, Cutler noted. Weve now gone and tried ibrutinib as frontline therapy for [patients with] cGVHD, in conjunction with steroids, and were looking forward to seeing the results.

Ruxolitinib was also examined for patients with steroid-refractory cGVHD in the phase 3 REACH3 trial (NCT03112603), where it was compared with best available therapy (BAT). The study enrolled 300 patients and results showed that responses at week 24, which was the primary end point of the trial, were 49.7% in the ruxolitinib arm vs 25.6% in the BAT arm (odds ratio [OR], 2.99; 95% CI, 1.86-4.80; P <.0001).15 However, in terms of best overall response, rates were 76.4% in the ruxolitinib arm vs 60.4% in the BAT arm (OR, 2.17; 95% CI, 1.34-3.52), which shows that a significant number of patients who responded lost that response at 6 months, Cutler noted.

Another area of interest are agents that can block ROCK2 signaling, such as belumosudil (KD025). KD025 is an oral selective ROCK2 inhibitor which targets the immune and fibrotic pathophysiology of cGVHD, explained Cutler. When examined in the phase 1/2 KD025-208 study (NCT02841995), the agent demonstrated an ORR of 59% in patients with cGVHD who had previously received 1 to 3 lines of systemic therapy.16

The agent was also being examined in the phase 2 ROCKstar trial (KD025-213; NCT03640481). In this study, patients who had previously received 2 to 5 lines of therapy were randomized to receive 1 of 2 doses of KD025: 200 mg daily or 200 mg twice daily.17 The agent elicited clinically meaningful and statistically significant ORRs of 75% for both arms together, and the median time to response was 4 weeks. Additionally, CRs were observed in all affected organ systems, and 7 patients achieved an overall CR. In November 2020, the FDA granted a priority review designation to a new drug application for belumosudil for the treatment of patients with cGVHD; the regulatory agency is expected to make a decision on the application by May 30, 2021.

A final area of interest that Cutler noted was CSF-1dependent donor derived macrophages. A compound called axatilimab (SNDX-6352) is currently under examination in very early phase 1/2 studies, noted Cutler.

Additionally, multiple ongoing studies are examining cGVHD prevention with methods such as T-cell depletion, T-cell modulation, T-cell migration, and prophylactic B-cell depletion. However, the one garnering the most attention is post-transplant cyclophosphamide, which should kill alloreactive T-cells, Cutler concluded.

References

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Investigative Interventions Gain Ground in GVHD - OncLive

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Combination Regimens for Multiple Myeloma Show Efficacy in the Transplant-Ineligible Population, According to Dingli – Targeted Oncology

Wednesday, March 3rd, 2021

David Dingli, MD, PhD, professor of Medicine at the Mayo Clinic, reviews the combination therapies available for the treatment of multiple myeloma in a patient who is 72-years-old and transplant-ineligible.

Targeted OncologyTM: Do you believe that treating patients with multiple myeloma with multiple therapies in the maintenance setting increases their duration of response?

DINGLI: There arent much data on long-term maintenance with multiple agents. I think that it would be an unusual patient with ultrahigh-risk disease who will probably go on maintenance with a doubletfor example, lenalidomide [Revlimid] and a proteasome inhibitor at the same timewithout much data to support it.

What are the best treatment options for a patient such as this who is not eligible for transplant?

The NCCN [National Comprehensive Cancer Network] guidelines with respect to therapy in the newly diagnosed setting for non transplant-eligible patients [say] the preferred regimens are bortezomib [Velcade]/lenalidomide/dexamethasone, daratumumab [Darzalex]/lenalidomide/dexamethasone, or even a doublet with lenalidomide/dexamethasone, or CyBorD [cyclophosphamide/ bortezomib/dexamethasone].1 Other regimens are also included, although probably not many people will use them.

The NCCN guidelines include daratumumab/bortezomib/ melphalan/prednisone [D-VMP] as a regimen because it is supported by a large phase 3 trial that was done in Europe. [They also include], without data, daratumumab/cyclophosphamide/ bortezomib/ dexamethasone, where melphalan is replaced by cyclophosphamide, because of the perceived lower risk of myelotoxicity. But, as far as I know, there is no study that has looked at this in multiple myeloma. There is a study that has come out, looking at this regimen in amyloidosis, and we do know that its superior, but not in multiple myeloma at this point in time.

What factors do you consider when choosing an induction regimen for patients like these?

Age, efficacy, logistics, cost, risk status, or, with respect to disease, geography, and performance status.

[Geriatric assessment] is something that is [being] incorporated more and more into clinical trials as part of the assessment of the patient, using various tools such as the Charlson index, etc, to assess frailty of patients and how suitable they are for a specific therapy versus some other therapy.

Which trials have supported the NCCN-recommended treatment regimens in the transplant-ineligible setting?

[There are] many studies in the nontransplant-eligible population.

The MAIA study [NCT02252172] randomized patients to daratumumab/lenalidomide/dexamethasone [DRd] versus lenalidomide/dexamethasone [Rd]. The ALCYONE study [NCT02195479] looked at D-VMP versus VMP; we dont use that regimen [in the United States]. SWOG [S0777; NCT00644228], a very important, large, randomized study in this country, is looking at VRd [bortezomib/lenalidomide/dexamethasone] versus Rd. Theres the VRd Lite, which is a variation of VRd where patients get a gentler regimen, often in patients who are rather elderly. Then, there will be studies looking at Rd versus MPT [melphalan/prednisone/thalidomide (Thalomid)], and KMP [carfilzomib (Kyprolis)/melphalan/prednisone] versus VMP, which I do notthink we need to discuss in detail, because this therapy has been rather surpassed.

We can look at some data from the more relevant studies, at how we treat patients nowadays. The MAIA study showed that PFS [progression-free survival] was clearly superior for the DRd versus Rd, with a significant improvement [not reached vs 31.9 months, respectively] and reduction in the hazard ratio by 44% [HR, 0.56; 95% CI, 0.43-0.73; P <.001].2 ALCYONE showed, again, that the addition of daratumumab to a triplet regimen that includes VMP was associated with significant improvement in PFS, almost 3 times as high [36.4 vs 19.3 months with VMP alone; HR, 0.42; 95% CI, 0.34-0.51; P <.0001].3 The SWOG study that looked at VRd versus Rd showed that with a rather long follow-up period of 84 months, median PFS was 41 months in patients with the triplet versus 29 months for the Rd doublet [HR, 0.74; P =.003].4 If we look at VRd Lite, the median PFS is approximately 35 months in patients who are not transplant eligible.5

Again, there are other trials that probably are not very relevant to our practice, because most of us will not be using melphalan in patients [with a new diagnosis] or regimens that include melphalan in some form.

Can you discuss the SWOG trial and its results in more detail?

The SWOG study is an important study that probably was a benchmark for a while on how we treat patients who are not transplant eligible.6 [The trial enrolled] patients with no intention to proceed with transplant, randomized to VRd induction, with lenalidomide at 25 mg for 14 days, dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12, and bortezomib given at standard dose IV [intravenously] on days 1, 4, 8, and 11, compared with standard Rd with a 28-day cycle. So, patients received either 8 cycles of the triplet versus 6 cycles of the doublet, and then all patients received lenalidomide and dexamethasone in maintenance therapy. The main outcome was PFS, with overall response rate [ORR], overall survival [OS], and safety [as key secondary end points]. In 68% of these patients, there was a possibility of moving to transplant later, although 43% were above the age of 65. Note that follow-up is substantial, with a median follow-up of around 55 months or more.

PFS clearly favored the use of the triplet therapy, with a 41-month median PFS for the patients on the triplet versus 29 months for the doublet, with a 26% reduction in risk.4

OS was also improved in patients who received the triplet. Median OS could not be reached versus 69 months for patients who were on Rd alone [HR, 0.709; 96% CI, 0.543- 0.926; P =.0114].

As expected, there was some more toxicity in patients who were on the triplet, and the main toxicity was neuropathy with VRd. Grade 3 neuropathy was about 33%.7 This is mainly because, in my opinion, the bortezomib was given every 4 days and given intravenously.

What is different about the VRd Lite regimen?

The modified VRd, also known as VRd Lite, regimen is given with bortezomib on days 1, 8, and 15; lenalidomide is given for 21 days; and dexamethasone is given on days 1, 8, and 15. So the intensity of therapy is substantially lower, with respect to both the dexamethasone and the bortezomib. In my practice, patients who are going to go for VRd Lite will probably not get 40 mg of dexamethasone weekly; rather, Ill go with 20 mg.

[From] a retrospective chart review, the ORR [with VRD Lite was] around 87%, although the number of patients was not high. The risk of peripheral neuropathy was substantially lower, at 11.6%, although it did increase in time to about 38%, mainly grade 1 and 2.8

Can you tell us more about MAIA?

The largest study that has been done recently in nontransplant- eligible patients was the MAIA study for patients who were randomized to Rd versus DRd.2 Daratumumab was given intravenously. The daratumumab was given, as we know it, weekly for the first 4 weeks, and then every 2 weeks for 4 months, and then monthly. Lenalidomide [was given at the] standard dose, 25 mg for 21 days, and dexamethasone, PO [orally] or IV weekly. The primary end point was PFS; secondary end points were the CR [complete response], VGPR [very good partial response] rates, MRD [minimal residual disease] negativity, ORR, OS, and safety. Most of these patients were elderly, 99%...being older than 65 years of age, with a median age of 73.

The median PFS has not been reached for the triplet regimen, compared to 32 months for the doublet. At 30 months, 71% of the patients on the triplet had not progressed compared to 56% who had not progressed [on the doublet]. Its too early to look at OS. The ORRs for the triplet were 93%; [there was] stringent CR in 30% and generally higher CR, VGPR, and stringent CR [rates]. MRD negativity [rate] was 24%, and this was, I believe, at the level of 10E-5. Patients who had achieved an MRD-negative state had a lower risk of progression or death in either arm.

The primary end point, PFS, clearly showed an improvement for the triplet regimen, and were seeing that patients who achieved MRD negativity, whether on the doublet or the triplet, had a better PFS. This is an important point that keeps coming up with different studies that are looking at MRD negativityachieving MRD negativity is critical, and it seems what is important is to achieve that state, not how we get it. Now, what people have not shown is whether we can stop therapy after [achieving an] MRD-negative state, or we give limited therapy after that, whether this is true for high risk or for standard risk. I think, for the standard-risk patients, if a patient with that type of disease achieves MRD negativity, one can be fairly confident that theyre going to do very well. Im not so sure about the high-risk patients. Ive had quite a few of these, where they achieve an MRD-negative state; unfortunately, it does not seem to be maintained for that long.

[Regarding] the safety characteristics from the study, the main toxicity is hematopoietic; [theres a] somewhat high risk of neutropenia and some increased risk of infections, especially respiratory infections with pneumonia, as well as sinusitis. Infusion reactions are also common, although thesemainly occur with the first and, at the most, second dose, and after that, its not an issue. Now, with the subcutaneous availability of daratumumab, the risk of infusion reactions has virtually disappeared.

How do these standard regimens compare with each other?

[PEGASUS is] an interesting study that tries to address a question that, so far, had not been looked at in a randomized study and perhaps will never occur. So, we know that VRd is considered by many [to be the] standard of care. Now we have DRd. So can one possibly determine which regimen is superior? And because no head-to-head comparison has been done, Durie et al looked at the Flatiron [Health] database, which is a large database of patients with multiple myeloma, where the medical record is available, and they did an in silico study comparing the patients on the MAIA study versus patients who had received VRd or Vd, compared to Rd.9 From the Flatiron database they could identify 2 cohorts so that they could have an internal control, so that the Rd [patients] in the Flatiron database [would do similarly] to patients in the Rd arm of the MAIA study. The study looked at DRd versus VRd, or DRd versus Vd, and they showed that the hazard ratio for response and PFS seems to be in favor of the DRd [HR, 0.54; 95% CI, 0.42-0.71; P <.001]. This is not a randomized study.

From the PEGASUS study, they could show that, at least in this in silico analysis, the patients with DRd seemed to do better compared to even patients who were on VRd or Rd.

The ENDURANCE trial [NCT01863550] was a phase 3 study through ECOG that randomized patients with newly diagnosed disease who were not planning to go to transplant, and who did not have high-risk disease, to therapy either with VRd versus KRd.10 The VRd was given as standard therapy, except that it could be given subcutaneously; the bortezomib could be given either subcutaneously or IV at physicians discretion. Arm B was carfilzomib, initially at 20 mg/m2 and then escalated to 36 mg/m2. Then, the patients were randomized a second time to either maintenance therapy with lenalidomide for 24 cycles, and then observed, or continue with lenalidomide until progression. Primary end point was OS, with 2 different maintenance strategies of lenalidomide, either fixed duration or indefinite, as well as PFS between the different induction regimens, followed by lenalidomide maintenance. In this study, the primary end point was not met. There is no difference in either PFS or OS, so far, between these 2 regimens.

The 2 arms of the study were well balanced, with a large number of patients. The ratio distribution was similar. There were patients even with an ECOG [performance status score of] 3. The distribution of ISS [International Staging System] 1, 2, or 3 was similar. Almost all the patients had to have measurable disease, fairly standard for this type of study. Virtually all patients had normal cytogenetics, or standard-risk disease. This was a defining criterion for entering the study.

There is no difference whatsoever with respect to both PFS [HR, 1.04; 95% CI, 0.83-1.31; P =.74] or OS [HR, 0.98; 95% CI, 0.71-1.36; P =.92]. At the last data cutoff, which was earlier this year, [there was a] median PFS of about 35 months for [both] these [regimens].

There was some increased risk of cardiac, renal, or pulmonary toxicity with respect to carfilzomib; this is expected. [There also was] somewhat more risk of neuropathy in patients who received bortezomib.

How would you approach patients with multiple myeloma who are eligible for transplant?

The standard approach that we take at Mayo [Clinic] with respect to patients who are considered transplant eligible [is that] if the patient has standard-risk disease, defined by trisomiestranslocation (11;14) or (6;14)we recommend 4 cycles of VRd, collection of stem cells, and then proceed to transplant. If the patient decides not to proceed with transplant, [we recommend] 4 more cycles of VRd, followed by maintenance therapy until progression.

In patients with high-risk disease, defined as deletion 17p, t(4;14), or translation (14;16) or (14;20), [we recommend] 4 cycles of KRd or quadruplet therapy. [We recommend] at least 1 transplant. In some of these patients, we consider a second transplant in tandem, based mainly on the studies from Europe that have shown that patients with high-risk disease seem to benefit from a tandem transplant, and then a proteasome-based inhibitor maintenance.

For patients with a double- or triple-hit multiple myeloma, for example, a 17p, t(4;14), or sometimes even 1q or...MYC translocation, we prefer quadruplet therapy, an autologous stem cell transplant [possibly tandem], and then proteasome inhibitor- based maintenance therapy.

What is your perspective on the results of this poll?

Intolerance seems to be the most common reason, and patient preference. I think these are valid reasons. The risk of second malignancies appears to be somewhat lower. The initial studies from France were quite concerning, but I think over the years weve learned that the risk of second malignancies with maintenance appears to be rather low. Its not 0, but probably somewhere in the range of maybe 2% to 3%. There is some risk. Even in patients who do not receive maintenance therapy, if one looks at the natural history of the disease, some...develop second malignancies independent of maintenance therapy.

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Combination Regimens for Multiple Myeloma Show Efficacy in the Transplant-Ineligible Population, According to Dingli - Targeted Oncology

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Martin Makes Sense of the Rapidly Evolving MCL Treatment Paradigm – OncLive

Wednesday, March 3rd, 2021

As more options emerge in the mantle cell lymphoma (MCL) paradigm, choosing among the agents available has become all the more challenging, according to Peter Martin, MD, who added that treatment is shifting beyond BTK inhibitors to the utilization of novel combinations and CAR T-cell therapies.

MCL, as we understand it, is a lot more complicated than just younger vs older patients. We now have 3 BTK inhibitors to choose from and that challenges us sometimes, Martin, an associate professor of medicine and chief of the Lymphoma Program at Weill Cornell Medicine, said during a presentation delivered at the 25th Annual International Congress on Hematologic Malignancies.1 More and more [often], were looking at novel combinations. We also have CAR T cells available, and we have to decide when to use them.

The original treatment algorithm for the disease was based mostly on the agent and fitness of the patients. Specifically, younger patients receiving more intensive approaches comprised of a cytarabine-based induction, followed by autologous stem cell transplant, followed by maintenance treatment with rituximab (Rituxan), according to Martin. Older patients primarily were given bendamustine plus rituximab, potentially followed by maintenance rituximab.

This algorithm has become more complicated in the past few years. Patients with indolent MCL, defined as being asymptomatic with a low tumor burden, a low Ki-67 score, and normal lactate dehydrogenase, without TP53 aberrations, is appropriate for a watch-and-wait approach, according to Martin.

Patients who are considered to have superhigh risk MCL, defined by having blastoid morphology, a high Ki-67 level, and TP53 alterations, pose more of a challenge. No one really knows how to manage those patients, admitted Martin. Its clear that high-dose chemotherapy is not very effective, and we suspect that many of these patients should be headed toward the use of CAR T cells.

Treatment decisions for patients who fall within the middle of the spectrum can be considered based on whether they have leukemic, non-nodal disease vs nodal disease, added Martin. Although approaches will differ depending on disease proliferation, many patients should be able to receive novel agents similar to what we have been doing with chronic lymphocytic leukemia [CLL], where chemotherapy is no longer relevant.

In his presentation, Martin discussed choosing among the BTK inhibitors available for use in MCL and how to choose among them, highlighted novel combination regimens that are under exploration and are showing early promise, and shed light on setting certain patients up for CAR T-cell therapy earlier rather than later.

Weighing the 3 BTK Inhibitors Available in the Arsenal

In November 2013, the FDA granted an accelerated approval to ibrutinib (Imbruvica) for use in patients with MCLwho had received at least 1 previous therapy. The decision was based on data from the single-arm, phase 2 PCYC-1104 trial (NCT01236391), where the agent elicited an overall response rate (ORR) of 67%, with a complete response (CR) rate of 23% in the overall study population.2 Data from a combined analysis of 3 different trials with ibrutinib showed that the median progression-free survival (PFS) ranged from 10.5 months to 15.6 months.3

To me, this indicates that the efficacy of these drugs is defined less by the drug and more by the patient population taking the drug, noted Martin. That is very critical to remember when we look at all of the available agents.

Four years later, in October 2017, the second-generation BTK inhibitor acalabrutinib (Calquence) was FDA approvedfor the same indication based on data from the phase 2 ACE-LY-004 trial (NCT02213926). Here, the agent resulted in an 81% ORR per investigator assessment, with a CR rate of 40%.4 Updated data presented during the 2020 ASH Annual Meeting and Exposition showed that the median PFS with the agent was 22.0 months.5

Most recently, in November 2019, zanubrutinib (Brukinsa) was given the green light from the FDA for use in this population. The approval was based on data from 2 single-arm studies (NCT03206970 and NCT02343120) which showed that the BTK inhibitor induced an ORR of 83.7%.6 Notably, however, the agent tends to be a little less active in patients with blastoid histology and a higher Mantle Cell Lymphoma International Prognostic Index (MIPI) score, added Martin.

We have been forced to become pharmacists and pharmacologists more than we ever expected in that when were using these medications, we have to be very aware of drug-drug interactions, warned Martin. All have significant interactions with CYP3A inhibitors and inducers, although ibrutinib probably has the greatest interaction with [those drugs]. However, acalabrutinib and zanubrutinib also tend to be impacted by CYP3A inhibitors and we may need to watch out for toxicity.

Additionally, acalabrutinib appears to have a significant interaction with gastric acidreducing agents, added Martin.

Taking a Closer Look at Toxicities

When choosing among the 3 options that are available, Martin mentioned that its important to look at the safety profiles of the agents. One nice thing about adverse effects [AEs] is that theyre disease agnostic, so we can look at other clinical trials in other diseases to look at the toxicities [of these agents], said Martin. CLL is a nice one to look at because patients are typically on these agents longer, so we can get a better idea of safety profiles, overall.

In one clinical trial, investigators examined the use of acalabrutinib in patients who were intolerant to ibrutinib. Results indicated that most of the toxicities that had been reported with ibrutinib, that required patients to stop treatment with the agent, did not recur, according to Martin. Moreover, the effects that did recur, were found to be of a lower grade.7 The ORR was 75.8%, so not all of the patients who stopped ibrutinib for tolerability responded to acalabrutinib, which I thought was interesting, noted Martin.

Data from the phase 3 ELEVATE-RR trial (NCT02477696) showed that acalabrutinib demonstrated noninferior PFS to ibrutinib in previously treated patients with high-risk CLL, meeting the primary end point of the trial.8 Notably, patients who received acalabrutinib also experienced a statistically significant lower incidence of atrial fibrillation vs those who were given ibrutinib. So, [we saw] similar efficacy with less atrial fibrillation, which I think is relevant, added Martin.

Additionally, data from the phase 3 ASPEN trial (NCT03053440) showed similar efficacy with zanubrutinib vs ibrutinib in patients with Waldenstrm macroglobulinemia.9 However, investigators also noted that zanubrutinib had a lower rate of atrial fibrillation compared with ibrutinib, at 2.0% vs 15.3%, respectively. [Zanubrutinib] also had a potentially lower rate of major hemorrhage [vs ibrutinib], noted Martin, at 5.9% vs 9.2%, respectively.

Moving Beyond Single Agents: Novel Combinations Under Exploration

The phase 2 AIM trial (NCT02471391) is examining the use of ibrutinib plus the BCL-2 inhibitor venetoclax (Venclexta) in 23 patients who had relapsed/refractory MCL (n = 23) or were treatment nave but not candidates for chemotherapy (n = 1).10,11 Results demonstrated that the regimen led to a median PFS of 29 months. Sixty-seven percent of patients were minimal residual disease (MRD) negative in the bone marrow per flow cytometry (n = 19), while 38% were negative in the peripheral blood (n = 16).

What is most interesting to me is that at 16 weeks, the majority of patients were negative [for MRD], which [indicates] a very rapid response and I think that may mean something, said Martin.

Another combination under investigation is that of ibrutinib, lenalidomide (Revlimid), and rituximab. This triplet regimen is being explored as part of the phase 2 Nordic MCL6 PHILEMON trial (NCT02460276) in patients with relapsed/refractory MCL.12 Results from the trial showed that at a median follow-up of 17.8 months, the ORR with the triplet was 76% (n = 38/50), with a CR rate of 56% (n = 28).

Here, it appeared that the TP53 mutation held less sway than it does with chemotherapy, noted Martin. I think looking at TP53 one way or another is really critical in MCL and targeting those patients toward novel agents and potentially combinations of novel agents will become increasingly relevant.

In the follow-up, phase 1/2 Nordic MCL7 VALERIA trial (NCT03505944), investigators examined venetoclax, lenalidomide, plus rituximab in patients with relapsed/refractory MCL and found that a response-adapted treatment strategy, by stopping treatment in molecular remission, was feasible.13 [The combination] did not seem to be quite as effective as ibrutinib/lenalidomide and there was a small number of patients, said Martin. What I liked about this design was the continual reassessment of MRD and the potential to stop treatment. We dont have a lot of follow-up data but this approach to treatment is attractive as we move toward combinations.

Another novel combination that is under exploration in a phase 1 trial (NCT02158755) is that of ibrutinib and the CDK4/6 inhibitor palbociclib (Ibrance) in patients with relapsed/refractory MCL.13 We have significant data that suggest that palbociclib can sensitize lymphoma cells to cell killing by other drugs including ibrutinib, Martin explained. The phase 1 trial showed a [2-year] PFS [rate] of 59%. The regimen is now under exploration in a phase 2 trial (NCT03478514) led by Kami J. Maddocks, MD, of The Ohio State University Comprehensive Cancer CenterJames.

Determining When to Set Patients Up for CAR T

When we see patients with high MIPI scores, with multiple prior lines of therapy, and especially very proliferative diseases with blastoid histology, we can predict that these patients may have a response [to BTK inhibitors], but it will be a suboptimal response; it will be a very short response, noted Martin. We also know that when these patients progress, their responses are going to be very short, and well need to move very quickly. My bias in looking at these patients, before even starting a BTK inhibitor, is to say that they will likely need CAR T cells within the next few months, and Ill set them up to receive them.

Data from the phase 2 ZUMA-2 trial (NCT02601313) examining the CAR T-cell product brexucabtagene autoleucel (KTE-X19) has shown that this modality can be effective in patients who are refractory to BTK inhibitors.14 Data from 60 patients with MCL who were treated on the trial showed that the product led to an ORR of 93% with a CR rate of 67% at a median follow-up of 12.3 months. Additionally, 57% of all participants proved to have durable responses.

Its still a bit too early to say how this is going to plateaubut the key is to target these patients toward CAR T cells because once they start progressing on BTK inhibitors, were really in trouble and so we need to think about this early on, concluded Martin. We also may find that blastoid histology does respond to CAR T cells well according to CR rates, but the OS may be a little bit less than what we see with regular MCL. Getting those patients toward CAR T cells early on is probably going to be critical.

References

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Martin Makes Sense of the Rapidly Evolving MCL Treatment Paradigm - OncLive

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Hoth Therapeutics Expands License Agreement to Include Innovative Cancer and Anaphylactic Treatment – BioSpace

Wednesday, March 3rd, 2021

NEW YORK, Feb. 26, 2021 /PRNewswire/ --Hoth Therapeutics, Inc. (NASDAQ: HOTH), abiopharmaceutical company, todayannounced it has expanded its licensing agreementfrom North Carolina State University ("NC State") to include the worldwide development and commercialization of treatments targeting mast cell derived cancers and anaphylaxis.

The application of this newly licensed indication will be developed as a novel therapy ("HT-KIT") and shares the same molecular class as the Hoth's current HT-004 drug. Both treatments are being developed by Dr. Glenn Cruse, Assistant Professor at NC State. Dr. Cruse is a leading mast cell biologist in allergic and inflammatory diseases formerly from the National Institute of Health and currently a Hoth Scientific Advisory Board member. Dr. Cruse has been developing this technology with his team at NC State since 2017 and has generated initial proof-of-concept data in a neoplastic cell line supporting the novel activity of this therapeutics.

"We are delighted to expand this strategic alliance with NC State and our Scientific Advisory Board member, Dr. Glenn Cruse," saidRobb Knie, CEO of Hoth Therapeutics. "We believe that the HT-KIT pathway is a promising novel target for combating both mast cell-derived cancers and mast cell-mediated anaphylaxis. This expanded license agreement highlights the broad potential of our diverse pipeline that is aimed at meeting critical unmet patient needs and further supports Hoth's strategy to build a sustainable therapeutics company that is patient focused."

The HT-KIT drug is designed to more specifically target the receptor tyrosine kinase KIT in mast cells, which is required for the proliferation, survival and differentiation of bone marrow-derived hematopoietic stem cells. Mutations in the KIT pathway have been associated with several human cancers, such as gastrointestinal stromal tumors and mast cell-derived cancers (mast cell leukemia and mast cell sarcoma). Based on the initial proof-of-concept success, Hoth intends to initially target mast cell neoplasms for development of HT-KIT, which is a rare, aggressive cancer with poor prognosis.

The same target, KIT, also plays a key role in mast cell-mediated anaphylaxis, a serious allergic reaction that is rapid in onset and may cause death. Anaphylaxis typically occurs after exposure to an external allergen that results in an immediate and severe immune response. Hoth also intends to pursue the anaphylaxis indication for HT-KIT in parallel to cancer treatment and HT-004 development.

About Hoth Therapeutics, Inc.

Hoth Therapeutics, Inc. is a clinical-stage biopharmaceutical company focused on developing new generation therapies for unmet medical needs. Hoth's pipeline development is focused to improve the quality of life for patients suffering from indications including atopic dermatitis, skin toxicities associated with cancer therapy, chronic wounds, psoriasis, asthma, acne, and pneumonia. Hoth has also entered into two different agreements to further the development of two therapeutic prospects to prevent or treat COVID-19. To learn more, please visitwww.hoththerapeutics.com.

Forward-Looking Statement

This press release includes forward-looking statements based upon Hoth's current expectations which may constitute forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995 and other federal securities laws, and are subject to substantial risks, uncertainties and assumptions. These statements concern Hoth's business strategies; the timing of regulatory submissions; the ability to obtain and maintain regulatory approval of existing product candidates and any other product candidates we may develop, and the labeling under any approval we may obtain; the timing and costs of clinical trials, the timing and costs of other expenses; market acceptance of our products; the ultimate impact of the current Coronavirus pandemic, or any other health epidemic, on our business, our clinical trials, our research programs, healthcare systems or the global economy as a whole; our intellectual property; our reliance on third party organizations; our competitive position; our industry environment; our anticipated financial and operating results, including anticipated sources of revenues; our assumptions regarding the size of the available market, benefits of our products, product pricing, timing of product launches; management's expectation with respect to future acquisitions; statements regarding our goals, intentions, plans and expectations, including the introduction of new products and markets; and our cash needs and financing plans. There are a number of factors that could cause actual events to differ materially from those indicated by such forward-looking statements. You should not place reliance on these forward-looking statements, which include words such as "could," "believe," "anticipate," "intend," "estimate," "expect," "may," "continue," "predict," "potential," "project" or similar terms, variations of such terms or the negative of those terms. Although the Company believes that the expectations reflected in the forward-looking statements are reasonable, the Company cannot guarantee such outcomes. Hoth may not realize its expectations, and its beliefs may not prove correct. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including, without limitation, market conditions and the factors described in the section entitled "Risk Factors" in Hoth's most recent Annual Report on Form 10-K and Hoth's other filings made with the U. S. Securities and Exchange Commission. All such statements speak only as of the date made. Consequently, forward-looking statements should be regarded solely as Hoth's current plans, estimates, and beliefs. Investors should not place undue reliance on forward-looking statements. Hoth cannot guarantee future results, events, levels of activity, performance or achievements. Hoth does not undertake and specifically declines any obligation to update, republish, or revise any forward-looking statements to reflect new information, future events or circumstances or to reflect the occurrences of unanticipated events, except as may be required by applicable law.

Investor Contact:LR Advisors LLCEmail:investorrelations@hoththerapeutics.comwww.hoththerapeutics.comPhone: (678) 570-6791

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SOURCE Hoth Therapeutics, Inc.

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Health Matters; Inflammation with Dr. Baumgartner [PODCAST] – WJON News

Sunday, February 14th, 2021

This week on WJON's Health Matters program I was joined by Dr. Joel Baumgartner from Rejuv Medical to talk about "Inflammation". He says inflammation doesn't always have to be bad. Dr. Baumgartner says degeneration is bad while inflammation can be good. He says if someone has a injured ankle they can see inflammation in the area signaling healing but sometimes the inflammation can be too much. Inflammation can be caused by a lack of sleep, what we eat, stress and many other triggers. Listen to our 4-part conversation below.

Dr. Baumgartner says at Rejuv Medical they can help treat inflammation in a variety of ways. He says PRP and Stem Cell replacement can be options for those looking to solve what has been chronic pain. Baumgartner says all Stem Cell replacement procedures involve PRP as part of the process to help trigger healing. Many people use anti-inflammatory pills to help with pain but he says some of those can have long-term negative effects. He warns against depending on those to get through chronic inflammation. He also suggests stretching, a proper diet, enough sleep, reduce stress and exercise meant to support the problem area.

Learn more about how Rejuv Medical can help. Health Matters airs on WJON Mondays and Saturdays from 9:10-10.

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Health Matters; Inflammation with Dr. Baumgartner [PODCAST] - WJON News

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G1 Therapeutics gains first FDA nod with myelopreservation therapy Cosela | 2021-02-12 – BioWorld Online

Sunday, February 14th, 2021

As expected, G1 Therapeutics Inc.s Cosela (trilaciclib) won FDA approval for use in extensive-stage small-cell lung cancer (SCLC) patients undergoing chemotherapy, becoming the first proactively administered myelopreservation therapy to hit the market.

The approval, conducted under the FDAs priority review, came late Feb. 12, just ahead of its Feb. 15 PDUFA date. Pricing has not yet been disclosed, but Research Triangle Park, N.C.-based G1 spent the latter half of 2020 prepping for commercial launch in the first quarter of 2021, with marketing, medical affairs and manufacturing operations fully in place and a field sales team from U.S. partner Boehringer Ingelheim GmbH trained and ready, the company reported during its presentation at the 2021 J.P. Morgan Healthcare Conference.

There are roughly 30,000 ES-SCLC patients treated annually in the U.S.

Chemotherapy remains the primary therapy for SCLC etoposide, topotecan, irinotecan and platinum-based drugs such as cisplatin or carboplatin, for example but its use results in damage to bone marrow stem cells, leading to myelosuppression. That, in turn, results in symptoms such as anemia, neutropenia or thrombocytopenia, which not only affects patients quality of life but can also disrupt treatment cycles and impact overall survival.

Some drugs are available to mitigate the damage. G-CSF drugs, for instance, are designed to prevent febrile neutropenia resulting from chemotherapy and erythropoiesis-stimulating agents are used to keep anemia in check. But those usually have their own treatment-limiting side effects.

Preserving immune function

Trilaciclib, a CDK4/6 inhibitor that received an FDA breakthrough therapy designation, is designed to preserve bone marrow and immune system function during chemotherapy treatment. Approval was based on data pooled from three pivotal studies that read out over 2018 and 2019.

In December 2018, G1 reported top-line data from its randomized, double-blind, placebo-controlled phase II trial evaluating combination of the therapy with topotecan as a treatment for second- and third-line SCLC, showing trilaciclib reduced clinically relevant consequences of myelosuppression vs. placebo. The trilaciclib arm demonstrated statistically significant reductions in both the duration of grade 4 neutropenia in cycle one (mean eight days vs. two days; adjusted one-sided p<0.0001) and occurrence of grade 4 neutropenia (75.9% vs. 40.6%; adjusted one-sided p=0.0160) as compared to the placebo arm.

Data from a phase II study testing trilaciclib with the combination of etoposide/carboplatin for the treatment of first-line SCLC demonstrated clinically meaningful improvements for neutrophil, red blood cell and lymphocyte measures in patients vs. placebo. In regard to lymphocytes, in particular, trilaciclib preserved or improved B-cell and T-cell subset counts, including activated CD8-positive cells, and increased CD8-positive/regulatory T-cell and activated CD8-positive/regulatory T-cell ratios in peripheral blood compared to placebo.

It also showed benefit in another phase II study in combination with chemotherapy and Tecentriq (atezolizumab), the PD-L1 inhibitor from Roche Holding AG. Data showed statistically significant improvements in both primary endpoints of occurrence of grade 4 neutropenia and duration of grade 4 neutropenia in cycle one, as well as a statistically significant reduction in grade 4 thrombocytopenia and clinically meaningful reduction in red blood cell transfusions. Trilaciclib reduced clinically relevant consequences of myelosuppression vs. placebo when administered in combination with chemotherapy (etoposide and carboplatin) and Tecentriq across neutrophils, red blood cells and platelets.

An established sales team

G1s three-year, SCLC-focused co-promotion deal with Boehringer, inked in June 2020, calls for G1 to lead marketing, market access and medical engagement initiatives, which are expected to extend to a focus on updating NCCN clinical practice guidelines to include trilaciclib. Boehringer brings to the table the established lung cancer sales team. Under the terms, G1 will book revenue and retain development and commercialization rights, paying Boehringer a promotion fee determined by net sales.

H.C. Wainwright analyst Edward White in Nov. 5, 2020, note, said he estimates trilaciclib sales of $21.4 million in 2021.

G1 also is looking to expand use of the drug beyond SCLC. In December, the company reported phase II data at the San Antonio Breast Cancer Symposium showing significantly improved overall survival in patients with triple-negative breast cancer (TNBC) treated with trilaciclib in combination with gemcitabine/carboplatin (GC) vs. GC alone. G1 plans to launch a registrational study this year to test trilaciclib plus GC in first-line patients with metastatic TNBC who have not received a PD-1/PD-L1 inhibitor and in second-line patients with metastatic TNBC who have received prior PD-1/PD-L1 therapy.

Trilaciclib also is included in the ongoing pivotal I-SPY 2 study in neoadjuvant breast cancer.

In August 2020, G1 licensed greater China rights for trilaciclib to Simcere Pharmaceutical Co. Ltd. in a $170 million deal.

Shares of G1 (NASDAQ:GTHX) were trading up 12% in after-hours trading Feb. 12.

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G1 Therapeutics gains first FDA nod with myelopreservation therapy Cosela | 2021-02-12 - BioWorld Online

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Kris Gopalakrishnan on innovation – Fortune India

Sunday, February 14th, 2021

Your familys philanthropic foundation, Pratiksha Trust, has also invested in brain research. In 2014, it donated 225 crore to set up the Centre for Brain Research (CBR), at IISc. How is that going?

There are two interesting projects the CBR is pursuing. The first one is a longitudinal study. It is studying 10,000 people over a period of 10 years in Kolar [district, in Karnataka] to see how the brain ages. These people are healthy individuals without dementia, aged 45 years and above.

There have been some hiccups in conducting the study and collecting data due to the pandemic. But it will restart soon. Till now, they have covered more than 2,000 people. It will be the first comprehensive database of Indian subjects on how they age. Theres a similar study done by CBR on urban subjects in Bengaluru which is funded by the Tata Trusts. The studies show interesting insights and the contrasting lifestyle between people in urban and rural areas.

The second programme is the Genome India Project (GIP) which is supported by the Department of Biotechnology [under the ministry of science and technology]. CBR at IISc is one of the over 20 labs involved in the project across the country. [The project aims to collect over 10,000 genetic samples from people across India to build a reference genome.] We dont have a comprehensive database of DNA sequences of Indian subjects. Besides my grant of 225 crore, there are other research programmes that I support. Overall, my support for research work alone is approximately 400 crore, currently spanning across brain, brain sciences, stem cell research, and others.

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Change is coming, and at an ever-accelerating pace – Al Jazeera English

Tuesday, January 12th, 2021

One of the great science and technology stories of 2020 is the development of COVID-19 vaccines, from start, through testing, to delivery, at a rate never seen before. Not just one vaccine. Three. (With more on the way and not counting the vaccines already in use in China and Russia.) All able to pass rigorous tests and examinations.

Two of them came from Big Pharma.

They threw lots of money and lots of researchers at the problem. We have been taught to expect that that is what they do for us. One of the reasons we think that maybe the primary one is that Big Pharma has thrown lots of money and employed lots of experts to tell us how very useful they are.

The throwing the money part seems to be true of Pfizer. But not for the others.

The US government put between $10bn and $18bn into Operation Warp Speed. Several of the programmes main recipients Johnson & Johnson, Novavax, Sanofi with GlaxoSmithKline have yet to deliver a successful vaccine. Moderna, which has, got about $2.5bn.

A headline from Scientific American stated cogently and concisely: For Billion-Dollar COVID Vaccines, Basic Government-Funded Science Laid the Groundwork. The subhead pointed out: Much of the pioneering work on mRNA vaccines was done with government money, though drugmakers could walk away with big profits.

The third vaccine came from Oxford University (In association with AstraZeneca which is Big Pharma and which received substantial sums from Operation Warp Speed). It appears to be much easier to use. It is going to market at about $6-8 for two doses. Compared with $40 for Pfizer and $50-74 for Moderna, per pair. (A fun fact is that these prices are about 25 percent higher in the US than in the European Union). This should remind us that much of the most important work in medicine has come out of universities and that contributing to health and making money are two separate things.

A far more obscure science and technology story appeared on the front page of the business section of the New York Times on December 29, 2019. It is about a guy named Mike Strizki.

Strizkis story is a throwback to the days of individual tinkerer-inventors. People like that telegraph operator, Thomas Edison, those bicycle mechanics, the Wright Brothers, and a daughter of American aristocracy, Mary Phelps Jacob who was later scandalously famous for her wild parties, drug use, open marriage, her whippet named Clytoris, and being the co-founder of the Black Sun Press, making her the literary godmother to the Lost Generation of expatriate writers in Paris who invented the modern brassiere when she was nineteen.

Strizki is the only guy on the East Coast who drives a hydrogen car.

There are more on the West Coast, nearly 9,000, plus 48 buses. They have 42 stations where they can refuel. There are none on the East Coast. Therefore, Mike makes his own hydrogen fuel in his back yard using solar power. The only byproduct from the process is one atom of oxygen for every two atoms of hydrogen. When the hydrogen is put through fuel cells creating the electricity that drives the car, it recombines with oxygen and the only byproduct is water.Such cars routinely go about 484 kilometres (300 miles) on a full tank. Hyperion claims they have a car that gets a bit over 1,609km (1,000 miles) on a single tank. Refilling them is quicker than refilling the gas tank on the old fashioned internal combustion vehicles most of us drive. They do not have to drag about 453 kilogrammes (1,000 pounds) of batteries like full electric vehicles. Yet, Elon Musk of Tesla, who is hugely invested in battery power cars, calls hydrogen fuel cell cars staggeringly dumb.

Mike has also made the first house in the United States to be powered entirely by hydrogen produced on-site using solar power. Keep in mind that Steve Jobs of Apple, Bill Gates of Microsoft and Mark Zuckerberg of Facebook all could be in that category of tinkerer-inventor, at least at their start.

Right now, Elon Musk and his Teslas seem way out ahead of Strizki and his single hydrogen vehicle. But that contest is far from over. Watch for the HTWO, Hyundais new brand dedicated to hydrogen fuel cell power. Daimler Truck, Iveco, OMV, Shell and the Volvo Group are in an alliance named H2Accelerate to promote hydrogen powered trucks.

The point of both of these stories the one about Big Pharma, Big Money, Big University and the other one about the home tinkerer is that science and technology are moving faster and faster.

We are moving closer to actual fusion power. The best research for it seems to be coming out of South Korea. Water cell batteries may soon replace lithium-ion batteries. Check your phone, youve got a computer in your pocket. Quantum computing is on the way. The exponential increase in the amount of material travelling over the internet means we need much greater communication capacity. It is happening. We have gone from megahertz, one million cycles per second, to gigahertz, a billion, and we are on the way to terahertz frequencies, a trillion cycles per second. 3D metal printing is here. Babel earbuds which translate as you go are ready though I must say if its translations are like the ones I get online, it may be like an illiterate babbling in your ear. An Alzheimers blood test may soon be on the market. We can now make artificial structures that mimic early embryos using only stem cells no egg or sperm necessary.

Human history, for the most part, has been a long, flat line of subsistence economies. There were brilliant moments with small brilliant elites but they always rested on the agricultural labour of peons, serfs, slaves, or peasants and fell back again. It was such from the beginning of time until about 1800 with the First Industrial Revolution. Since then, the curve of productivity has been on an upward climb. The 19th and early 20th century is often called the Second Industrial Revolution. We are now in the third, or fourth, or even the fifth industrial revolution or maybe it is the Post-Industrial Revolution or the Digital Age depending on whose book you are reading. Whatever name you prefer to give to this current period, its defining feature remains the same: The changes are coming faster and faster. They are reaching more and more people. They are coming from more and more people.

Yes, of course, we know from the machine guns of WWI, the bombers and then the nuclear weapons of WWII, that technology can be used for destruction. The speed and almost zero cost of internet communication have freed us from the grip of media barons and governments, but then opened the way for exploitation and the spread of disinformation, the existence of alternative facts and tribal truths. Even the changes that would be rated as positive for the general good, are often negative for specific individuals.

We may have anti-science governments. Like the Trump administration has so obviously and obnoxiously been. Yet while they muddled the airwaves with disinformation about the pandemic, they were also the ones who threw billions to science to come up with a vaccine. Big Oil ran campaigns denying climate change, modelled on Big Tobaccos past campaigns claiming cigarettes do not cause cancer,. Yet most of the major oil companies are investing in alternative energy technology.

Big Money invested in established business resists change. Speculative Money and theres lots of it wants to bet on the next big thing which usually has to be, by definition, based on new science and new technology.

This election cycle weve seen that the Internet and social media can do black magic, spreading disinformation, misinformation, and lots of outright lies. They also mean that real information from grammar school to graduate school and beyond is getting to be within reach of the whole world. Its a two-way street. Information, ideas, and research can zip in an instant from a mountain village, a yurt in the desert, public housing, to Harvard, Tohoku, and Oxford.

It would be wonderful if politicians, public intellectuals (if they still exist), sociologists, and economists (should they wish to deal with realities rather than models), turned their thinking and their efforts into figuring out how we as societies and as individuals can best deal with all this change.

Whether they do or they do not, the changes will come, are coming, are here, at that ever-accelerating rate.

The views expressed in this article are the authors own and do not necessarily reflect Al Jazeeras editorial stance.

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Change is coming, and at an ever-accelerating pace - Al Jazeera English

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MCL Landscape Adapts to Changes After CAR T-Cell Therapy Approval – OncLive

Saturday, January 9th, 2021

Despite the introduction of CAR T-cell therapy to the mantle cell lymphoma (MCL) armamentarium, induction therapy followed by stem cell transplant has maintained a role, said James Gerson, MD, who added that he continues to recommend transplant for patients, since they are still eligible for CAR T-cell therapy upon relapse on transplant.

I tell patients that we have very long-term data that a consolidative transplant for those who are eligible leads to a prolonged remission, Gerson explained. If a patient can be in remission for 10 years, maybe 10 years from now we will have something that is even better and more tolerable than CAR T-cell therapy.

In July 2020, the FDA approved brexucabtagene autoleucel (Tecartus) for the treatment of adult patients with relapsed/refractory MCL. The indication was based on findings from the phase 2 ZUMA-2 trial where brexucabtagene autoleucel, given as a single infusion, induced an 87% objective response rate and a 62% complete response rate in this patient population.

Unlike in diffuse large B-cell lymphoma where more restrictions [with CAR T-cell therapy] exist, any patient with MCL who had 1 prior therapy and relapsed can go straight to CAR T-cell therapy, Gerson said. We can use BTK inhibitors to bridge them, but we dont have to. There are a lot of possibilities.

Though not yet planned, further studies evaluating CAR T-cell therapy in the frontline setting for patients with high-risk MCL may be worth exploring, said Gerson.

In an interview with OncLive during a 2020 Institutional Perspectives in Cancer webinar on hematologic malignancies, Gerson, an assistant professor of clinical medicine at Penn Medicine, discussed navigating treatment selection amid the approval of CAR T-cell therapy in MCL and the role of transplant after induction therapy.

OncLive:What induction regimens do you consider for your patients with MCL and how do you select between possible options?

Gerson: For young, fit patients, there is really no right answer for induction therapy because [treatment selection] is based on phase 2, nonrandomized data. Typically, induction therapy involves high-dose chemotherapy. Im actually very intrigued by a recent publication from the French group that looked at obinutuzumab [Gazyva] with DHAP [dexamethasone, cytarabine, and cisplatin; O-DHAP] as frontline therapy for young patients prior to consolidative transplant.

Ive used a lot of R-DHAP [rituximab (Rituxan) plus DHAP], but I havent used this O-DHAP. I think there is rationale to be excited about that option. Even though it is a phase 2 trial, it should [yield] reasonable data to take to insurance and get approval for. Again, it is not something Ive given, but Im very compelled by it and it is something I will try in the coming months.

Then, [we] usually follow [induction therapy] with a stem cell transplant for patients who are eligible.

In the relapsed setting, second-line BTK inhibition is pretty much the standard of care now. There is no right answer between [ibrutinib (Imbruvica) and acalabrutinib (Calquence)]. Anecdotally and by some limited published data, ibrutinib seems to have a higher occurrence of adverse effects [AEs]. Acalabrutinib is a little bit different but seems to be more tolerable in the long run. I tend to tell patients that and then they tend to want the medication that probably has fewer AEs. A lot of us end up choosing acalabrutinib, but from an efficacy standpoint, we have no comparative data. The curves are pretty similar when we look between the 2 trials.

In the era of cellular therapy, what is the role of transplant in MCL?

The challenge, of course, is that with the FDA approval of brexucabtagene autoleucel and CAR T-cell therapy coming into MCL, it is hard to know if we should still be transplanting patients. No one knows the answer because it is obviously not something that has been explored. The only thing that is known is that patients who have been transplanted can still go forward with [CAR T-cell] therapy and respond quite well. Therefore, it is not that getting a transplant means a patient cannot get CAR T-cell therapy in the future.

[With that], I usually tell my patients not to skip transplant because of the approval of brexucabtagene autoleucel in the relapsed/refractory setting. That said, it is an individualized choice. Certainly, some patients might make that choice not to undergo a transplant now that CAR T-cell therapy is available to them should they relapse. Still, in my practice, I will still offer transplant to a patient who is young and fit as a consolidative measure after induction therapy.

Do you see CAR T-cell therapy gaining a more significant role in MCL? Will it eventually moveinto the frontline setting?

Right now, the label given to brexucabtagene autoleucel was very open, [encompassing] any relapsed/refractory patient [with MCL]. That is great not only for patients but for practicing physicians.

[Bringing CAR T-cell therapy to] the frontline setting will likely be investigated in the future, especially for high-risk patients with high MIPI [Mantle Cell Lymphoma International Prognostic Index] scores,TP53mutations, blastoid variant MCL, or pleomorphic variant MCL. [These features] tend to [confer] worse outcomes. There are areas where using [CAR T-cell therapy] in the frontline setting is worth looking into.

It is completely up to the company whether they want to pursue it. Otherwise, it is going to be left to investigator-initiated trials, which are going to be difficult because of the cost associated with CAR T-cell therapy. Some centers may pursue using homegrown CAR T-cell therapy where the cost is much lower for some of these high-risk patients, but I hope the company will pursue such trials in the frontline setting.

What other regimens are potentially on the horizon in MCL and how could they best fit into the paradigm?

There are a lot of similarities between chronic lymphocytic leukemia [CLL] and MCL. A similar triplet strategy to ibrutinib, obinutuzumab, and venetoclax [(Venclexta) in CLL] is being looked at in frontline and relapsed/refractory MCL. That is incredibly exciting and could very well supplant typical [cytarabine]-based induction and transplant. We will need long-term follow-up, so we probably wont know for many years.

Thankfully, with minimal residual disease [MRD], we will possibly be able to know much sooner, because if we can get a large percentage of patients into an MRD-negative state, that is a proxy for outcome. Again, we wont know for probably about 10 years before we get that long-term follow-up, but we will have a good enough idea if we [should] use MRD as a surrogate end point.

Reference

Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Eng J Med. 2020;382(14):1331-1342. doi:10.1056/NEJMoa1914347

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MCL Landscape Adapts to Changes After CAR T-Cell Therapy Approval - OncLive

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