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New Jersey, United States,-The Human Mesenchymal Stem Cells (hMSC) Market report provides in-depth knowledge and insights into the Human Mesenchymal Stem Cells (hMSC) market in terms of market size, market share, factors influencing growth, opportunities, and current and emerging trends. The report has the updated and latest information on the Human Mesenchymal Stem Cells (hMSC) market that has been further validated and verified by industry experts and professionals. The Human Mesenchymal Stem Cells (hMSC) market report provides historical, current, and forecast estimates of sales generation and profit for each segment and sub-segment of the Human Mesenchymal Stem Cells (hMSC) market in every key region around the world. The report also highlights the emerging growth opportunities in the business that are designed to support market growth.

The latest report is the latest study to offer 360 coverage of the Human Mesenchymal Stem Cells (hMSC) industry, which is facing the worst negative economic impact of the COVID-19 outbreak since the beginning of this year.

The report covers the following key players in the Human Mesenchymal Stem Cells (hMSC) Market:

PromoCell ThermoFisher KURABO Lifeline Cell Technology Merck

Segmentation of Human Mesenchymal Stem Cells (hMSC) Market:

The report provides an in-depth analysis of various market segments based on the product line, applications, major regions, and key companies in the industry. In addition, the report has a single section that provides a detailed analysis of the manufacturing process and includes information gathered from primary and secondary data collection sources. The main source for data collection is interviews with industry experts who provide accurate information about the future market scenario.

By the product type, the market is primarily split into:

Umbilical Cord Matrix hMSC Bone Marrow hMSC Adipose Tissue hMSC Other

By the application, this report covers the following segments:

Medical Application Research Other Applications

Human Mesenchymal Stem Cells (hMSC) Market Report Scope

Human Mesenchymal Stem Cells (hMSC) Geographic Market Analysis:

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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Human Mesenchymal Stem Cells (hMSC) Market Size 2021 | Global Trends, Business Overview, Challenges, Opportunities and Forecast to 2027 The Bisouv...

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.

1. Board WCoTE. Breast Tumours. Lyon, France: Interantional Agency for Research on Cancer; 2019.

2. Reis-Filho J, Gobbi H, McCart Reed A, et al. Metaplastic Breast Cancer. Board WCoTE, editor. Breast Cancer. Lyon, France: International Agency for Research on Cancer. 2019. 135138.

3. Schroeder MC, Rastogi P, Geyer CE, Miller LD, Thomas A. Early and Locally Advanced Metaplastic Breast Cancer: presentation and Survival by Receptor Status in Surveillance, Epidemiology, and End Results (SEER) 20102014. Oncologist. 2018;23(4):481488.

4. Lei T, Pu T, Wei B, et al. Clinicopathologic characteristics of HER2-positive metaplastic squamous cell carcinoma of the breast. J Clin Pathol. 2020.

5. Hennessy BT, Gonzalez-Angulo AM, Stemke-Hale K, et al. Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res. 2009;69(10):41164124.

6. Taube JH, Herschkowitz JI, Komurov K, et al. Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc Natl Acad Sci U S A. 2010;107(35):1544915454.

7. Fougner C, Bergholtz H, Norum JH, Sorlie T. Re-definition of claudin-low as a breast cancer phenotype. Nat Commun. 2020;11(1):1787.

8. Ai D, Yao J, Yang F, et al. TRPS1: a highly sensitive and specific marker for breast carcinoma, especially for triple-negative breast cancer. Mod Pathol. 2020.

9. Rakha EA, Coimbra ND, Hodi Z, Juneinah E, Ellis IO, Lee AH. Immunoprofile of metaplastic carcinomas of the breast. Histopathology. 2017;70(6):975985.

10. Rakha E, Quinn CM, Pia Foschini M, et al. Metaplastic carcinomas of the breast without evidence of epithelial differentiation: a diagnostic approach for management. Histopathology. 2020. doi:10.1111/his.14290

11. McCart Reed AE, Kalaw E, Nones K, et al. Phenotypic and molecular dissection of Metaplastic Breast Cancer and the prognostic implications. J Pathol. 2019;247(2):214227. doi:10.1002/path.5184

12. Rayson D, Adjei AA, Suman VJ, Wold LE, Ingle JN. Metaplastic breast cancer: prognosis and response to systemic therapy. Ann Oncol. 1999;10(4):413419. doi:10.1023/A:1008329910362

13. Tzanninis I-G, Kotteas EA, Ntanasis-Stathopoulos I, Kontogianni P, Fotopoulos G. Management and Outcomes in Metaplastic Breast Cancer. Clin Breast Cancer. 2016;16(6):437443. doi:10.1016/j.clbc.2016.06.002

14. Sulaiman A, McGarry S, Han X, Liu S, Wang L. CSCs in Breast CancerOne Size Does Not Fit All: therapeutic Advances in Targeting Heterogeneous Epithelial and Mesenchymal CSCs. Cancers. 2019;11(8):8. doi:10.3390/cancers11081128

15. Zhang Y, Toy KA, Kleer CG. Metaplastic breast carcinomas are enriched in markers of tumor-initiating cells and epithelial to mesenchymal transition. Mod Pathol. 2012;25(2):178184. doi:10.1038/modpathol.2011.167

16. Gerhard R, Ricardo S, Albergaria A, et al. Immunohistochemical features of claudin-low intrinsic subtype in metaplastic breast carcinomas. Breast. 2012;21(3):354360. doi:10.1016/j.breast.2012.03.001

17. May CD, Sphyris N, Evans KW, Werden SJ, Guo W, Mani SA. Epithelial-mesenchymal transition and cancer stem cells: a dangerously dynamic duo in breast cancer progression. Breast Cancer Res. 2011;13(1):202. doi:10.1186/bcr2789

18. Nunes T, Hamdan D, Leboeuf C, et al. Targeting Cancer Stem Cells to Overcome Chemoresistance. Int J Mol Sci. 2018;19(12):12. doi:10.3390/ijms19124036

19. Yuan H, Chen J, Liu Y, et al. Association of PIK3CA mutation status before and after neoadjuvant chemotherapy with response to chemotherapy in women with breast cancer. Clin Cancer Res. 2015;21(19):43654372. doi:10.1158/1078-0432.CCR-14-3354

20. Mosele F, Stefanovska B, Lusque A, et al. Outcome and molecular landscape of patients with PIK3CA-mutated metastatic breast cancer. Ann Oncol. 2020;31(3):377386. doi:10.1016/j.annonc.2019.11.006

21. Krings G, Chen -Y-Y. Genomic profiling of metaplastic breast carcinomas reveals genetic heterogeneity and relationship to ductal carcinoma. Mod Pathol. 2018;31(11):16611674. doi:10.1038/s41379-018-0081-z

22. Gonzalez-Martinez S, Perez-Mies B, Carretero-Barrio I, et al. Molecular features of metaplastic breast carcinoma: an infrequent subtype of triple negative breast carcinoma. Cancers. 2020;12(7):7. doi:10.3390/cancers12071832

23. Ng CKY, Piscuoglio S, Geyer FC, et al. The landscape of somatic genetic alterations in metaplastic breast carcinomas. Clin Cancer Res. 2017;23(14):38593870. doi:10.1158/1078-0432.CCR-16-2857

24. Hayes MJ, Thomas D, Emmons A, Giordano TJ, Kleer CG. Genetic changes of Wnt pathway genes are common events in metaplastic carcinomas of the breast. Clin Cancer Res. 2008;14(13):40384044. doi:10.1158/1078-0432.CCR-07-4379

25. Avigdor BE, Beierl K, Gocke CD, et al. Whole-Exome Sequencing of Metaplastic Breast Carcinoma Indicates Monoclonality with Associated ductal carcinoma component. Clin Cancer Res. 2017;23(16):48754884. doi:10.1158/1078-0432.CCR-17-0108

26. Moukarzel L, Ferrando L, Da Cruz Paula A, et al. The genetic landscape of metaplastic breast cancers and uterine carcinosarcomas. Mol Oncol. 2020. doi:10.1002/1878-0261.12813

27. Hennessy BT, Krishnamurthy S, Giordano S, et al. Squamous cell carcinoma of the breast. J Clin Oncol. 2005;23(31):78277835. doi:10.1200/JCO.2004.00.9589

28. Abouharb S, Moulder S. Metaplastic breast cancer: clinical overview and molecular aberrations for potential targeted therapy. Curr Oncol Rep. 2015;17(3):431. doi:10.1007/s11912-014-0431-z

29. El Zein D, Hughes M, Kumar S, et al. Metaplastic carcinoma of the breast is more aggressive than triple-negative breast cancer: a study from a single institution and review ofliterature. Clin Breast Cancer. 2017;17(5):382391. doi:10.1016/j.clbc.2017.04.009

30. Han M, Salamat A, Zhu L, et al. Metaplastic breast carcinoma: a clinical-pathologic study of 97 cases with subset analysis of response to neoadjuvant chemotherapy. Mod Pathol. 2019;32(6):807816.

31. Al-Hilli Z, Choong G, Keeney MG, et al. Metaplastic breast cancer has a poor response to neoadjuvant systemic therapy. Breast Cancer Res Treat. 2019;176(3):709716.

32. Cimino-Mathews A, Verma S, Figueroa-Magalhaes MC, et al. A clinicopathologic analysis of 45 patients with metaplastic breast carcinoma. Am J Clin Pathol. 2016;145(3):365372.

33. Hennessy BT, Giordano S, Broglio K, et al. Biphasic metaplastic sarcomatoid carcinoma of the breast. Ann Oncol. 2006;17(4):605613.

34. Nagao T, Kinoshita T, Hojo T, Tsuda H, Tamura K, Fujiwara Y. The differences in the histological types of breast cancer and the response to neoadjuvant chemotherapy: the relationship between the outcome and the clinicopathological characteristics. Breast. 2012;21(3):289295.

35. Aydiner A, Sen F, Tambas M, et al. Metaplastic breast carcinoma versus triple-negative breast cancer: survival and response to treatment. Medicine. 2015;94(52):e2341.

36. Moroney J, Fu S, Moulder S, et al. Phase I study of the antiangiogenic antibody bevacizumab and the mTOR/hypoxia-inducible factor inhibitor temsirolimus combined with liposomal doxorubicin: tolerance and biological activity. Clin Cancer Res. 2012;18(20):57965805.

37. Basho RK, Gilcrease M, Murthy RK, et al. Targeting the PI3K/AKT/mTOR pathway for the treatment of mesenchymal triple-negative breast cancer: evidence from a phase 1 trial of mTOR inhibition in combination with liposomal doxorubicin and bevacizumab. JAMA Oncol. 2017;3(4):509515.

38. Basho RK, Yam C, Gilcrease M, et al. Comparative Effectiveness of an mTOR-based systemic therapy regimen in advanced, metaplastic and nonmetaplastic triple-negative breast cancer. Oncologist. 2018;23(11):13001309.

39. Yang MH, Chen IC, Lu YS. PI3K inhibitor provides durable response in metastatic metaplastic carcinoma of the breast: a hidden gem in the BELLE-4 study. J Formos Med Assoc. 2019;118(9):13331338.

40. Lu YS, Lee KS, Chao TY, et al. A phase ib study of alpelisib or buparlisib combined with tamoxifen plus goserelin in premenopausal women with hr-positive her2-negative advanced breast cancer. Clin Cancer Res. 2020.

41. Coussy F, El Botty R, Lavigne M, et al. Combination of PI3K and MEK inhibitors yields durable remission in PDX models of PIK3CA-mutated metaplastic breast cancers. J Hematol Oncol. 2020;13(1):13.

42. Matutino A, Amaro C, Verma S. CDK4/6 inhibitors in breast cancer: beyond hormone receptor-positive HER2-negative disease. Ther Adv Med Oncol. 2018;10:1758835918818346.

43. Seo T, Noguchi E, Yoshida M, et al. response to dabrafenib and trametinib of a patient with metaplastic breast carcinoma harboring a braf v600e mutation. case rep oncol med. 2020;2020:2518383.

44. Henneman L, van Miltenburg MH, Michalak EM, et al. Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer. Proc Natl Acad Sci U S A. 2015;112(27):84098414.

45. Tray N, Taff J, Adams S. Therapeutic landscape of metaplastic breast cancer. Cancer Treat Rev. 2019;79:101888.

46. Adams S. Dramatic response of metaplastic breast cancer to chemo-immunotherapy. NPJ Breast Cancer. 2017;3:8.

47. Al Sayed AD, Elshenawy MA, Tulbah A, Al-Tweigeri T, Ghebeh H. Complete response of chemo-refractory metastatic metaplastic breast cancer to paclitaxel-immunotherapy combination. Am J Case Rep. 2019;20:16301635.

48. Adams S, Othus M, Patel S, et al. Dual anti-CTLA-4 and anti-PD-1 blockade in metaplastic carcinoma of the breast: dart (SWOG S1609, Cohort 36). J Clin Oncol. 2020;38.

49. Afkhami M, Schmolze D, Yost SE, et al. Mutation and immune profiling of metaplastic breast cancer: correlation with survival. PLoS One. 2019;14(11):e0224726.

50. Bataillon G, Fuhrmann L, Girard E, et al. High rate of PIK3CA mutations but no TP53 mutations in low-grade adenosquamous carcinoma of the breast. Histopathology. 2018;73(2):273283.

51. Beca F, Sebastiao APM, Pareja F, et al. Whole-exome analysis of metaplastic breast carcinomas with extensive osseous differentiation. Histopathology. 2020.

52. Edenfield J, Schammel C, Collins J, Schammel D, Edenfield WJ. Metaplastic breast cancer: molecular typing and identification of potential targeted therapies at a single institution. Clin Breast Cancer. 2017;17(1):e1e10.

53. Joneja U, Vranic S, Swensen J, et al. Comprehensive profiling of metaplastic breast carcinomas reveals frequent overexpression of programmed death-ligand 1. J Clin Pathol. 2017;70(3):255259.

54. Ross JS, Badve S, Wang K, et al. Genomic profiling of advanced-stage, metaplastic breast carcinoma by next-generation sequencing reveals frequent, targetable genomic abnormalities and potential new treatment options. Arch Pathol Lab Med. 2015;139(5):642649.

55. Tray N, Taff J, Singh B, et al. Metaplastic breast cancers: genomic profiling, mutational burden and tumor-infiltrating lymphocytes. Breast. 2018;44:2932.

56. Vranic S, Stafford P, Palazzo J, et al. Molecular profiling of the metaplastic spindle cell carcinoma of the breast reveals potentially targetable biomarkers. Clin Breast Cancer. 2020;20(4):326331.

57. Zhai J, Giannini G, Ewalt MD, et al. Molecular characterization of metaplastic breast carcinoma via next-generation sequencing. Hum Pathol. 2019;86:8592.

58. Dave B, Gonzalez DD, Liu ZB, et al. Role of RPL39 in Metaplastic Breast Cancer. J Natl Cancer Inst. 2017;109:6.

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.

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

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.

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

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

Read the original:
Investigative Interventions Gain Ground in GVHD - OncLive

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.

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

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

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

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

Global Bionic Eye Market: Introduction

According to Encyclopedia Britannica, Inc., bionic eye is an electrical prosthesis, which is surgically implanted into a human eye in order to allow for the transduction of light, i.e. the change of light from the environment into impulses the brain can process in people who have sustained severe damage to the retina. The bionic eye comprises an external camera and transmitter and an internal microchip. The camera is mounted on a pair of eyeglasses, where it serves to organize the visual stimuli of the environment before emitting high-frequency radio waves. In the U.S., the FDA has approved just one commercially available bionic eye system. The device, called the Argus II Retinal Prosthesis System, was developed by a California-based company Second Sight Medical Products. Different bionic eye models take aim at different target areas in the visual pathway. Bionic eye implants work inside the existing eye structure or in the brain. These are designed to achieve functional vision goals as opposed to physical, cosmetic ones.

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Key Drivers of Global Bionic Eye Market

Rise in Prevalence of Vision Loss

The global population has increased by 18.5% in 2002 over that in 1990. The population 50 years of age and older has increased by nearly 30%. Population increase is more prominent in developing countries. Health is the centerpiece of development and poverty alleviation continuing to eliminate avoidable blindness among the poorest of the poor is a moral imperative. According to The Lancet Global Health, a report estimated that in 2015, 36.0 million people were blind, 217 million had moderate and severe vision impairment, 188 million had mild vision impairment, and 667 million additional people had vision impairment from uncorrected presbyopia.

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Rise in Prevalence of Eye Diseases

According to the World Health Organization, globally, at least 2.2 billion people have a vision impairment or blindness, of whom at least 1 billion have a vision impairment that could have been prevented or has yet to be addressed. Tens of millions have a severe vision impairment and could benefit from rehabilitation, which they are not currently receiving. Aging population coupled with rise in sedentary lifestyle and unhealthy eating habits also contribute toward increase in number of people with eye conditions and vision impairment are likely to augment the global market.

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North America to Account for Major Share of Global Bionic Eye Market

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Key Players Operating in Global Bionic Eye Market

The global bionic eye market is highly consolidated owing to the presence of several key players.

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Bionic Eye Market: Rise in Prevalence of Eye Diseases is expected to drive the market - BioSpace

No one can dispute the value that our eyes hold in our lives. One of the most vital organs, a pair of good healthy eyes can not only help us safely and ably navigate the challenges in our day-to-day life but ensures a lifetime of attainment and self-realization. Conversely, a not-so-healthy pair of eyes can become such a debilitating handicap in our daily routine. While some minor as well as major eye diseases are fairly common and treatable, there are some which continue to pose a challenge to the ophthalmic community. Glaucoma is one of those eye conditions. If timely detection and treatment is not carried out, it can lead to an individual even losing his eyesight. In fact, glaucoma is one of the leading causes of irreversible blindness.

What is Glaucoma?

Glaucoma is a term used to depict a group of diseases which entail a progressive or irreversible damage to the optic nerve of the eye, which if untreated may lead to loss of sight. It is a result of the increased pressure inside the eye which usually happens because of the build-up of a fluid known as aqueous humor in the eye. As this fluid gets obstructed or blocked, the resultant increase in intraocular pressure can damage the optic nerve which in time can weaken the eyesight and eventually lead to complete loss of vision.

Mass screening doesnt help, opportunistic screening important

Unlike Cataract, which can be detected during mass screening of a given population, Glaucoma requires a patient to specifically visit an eye doctor. This visit could be for any eye condition when an opportunistic screening can reveal whether an individual has the dreaded eye condition or not. A comprehensive eye examination with a set of tests such as dilated eye exam (to widen pupils and view optic nerve), slit lamp exam (to view inside of eye), visual acuity test (to check for vision loss), tonometry (to evaluate eye pressure), gonioscopy (to check for eye drainage), pachymetry (to measure corneal thickness), optical coherence tomography (changes in optic nerve), optic nerve head examination (to examine loss of ganglion cells and their fibres), and visual field examination(to check for any peripheral vision loss) would need to be conducted in order to establish whether an individual has glaucoma or not.

Types of Glaucoma

Generally, there are three major types of glaucoma: primary open angle glaucoma (POAG), primary angle closure glaucoma (PACG) and Secondary glaucoma. POAG is the most common type and occurs when the drainage system gets choked and progresses imperceptibly over a long time. Then PACG, a more serious type, is the result of the iris being too close to the drainage canals in the cornea. In this, the eye pressure can rise suddenly due to complete blockage of the drainage angle and unless medically intervened immediately, the individual can lose his eyesight. In a variant called Normal Tension Glaucoma, the optic nerve is damaged without the eye pressure going beyond the average range and is caused by the abnormalities in the blood flow to the optic nerve, and structural weakness of the optic nerve tissue. NTG is not very common. Secondary glaucoma is caused by other diseases which may increase eye pressure leading to optic nerve damage. These include Pigmentary glaucoma, Pseudoexfoliativeglaucoma, traumatic glaucoma, neovascular glaucoma, Irido-Corneal Endothelial Syndrome and Congenital/Childhood glaucoma.

Signs and Symptoms of Glaucoma

Each type of glaucoma has its own signs and symptoms. For instance, POAG has no perceivable or visible symptoms in the early stages and in due course of time as the disease progresses, blind spots develop in the peripheral vision. Similarly, PACG exhibits no apparent symptoms as such and can lead to a sudden attack. Signs of an acute attack would include intense pain in the eye or forehead, foggy vision, redness in the eye, halos around eyes, nausea and vomiting. Again in NTG, blind spots emerge in the field of vision which is a symptom. The symptoms in Secondary glaucoma would depend on the additional disease which is responsible for glaucoma. For Childhood or Congenital glaucoma, a baby would show sensitivity to light and clouding of Cornea. Children are also likely to frequently rub their eyes.

Who are at risk?

Although it can afflict anyone, those with a family history, advanced age or with co-morbidities such as high blood pressure, heart disease or diabetes are more likely to be at risk of getting glaucoma. In addition, those who have been on corticosteroid medications for long, or have undergone certain eye surgeries are also more at risk. Importantly, those with normal eye pressure can also get glaucoma.

Treatment

Again, the line of treatment would depend on the symptoms, stage and type of glaucoma. Typically, there are three major forms of treatment: medication/eye drops, laser treatment and surgery. And often a combination of treatments is also followed. For instance, POAG is most often treated with a combination of eye drops and surgery. But PACG is treated with a laser procedure called iridotomy in which the doctor creates a small opening in your iris using a laser allowing fluid to flow through it, relieving eye pressure. Another laser procedure is called Trabeculoplasty which is used for POAG patients. However in some cases, operating room surgery is opted for. Trabeculectomy is an important surgery in which an opening in the white of the eye (sclera) is created whilea part of the trabecular meshwork is removed by the doctor. You must remember that surgery may require follow-up sessions and a repeat surgery may also not be impossible.For Infants and congenital glaucoma, surgery is the main treatment.

Therefore, glaucoma is aptly called the silent thief of sight. With 12 million people affected and nearly 1.2 million people being blind from the disease in India, mass-level awareness campaigns must be mounted throughout the country. Also, individuals of all age groups must subject themselves to a comprehensive eye examination periodically. Parents should be alert to their babys eye conditions.Because glaucoma simply doesnt give you a second chance.

Views expressed above are the author's own.

END OF ARTICLE

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Glaucoma: A leading cause of irreversible blindness - The Times of India Blog

Dr. Marshall Walker will be the guest speaker for Stillwater Medical Foundations First Friday presentation March 5.

Walker is an optometrist whose topic will be Low Vision and Vision Rehabilitation. He is the only board certified low vision specialist in north central Oklahoma. First Friday is still a virtual event, so it will begin its Facebook live stream noon Friday.

1.Can you tell us a little of your background?

I earned his doctorate of optometry with honors from Pennsylvania College of Optometry. I trained at the prestigious Bascom Palmer Eye Institute in Miami, Florida and Feinbloom Low Vision Center in Philadelphia. Afterward, I completed a post-graduate residency in ocular disease and refractive surgery through Northeastern State University Oklahoma College of Optometry. I served as an assistant clinical professor at the Oklahoma College of Optometry and served at Indian Health Service Clinics throughout Northeastern Oklahoma before starting my practice at Stillwater Eyecare.

2. What are some highlights of your discussions?

Gain an understanding of the difference between low vision and blindness. Learn about the most common eye and brain conditions that can vision loss and how to avoid complications. Introduce assistive technologies to education attendees on ways to improve quality of life in individuals suffering vision impairment.

3. Can you give us an example of the kind of therapy involved in low-vision rehabilitation?

Vision rehabilitation is a team approach which includes a low vision specialist, occupational therapists, mental health professionals and social services coordinators. Different therapy recommendations depend on the needs of the individual patient. Specific rehabilitation therapies vary vastly and could be education of how to use a device to read text, or a training someone to navigate their environment with a white cane.

4. Whats a common misconception about eyesight?

Prevention is key. A common misconception about eyesight is a person will notice if they have a problem. There are many potentially blinding conditions that have no perceivable effects until the condition is advanced. This is why yearly comprehensive eye exams are so important.

5. Is there anything youd like us to know?

If someone has sudden vision change or loss, sudden eye pain or a red eye, they should call to be seen as soon as possible.

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Q5: First Friday will feature discussion on low vision - Stillwater News Press

The Automotive Recognition System market study provides a comprehensive narrative of the global market landscape and lays out the essentials as well as the other business affecting factors for the client to better understand the market scope and potential. The Automotive Recognition System market report delivers information on various crucial business and market dynamics and anticipates the market growth in the forecast.

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NOTE: The Automotive Recognition System report has been formulated while considering the COVID-19 Pandemic and its impact on the market.

Key Stakeholders mentioned in this report: CogniVue, EyeSight Technologies, Intel, Qualcomm, Gestsure Technologies, Microsoft

This research study will help you in strengthening the position of your business and organization in the global Automotive Recognition System market landscape. The report will help you to draft strategies that will sustain your business in the long term and give you credible information to implement these strategies in the most effective way possible.

Based on Type Coverage:

Hand/Leg/Finger Print RecognitionFace RecognitionVision/Eye Recognition

Based on Application Coverage:

MultimediaLightingsOthers

Based on Regions and included:

North America(the United States, Canada, and Mexico)Europe(Germany, France, UK, Russia, and Italy)Asia-Pacific(China, Japan, Korea, India, and Southeast Asia)South America(Brazil, Argentina, Colombia, etc.)The Middle East and Africa(Saudi Arabia, UAE, Egypt, Nigeria, and South Africa)

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Scope:

The Automotive Recognition System market comes up with detailed information related to critical aspects which are essential for a good growth strategy in the market landscape. The market study also profiles the vital players and details their business models.

Highlights of Automotive Recognition System Market Report:

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Automotive Recognition System Market landscape are detailed in this report for your convenience by: CogniVue, EyeSight Technologies, Intel, Qualcomm,...

Some of the most recognizable traditional sports players in the world wear Oakley. Now, Oakley can add Call of Duty League All-Star Seth Scump Abner to its roster to go alongside other Oakley athletes such as Patrick Mahomes, JuJu Smith-Schuster, Erika Hara, and others. Abner, who currently plays for OpTic Chicago, is now the first-ever esports athlete to sign with the iconic sunglass maker. Abner will be relying on Oakleys first eye-wear solution developed specifically for gaming Prizm Gaming Lens Technology.

Why Oakley? The name speaks for itself. When you hear the word Oakley, you think of a very prestigious brand in the glasses space, Abner told The Esports Observer. I watch a ton of sports. I see Oakley all over the place. My favorite sport to watch is baseball and you see those players wearing them every day. Oakley is just an amazing brand, a very cool, and a very hip brand as well. I think Oakley just kinda speaks for itself.

Oakley, with roots already laid deep inside the traditional sports space, sees esports as another competitive space where players share in the pursuit of progression, giving it everything theyve got. Abner encapsulates that vision as he had had to overcome various vision problems in order to become the player he is today.

I cant see anything. Having glasses that help me see and are comfortable are the two most important things I need in a pair, Abner said. Playing at the highest level, I need to be able to see everything and react to everything perfectly with no discomfort. You dont want to have to worry about things inside of the game because of things outside of the game. These Oakleys are pretty much an attachment of me now.

Abner, who used to wear contacts which he said sometimes itch because of bad allergies, now says he wears glasses again. And the prescription lenses that come with a blue-blocking agent, have helped him tremendously.

I used to wear contacts quite a bit, but now I wear only glasses exclusively, Abner said. So again, its just really important and amazing that Ive found a pair that I really like helps with my eye strain. Its just as cool that the brand is Oakley.

Despite the ailments with allergies and eyesight, Abner has been able to dominate the Call of Duty esports scene. In fact, the two-time Major League Gaming (MLG) X Games gold medalist who was awarded the Best Console Player at the 2017 Esports Industry Awards is often referred to as The King.

Ive been wearing their product for probably two months now, Abner said. The prisms fit perfectly under my Turtle Beachs [headset]. With the Oakleys and the Turtle Beachs, I have no strain on the top of my ears, which after eight hours, you can imagine how much that would hurt. I havent had any issues with these so far and theyre just really comfortable and easy to wear while Im gaming.

However, it wasnt just Abners skill in playing Call of Duty that saw Oakley reach out to him for this partnership, but also his philanthropic endeavors. Abner has grown into a global ambassador for esports by interacting with his fans and followers through various forms of content creation. He has also participated in charity streams and recently took part in a philanthropic campaign to honor those battling COVID-19.

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Seth 'Scump' Abner Signed by Oakley as its First Professional Esports Athlete - The Esports Observer

Mrs Beryl Close, from Tonypandy. Image:Freshwater.

Submitted by Freshwater on behalf of Specsavers

A Rhondda man was so concerned about his mother's eyesight and that it was affecting her mental health, that he arranged for an optician home visit during lockdown.

Beryl Close, 75, from Tonypandy in the Rhondda Valley, struggled with her mobility and when her eyesight started worsen during the lockdown. So much so that it began to have a big impact on her life.

Her son, Mike, got in touch with Specsavers, as he was concerned about his mums vision. She couldnt read or see the TV and he was worried that it was affecting her mental health.

During his visit to see Mrs Close, optometrist and director of home visits in Cardiff and the Vale of Glamorgan for Specsavers, Jason Scaife found that she had bad cataracts in both eyes and needed surgery. Cataract removal surgery is a quick procedure, which takes between 15 to 45 minutes, and leaves patients with much brighter and clearer vision.

Having had her surgery at Nuffield Health Hospital in Cardiff Bay to remove the cataracts, Mrs Close has now made a full recovery.

Mr Scaife said: "Her whole demeanour was different after the operation. It became evidently clear that it was her sight problems that were causing her anxiety. She was back to her usual self after the procedure, which was heart-warming to see.

"Beryls story is yet another example of why primary health services cannot stall because of Covid-19. We completely understand why people may be anxious to seek treatment and medical advice while Covid-19 remains prevalent in our communities, which is why our staff both those working remotely as well as colleagues in Specsavers stores have worked hard to ensure we are Covid-secure at all times."

Specsavers staff use personal protective equipment (PPE) while visiting someones home and thoroughly sanitise all equipment and glasses frames between appointments.

Specsavers stores and home visits service in Wales currently remain open for all eye and hearing needs. Specsavers will adhere to each countrys industry guidance if and when changes to local rules are made.To find out more information, request an appointment or browse the online store, visit http://www.specsavers.co.uk/stores.

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Optician's home visit helped save Rhondda woman's deteriorating eyesight - In Your Area

NESS ZIONA, Israel--(BUSINESS WIRE)--Foresight Autonomous Holdings Ltd., an innovator in automotive vision systems (Nasdaq and TASE: FRSX), today reported financial results for the fourth quarter and full year 2020. Foresight ended the fourth quarter of 2020 with $43.9 million in cash and short-term deposits.

Foresight reported a GAAP operating loss of $12.84 million for the full year 2020 which is an approximately 15% less than the GAAP operating loss of $15.03 million reported for the full year 2019. Foresight reported a GAAP net loss of $3.96 million and $15.32 million for the fourth quarter 2020 and the full year, respectively, and a non-GAAP net loss of $3.71 million for the fourth quarter and $14.16 million for the full year 2020.

We achieved important key milestones during the fourth quarter of 2020 and maintained solid progress throughout the year in spite of the COVID-19 pandemic, said Haim Siboni, Foresights CEO. We are entering 2021 with a strong balance sheet, following successful capital raises including $26 million raised in our registered direct offering announced on December 28, 2020. We will continue to build on our innovative product portfolio, which has been validated through key prototype orders and partnerships in Europe, Asia and North America.

The successful year also extends to our subsidiary, Eye-Net Mobile, and our affiliate, Rail Vision. Both companies achieved major business milestones during the fourth quarter of 2020, as Rail Vision received a second investment of $10 million from a leading Tier One European-based group, Knorr-Bremse, in October 2020, and Eye-Net Mobile signed a distribution agreement with Cornes Technologies, a leading Japanese trading house. We believe that Rail Vision and Eye-Net Mobile are poised for further growth in 2021, concluded Mr. Siboni.

Fourth Quarter 2020 Financial Results

Full Year 2020 Financial Results

Full year endedDecember 31,

Three months endedDecember 31,

(thousands of U.S. dollars)

2020

2019

2020

2019

GAAP Results

Net loss

$(15,324)

$(15,439)

$(3,964)

$(4,370)

Non-GAAP Results

Net loss

$(14,162)

$(13,476)

$(3,712)

$(4,018)

Balance Sheet Highlights

Fourth Quarter Corporate Highlights:

Use of Non-GAAP Financial Results

In addition to disclosing financial results calculated in accordance with United States generally accepted accounting principles (GAAP), the company's earnings release contains non-GAAP financial measures of net loss for the period that excludes the effect of share-based compensation expenses, the revaluation of other investments and revaluation of derivative warrant liability, and non-GAAP financial measures of shareholders equity that excludes the effect of derivative warrant liability and the revaluation of other investments. The companys management believes the non-GAAP financial information provided in this release is useful to investors understanding and assessment of the company's ongoing operations. Management also uses both GAAP and non-GAAP information in evaluating and operating business internally and as such deemed it important to provide all this information to investors. The non-GAAP financial measures disclosed by the company should not be considered in isolation or as a substitute for, or superior to, financial measures calculated in accordance with GAAP, and the financial results calculated in accordance with GAAP and reconciliations to those financial statements should be carefully evaluated. Reconciliations between GAAP measures and non-GAAP measures are provided later in this press release.

About Foresight

Foresight Autonomous Holdings Ltd. (Nasdaq and TASE: FRSX) is a technology company developing smart multi-spectral vision software solutions and cellular-based applications. Through the companys wholly owned subsidiaries, Foresight Automotive Ltd. and Eye-Net Mobile Ltd., Foresight develops both in-line-of-sight vision systems and beyond-line-of-sight accident-prevention solutions.

Foresights vision solutions include modules of automatic calibration, sensor fusion and dense 3D point cloud that can be applied to different markets such as automotive, defense, autonomous vehicles and heavy industrial equipment. Eye-Net Mobiles cellular-based solution suite provides real-time pre-collision alerts to enhance road safety and situational awareness for all road users in the urban mobility environment by incorporating cutting-edge AI technology and advanced analytics.

For more information about Foresight and its wholly owned subsidiary, Foresight Automotive, visit http://www.foresightauto.com, follow @ForesightAuto1 on Twitter, or join Foresight Automotive on LinkedIn.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995 and other Federal securities laws. Words such as expects, anticipates, intends, plans, believes, seeks, "estimates" and similar expressions or variations of such words are intended to identify forward-looking statements. For example, Foresight is using forward-looking statements in this press release when it discusses its belief that it is entering 2021 with a strong balance sheet, that it will continue to build on its innovative product portfolio, which it believes has been validated through key prototype orders and partnerships in Europe, Asia and North America, that it believes that Rail Vision and Eye-Net Mobile are poised for further growth in 2021, Rail Visions expected revenue from Knorr-Bremse, and that Foresight will work with students from the University of Michigan to further develop its automotive vision system designed for Advanced Driver Assistance Systems and autonomous vehicles. Because such statements deal with future events and are based on Foresights current expectations, they are subject to various risks and uncertainties and actual results, performance or achievements of Foresight could differ materially from those described in or implied by the statements in this press release. The forward-looking statements contained or implied in this press release are subject to other risks and uncertainties, including those discussed under the heading Risk Factors in Foresights annual report on Form 20-F filed with the Securities and Exchange Commission (SEC) on March 31, 2020, and in any subsequent filings with the SEC. Except as otherwise required by law, Foresight undertakes no obligation to publicly release any revisions to these forward-looking statements to reflect events or circumstances after the date hereof or to reflect the occurrence of unanticipated events. References and links to websites have been provided as a convenience, and the information contained on such websites is not incorporated by reference into this press release.

FORESIGHT AUTONOMOUS HOLDINGS LTD.

INTERIM CONDENSED CONSOLIDATED BALANCE SHEETS

U.S. dollars in thousands

As ofDecember31, 2020(Unaudited)

As ofDecember31, 2019

ASSETS

Current assets:

Cash and cash equivalents

$

38,772

$

4,827

Short term deposits

Link:
Foresight Announces Fourth Quarter and Full Year 2020 Financial Results - Business Wire

Spinal cord injuries are sustained by hundreds of thousands of people every year, with many patients experiencing a significant and often permanent loss of movement and physical sensation resulting from nerve damage.

Beyond intensive physical rehabilitation programs which can improve outcomes in some cases treatment options are virtually non-existent. But new results from a phase 2 clinical trial offer fresh hope for remedies on the horizon.

In an experimental collaboration by scientists in Japan and the US, 13 patients with spinal cord injuries (SCI)experienced a range of functional improvements in their condition after being treated with an intravenous infusion of their own stem cells, derived from their bone marrow.

The stem cells in question are known as mesenchymal stem cells (MSCs), which are multipotent adult stem cells with the ability to differentiate into a variety of cell types, enabling them to repair bone, cartilage, muscle, or fat tissue.

Despite the potential promise of these cells, their use as an actual therapy has generated considerable controversy, especially after Japan fast-tracked commercialisation approval in late 2018in advance of thorough data on the safety and effectiveness of the experimental treatment.

Over two years later, the researchers behind the therapy, called Stemirac, now have more of those data to share, and while it won't be enough to placate critics, the findings nonetheless offer valuable new information on what MSCs may do for patients with SCI.

"The idea that we may be able to restore function after injury to the brain and spinal cord using the patient's own stem cells has intrigued us for years," explains neurologist Stephen Waxman from Yale University, a senior author of the study .

"Now we have a hint, in humans, that it may be possible."

In the study, the researchers point out that while other trials have also looked at using MSCs to treat SCI via injection methods, their own technique, using intravenous infusion, could have particular benefits.

"Importantly, intravenously infused MSCs may affect not only the injury site, but other parts of the central nervous system including brain and blood vessels," the authors explain in their paper.

Whether that explains some of the results seen in their 13 patients is unclear, but the outcomes themselves are notable.

Of the individuals treated with Stemirac, all of whom had non-penetrative SCIs (meaning their spinal cords were not severed) sustained during serious physical accidents, all but one had demonstrated improvements in key sensory or motor functions by six months after the infusion.

Over half the group showed substantial improvements in things like walking ability or using their hands, and in many cases, graded improvements on a standardised impairment scale could be seen as soon as one day after the treatment, although other cases took weeks.

Significantly, no adverse effects were reported.

While the researchers acknowledge that theirs is a small trial with various limitations including the possibility that the recoveries seen may have been somewhat spontaneous they contend that the initial data show we're looking at something here that's safe, feasible, and worthy of follow-up studies with greater amounts of patients.

"Although this initial case study was unblinded and uncontrolled, the SCI patients appeared to demonstrate a tendency of relatively rapid improvement of neurological function that was often apparent within a few days following infusion of MSCs," the team writes.

As for how the MSC infusion delivers its healing, results from studies on animals have made the researchers think the stem cells secrete neural growth factors that restore important structures that reduce swelling, while restoring vital chemical activity.

In terms of the rapid improvements, the team suggests a chemical called brain derived neurotrophic factor (BDNF) may be involved, which is known to support the health of neurons via numerous mechanisms.

Hopefully, more research in the future can demonstrate the true extent of the potential benefits of this treatment.

The findings are reported in Journal of Clinical Neurology and Neurosurgery.

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Controversial Stem Cell Therapy Has Helped Repair Injured Spinal Cords in 13 Patients - ScienceAlert

ASX-listed Cynata Therapeutics has signed an MoU with TekCyte Pty Ltd to access its wound dressing technology in the hope of commercialising TekCytes proprietary surface modifications of polymer-coated dressings for the delivery of Cynatas mesenchymal stem cells, or MSC, to wounds.

The Melbourne-based clinical-stage stem cell and regenerative medicine company is specifically looking to use TekCytes technologies in the commercial development of Cynatas MSC product for the treatment of diabetic foot ulcers.

Cynata said its trademarked Cymerus MSCs have already demonstrated promising efficacy in a pre-clinical model of diabetic wounds, often referred to as diabetic ulcers, utilising TekCytes dressing when seeded with MSCs or similar cells.

The company now plans to build on the solid pre-clinical foundation by conducting a clinical trial of its Cymerus MSC product on patients with diabetic foot ulcers using an active dressing supplied by TekCyte.

Cynata expects to start the clinical trial as soon as possible after it completes negotiations with TekCyte on a formal license agreement.

The company says diabetic foot ulcers are a significant medical problem with an estimated market value of nearly US$10 billion based on data sourced from Transparent Market Researchs review of the global diabetic foot ulcers treatment market out to 2027.

In Australia alone, diabetic foot disease results in more than 27,000 hospitalisations, 4,400 amputations and 1,700 deaths annually. Unfortunately, there is also evidence that the burden of this disease is growing year-on-year, and existing treatment options have limited success.

The very encouraging data from the pre-clinical studies at the CTM-CRC with our Cymerus MSC product, especially when compared with other cell products, provides a rational and sound basis for us to proceed with TekCytes patch technology.

Elsewhere in Cynatas labs and clinical trial sites, the company is working to deploy its stem cell technology across a range of ailments, including Osteoarthritis, renal transplantation, idiopathic pulmonary fibrosis and even COVID-19.

Stem cells, most familiar as embryonic stem cells, are special human cells capable of morphing into all other cell varieties from muscles to brain cells.

Whilst stem cell technology has been developing for a decade or two now, it has been routinely based on using hematopoietic stem cells to treat disease. However, a donor can currently transplant these cells only if a perfect match is available.

Instead of the arduous process of undertaking donor match searches, Cynata believes plentiful stem cells can be derived another way. By transforming adult stem cells with a type of genetic reprogramming, the company says it can create pluripotent stem cells that are capable of operating identically to the valuable embryonic cells.

The companys proprietary Cymerus technology uses pluripotent cells combined with a precursor cell called mesenchymoangioblasts, or MCA to fabricate numerous cell therapy products, including mesenchymal stem cells or MSCs.

Importantly, Cynata says it can produce those essential cells at a commercial scale, forgoing the need for multiple donors and conquering the usual supply bottlenecks currently frustrating stem cell therapies and researchers worldwide.

Other candidate diseases facing this potentially boundless technology include asthma, heart attack, sepsis, acute respiratory distress syndrome, or ARDS and cytokine release syndrome.

Plans are already well advanced for further clinical trials of the fascinating Cymerus MSC products in Graft-versus-host Disease, or GvHD through licensee Fujifilm.

GvHD is an all-too-common consequence of traditional stem cell therapies and is one of the earliest ailments to be attacked by Cynatas technology.

Cynata looks to be hurtling down a path to turn science fiction into reality by developing a wound patch that can effectively regenerate the bodys own cells a bit more than just a band-aid approach, perhaps?

Is your ASX-listed company doing something interesting? Contact: matt.birney@wanews.com.au

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Cynata tests wound dressing tech for stem cell therapy delivery - The West Australian

Injecting bone marrow stem cells in patients with spinal cord injuries significantly improved their motor functions.

Scientists from Yale University and Sapporo Medical University in Japan reported their findings in the Journal of Clinical Neurology and Neurosurgery on February 18.

The stem cells were prepared from the patients' own bone marrow, and injected intravenously back into the patients, with no side effects from the therapy noted by the researchers. This was not a blind trial, and no placebos were administered.

Over half of the patients reported improved motor functions within weeks of the injections. Key motor functions include walking and using hands.

The patients in question had experienced non-penetrating spinal cord injuries a few weeks prior to the study, which were caused by minor falls or trauma. These injuries left them without motor function or coordination, sensory loss, and bowel and bladder dysfunction.

This type of therapy isn't only ideal for spinal cord injuries, but also for brain injuries, such as strokes. As Jeffery Kocsis of Yale University said "Similar results with stem cells in patients with stroke increases our confidence that this approach may be clinically useful."

Adding to this comment, Stephen Waxman from Yale University said "The idea that we may be able to restore function after injury to the brain and spinal cord using the patients own stem cells has intrigued us for years. Now we have a hint, in humans, that it may be possible."

It's still the early days of this stem cell therapy for spinal cord injuries, and the authors of the study stress that further studies need to be carried out before confirming the results of their initial, unblinded trial something that could take years.

It's still exciting news, as stem cell therapy has been researched for years as a potential remedy for such injuries. Just last year, the Mayo Clinic carried out trials on stem cell therapy for spinal cord injuries. While in Japan, a few eyebrows were raised in 2019 as the nation accepted stem cell therapy to treat spinal cord injuries, perhaps a little prematurely some scientists suggested in the journal Nature.

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Stem Cell Injections Could Treat Spinal Cord Injuries | IE - Interesting Engineering

Theglobal Canine Arthritis Treatment Marketis expected to reachUS$ 3051.8 Mnby 2028, growing at a moderate CAGR of 4.4%, as per a market intelligence outlook by Future Market Insights, a premier market research firm delivering actionable insights to key leaders across the globe. Mostly found in ageing canines, canine arthritis is a degenerative condition that results in joints inflammation and progresses with time if left untreated. The condition further worsens resulting in associated conditions like osteoarthritis, osteophytosis, and loss of cartilage, in response to pain and inflammation. Injuries, obesity, and poor bone development often leads to canine arthritis.

Rising number of chronic diseases in dogs, globally, is the primary factor driving canine arthritis treatment adoption. Additional factors like increasing number of veterinary clinics couple with stem cell transplants and Non-steroidal anti-inflammatory medications (NSAIDs) are likely to push the market for canine arthritis treatment. Non-steroidal anti-inflammatory medications (NSAIDs) segment is expected to made substantial revenue contribution to overall canine arthritis treatment market followed by opioids during forecast period.

North America, followed byEuropeandAsia Pacific, is expected to be largest consumer of canine arthritis treatment drugs and therapies, owing to existence of developed regulations and superior healthcare infrastructure. For more collaborative research in the canine arthritis market,JapanandSpainare projected to be promising markets.

A sample of this report is available upon request @https://www.futuremarketinsights.com/reports/sample/rep-gb-3552

Use of NSAIDs to Further Shape Canine Arthritis Market

Ease of FDA approval for novel and innovative canine arthritis treatment drugs coupled with growing adoption of canine stem therapy to treat arthritis and huge investments in research and development for the production of NSAIDs and opioids indicated for arthritis especially in European countries is projected to projected to present opportunities to canine arthritis treatment product manufacturers.

The focus presently is on developing high grade NSAIDs, as these drugs are frequently used to manage canines condition-offering a dramatic improvement in mobility and quality of life. The demand for NSAIDs in on a perpetual rise as it lowers the production of prostaglandins-associated with driving inflammation leading to arthritis. In terms of treatment, NSAIDs are continue to be the globally accepted mainstay of pharmaceutical treatment for canine arthritis, further shaping the canine arthritis treatment market. Research suggests that more than 60% of canines above the age of 7, suffer from degenerative joint diseases.

According to a Healthcare Expert at Future Market Insights, Factors such as growing prevalence of chronic diseases in dogs, rising pets adoption, increased consumer spending on veterinary care and fast FDA approvals for drugs used for canine arthritis treatments are expected to boost the global canine arthritis treatment market during the forecast period. Additionally, canine owners opting for canine stem cell therapy over drug medicines is the most lucrative segment in terms of investment opportunities. However, safety issues affecting clinical efficacy of canine pluripotent cells and high therapy costs limit the adoption of canine stem cell therapy. FDA-approved MediVets Autologous Stem Cell and Aratanas Galliprant to control pain and inflammation associated with arthritis, are expected to contribute to the growth of the canine arthritis treatment market.

However, illicit drugs that are falsely registered could restrain the canine treatment market. Such drugs are not manufactured in accordance with regulations, inversely affecting the dogs health coupled with sales of approved drugs. Research shows that counterfeit medicines are more prevalent in under-developed and developing countries. Growing international trade and ecommerce penetrations are fuelling the sales of sub-standard medicine.

Get Access to Research Methodology Prepared by Experts>>>https://www.futuremarketinsights.com/ask-question/rep-gb-3552

Canine Insurances & Direct Drug Sales to Open Canine Arthritis Treatment Opportunities

Pet insurance is an upcoming trend, especially in mature economies. With only 1% dogs insured in the US, the trend is catching up in the region, opening up opportunities for veterinary insurance vendors. However, this number is as high as 50% for pet dogs in some European countries. Moreover, introduction of third-party payers is expected to boost the turnover of the canine arthritis drugs, mostly for the NSAIDs and stem cell therapy segments globally, and lead to build-up of new sales channels for drugs treating canine arthritis.

Also, canine healthcare products manufacturers are relying on direct sales to end-users in a bid to reach out to a larger consumer base. Furthermore, by adopting this sales route, companies are also providing additional training and support in terms of disease management and adherence to treatment protocols.

Key players including Boehringer Ingelheim, Elanco (Eli Lilly and Company), Zoetis Inc., Bayer AG, Aratana Therapeutics Inc., Vetoquinol S.A., Norbrook Laboratories Limited, VetStem Biopharma, and Dechra Pharmaceuticals Plc are developing cost-effective drugs for canine arthritis treatment and increasing sales through acquisitions to enhance their respective market share. Manufacturers are also focusing in developing novel stem cell therapies for treating arthritis. Moreover, companies are focusing partnering with wholesalers, distributors and other channel partners to gain ownership over value chain.

Preview Analysis OnCanine Arthritis Treatment Market Segmentation By treatment type Non-steroidal anti-inflammatory drugs, Opioids, Stem Cell Therapy; route of administration Oral, Injectable:https://www.futuremarketinsights.com/reports/canine-arthritis-market

More from Healthcare, Pharmaceuticals and Medical devices:

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NSAIDs to Treat Arthritic Canines Through 2028; Stem Cell Therapies to Invigorate Canine Arthritis T - PharmiWeb.com

This article was originally published here

Neurol Res. 2021 Feb 25:1-17. doi: 10.1080/01616412.2021.1893564. Online ahead of print.

ABSTRACT

Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of upper and lower motor neurons with high burden on society. Despite tremendous efforts over the last several decades, there is still no definite cure for ALS. Up to now, only two disease-modifying agents, riluzole and edaravone, are approved by U.S. Food and Drug Administration (FDA) for ALS treatment, which only modestly improves survival and disease progression. Major challenging issues to find an effective therapy are heterogeneity in the pathogenesis and genetic variability of ALS. As such, stem cell therapy has been recently a focus of both preclinical and clinical investigations of ALS. This is because stem cells have multifaceted features that can potentially target multiple pathogenic mechanisms in ALS even though its underlying mechanisms are not completely elucidated. Methods & Results: Here, we will have an overview of stem cell therapy in ALS, including their therapeutic mechanisms, the results of recent clinical trials as well as ongoing clinical trials. In addition, we will further discuss complications and limitations of stem cell therapy in ALS. Conclusion: The determination of whether stem cells offer a viable treatment strategy for ALS rests on well-designed and appropriately powered future clinical trials. Randomized, double-blinded, and sham-controlled studies would be valuable.

PMID:33632084 | DOI:10.1080/01616412.2021.1893564

Read the original:
Overview of stem cells therapy in amyotrophic lateral sclerosis - DocWire News

Using a somewhat controversial stem cell therapy, a joint team of Japanese and US-based researchers have successfully repaired some damage in 13 patients with spinal cord injuries (SCI).

SCIs can often cause permanent loss of movement and physical sensation from resultant nerve damage. While physical rehabilitation programs can partially improve outcomes, actual treatment and recovery of lost mobility and function is nigh on impossible. Until now, perhaps.

According to new results from a phase 2 clinical trial conducted in an experimental collaboration by scientists in Japan and the US, patients treated with an intravenous infusion of their own mesenchymal stem cells (MSCs), harvested from their bone marrow, saw significant functional improvements.

MSCs are adult stem cells with the uncanny ability to morph into numerous different cell types, affording them the ability to repair different tissues in the human body, ranging from bone and cartilage to muscle or other tissues.

In 2018, Japan fast-tracked commercial approval of the treatment, opting to forego full testing and regulatory approval despite a lack of complete data on its safety and efficacy. This was much to the consternation of the medical industry at large, and caused considerable controversy in the process.

Fast-forward to the present day and the therapy, called Stemirac, may prove revolutionary in treating non-penetrative SCIs, in which the spinal cord is damaged but remains intact.

In the trials, all 13 patients demonstrated improvements in sensory and motor function six months after they received their infusion, while more than 50 percent of the participants saw substantial improvements in motor function, including walking within a day, though for others it took weeks.

"The idea that we may be able to restore function after injury to the brain and spinal cord using the patient's own stem cells has intrigued us for years," explains neurologist Stephen Waxman from Yale University, a senior author of the study.

"Now we have a hint, in humans, that it may be possible."

Other research has examined the efficacy of injected MSCs to treat SCI, but this new method involves intravenous infusion, which operates in a different way and, so far, has no adverse effects. Still, the researchers acknowledge the limited scope of the trial, as well as the fact that it was unblinded and uncontrolled.

"Importantly, intravenously infused MSCs may affect not only the injury site, but other parts of the central nervous system including brain and blood vessels," the authors explain in their paper.

For now, they suspect the stem cells secrete neural growth factors, particularly brain-derived neurotrophic factor (BDNF), which have a restorative as well as anti-inflammatory effect. While a lot more research is needed to determine the long term safety and efficacy of the treatment, it could one day prove revolutionary.

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We have a hint it may be possible: Controversial stem cell therapy repaired injured spinal cords in 13 patients - RT