StemCell Therapy

Adding the anti-CD20 monoclonal antibody rituximab (various brands) to induction chemotherapy in patients with B-precursor acute lymphoblastic leukaemia (B-ALL) does not improve outcomes, UK researchers have found in a primary analysis of phase 3 trial data.

However, a separate examination of findings from the same study may nevertheless point to an update to the genetic classification for the disease that could help in creating an overall combined clinical and genetic risk score.

The research was published as an abstract from the British Society for Haematology 60th Annual Scientific Meeting, which was cancelled due to the COVID-19 pandemic.

UKALL14 involved patients with B-ALL aged 2565 years, regardless of Philadelphia chromosome (Ph) status or CD20 expression, who were randomised to standard induction chemotherapy (SOC) with or without 4 doses of rituximab (SOC+R).

Focusing on patients recruited after an amendment to the SOC regimen in April 2012, the team conducted an intention-to-treat analysis in 288 SOC patients and 289 given SOC+R, of whom 95.5% received all 4 doses of the immunotherapy.

Adele Fielding, professor of haematology at University College London Cancer Institute, London, and colleagues report that complete remission rates, at 92.7% with SOC and 94.8% with SOC+R, were similar in the two treatment arms.

There was also no difference in minimal residual disease (MRD) rates, with 42.2% and 41.8%, respectively, negative for residual disease.

Adverse, including severe, event rates were similar between the two cohorts, and there was no difference in non-relapse mortality.

After a median follow-up of 50.5 months, the researchers calculate that the 3-year event-free survival (EFS) for patients given SOC was 41.9% versus 48.7% for those receiving SOC+R, at a hazard ratio of 0.88 (p=0.28).

This contrasts with the French GRAALL-2005/R study, in which adults aged 1859 years with CD20-positive, Phnegative ALL were randomised to chemotherapy with or without rituximab, with a total of 16 to 18 infusions given across all treatment phases.

Their results indicated that adding rituximab to the ALL chemotherapy protocol improved outcomes, increasing EFS by 33% versus chemotherapy alone (p=0.04).

Prof Fielding told Medscape News UK that, for UKALL14, they had "hypothesised that giving rituximab early would make the difference, namely in helping to eliminate MRD early on".

"We were anxious not to give too much in case of toxicity from infections. It turned out that it is not toxic and doesnt seem to work to eliminate MRD early on."

She added that, in fact, "the French data showed that too," which prompts her to wonder at the mechanism of action of rituximab in B-ALL.

"Maybe you need more doses at times when patients have functional neutrophils or macrophages, or natural killer cells."

Prof Fielding also pointed out that, in the French study, they focused on patients with Ph-negative disease and in those in whom more than 20% of blasts expressed CD20.

"An important finding from our workis that the level of CD20 expression does not correlate with response to rituximab."

Approached for comment, Rachel Kahn, research communications manager at Blood Cancer UK, said that, "the immunotherapy drug rituximab remains a vital treatment for many types of blood cancer".

She told Medscape News UK, however, that "this interesting research suggests that there may not be any additional benefit of taking this drug for people with ALL".

She highlighted that the results nevertheless suggested that patients who underwent myeloablative allogeneic stem cell transplant (MAallaSCT) appeared to derive a significant benefit from adding rituximab to SOC.

Three-year EFS was 50.7% among MAallaSCT patients given SOC alone versus 72.2% in those receiving SOC+R, at a hazard ratio of 0.47 (p=0.03), which was related to a reduction in relapse risk.

This effect was not seen in patients given reduced intensity allogeneic stem cell transplantation or in maintenance groups, prompting Rachel Kahn to call for further research to identify which patients with ALL "may benefit from taking rituximab".

Prof Fielding said that, as they "do not have any plausible biological explanation" for the finding, the team is "going to be cautious about interpreting" it.

Overall, she feels that, as rituximab is "safe, its probably better to give it to everyone", as "our ability to do that is greater than our ability to do proper flow cytometry in local centres to accurately quantify CD20".

In a separate analysis, Prof Fielding and colleagues looked at all 653 patients who started treatment both before and after the SOC regimen amendment, of whom 49% were found to have high-risk chromosomal abnormalities.

These included 31% with BCR-ABL1, 8% with KMT2A-AFF1, 9% with HoL and 5% with CK abnormalities.

CK and HoL patients had lower 3-year overall survival than the overall cohort, at 24% and 19%, respectively, versus 52%, while patients with KMT2A-AFF1 fusion had an overall survival of 44% and BCR-ABL1 patients had a similar survival to the overall group.

The team also identified a series of other chromosomal abnormalities, including 1.3% with ABL-class fusions and the same proportion with JAK-STAT abnormalities, the latter had reduced 3-year overall survival, at 35%.

In contrast, among the 3% of patients with ZNF384 fusions, only two relapsed and none died.

Having found that secondary copy number alterations affecting key genes had no impact on outcomes, the team proposed "an amendment to the genetic risk classification for adult ALL", consisting of:

very high risk: CK, HoL or JAK-STAT abnormalities

high risk: all KMT2A fusions

tyrosine kinase sensitive: BCR-ABL1 and ABL-class fusions

low-risk: ZNF384 fusions

standard risk: all other patients

The team writes: "The integration of these primary genetic risk factors with other risk factors such as age, white cell count and MRD into an overall risk score is a key goal of our current work."

Prof Fielding said that the "immediate goal" of the team is "evaluating an overall risk score in our next trial, UKALL15, which has been submitted to Cancer Research UK for funding".

Rachel Kahn commented that "this research is a key example of how important it is to continue developing risk scores based on the make-up of the cancer, which can help clinicians understand how likely someone is to respond to treatment".

"This study shows that further clues can be found based on changes to a patients chromosomes."

She continued: "The more we know about how abnormalities influence how risky a cancer is thought to be, the closer we get to being able to personalise treatment to each individual to give them the most effective treatments and the best possible chance of survival."

The study was funded by Cancer Research UK.

No conflicts of interest declared.

[However, Fielding declared to ASH : Amgen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Incyte: Consultancy.

BSH 2020: Abstracts BSH2020-OR-001 & BSH2020-OR-004

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Rituximab Offers No Extra Benefit to Induction Chemo in ALL - Medscape

The first-in-human, universal chimeric receptor antigen (CAR) T-cell (CAR-T) therapy GC027 was tolerable and resulted in antileukemic responses among patients with relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL), according to results from a phase 1 trial presented at the American Association for Cancer Research (AACR) Virtual Annual Meeting I 2020.1

Theuniversal CAR T cells target CD7, which, according to Xinxin Wang, PhD, ofGracell Biotechnologies Co, Ltd, in China, and lead author and presenter of thestudy, is a good target for T-ALL because it is expressed by more than 95% ofT-ALL patients.

GC027 isallogeneic, which may prevent the development of graft-versus-host disease. Theproduct is introduced using lentivirus for rapid elimination of T-ALL cells. Preclinicalstudies showed efficacy in a T-ALL xenograft model, and this prospective studyevaluated the safety and efficacy in humans.

Thesingle-arm, open-label study treated 5 adult patients with relapsed/refractoryCD7-positive T-ALL with a single infusion of 1 of 3 different dose levels ofG027: 0.6 x 107/kg, 3 x 107/kg, and 1.5 x 107/kg.Lymphodepletion therapy was administered prior to the G027 infusion. Theprimary endpoint was safety and the secondary endpoints included objectiveresponse rate (ORR) within 3 months after G027 infusion.

Patientswith extramedullary or central nervous system disease were excluded. Atbaseline, the median age was 24 (range, 19-38). Patients were heavilypretreated, with 5 median number of prior therapies (range, 1-9). Two patientshad high-risk disease and the median bone marrow tumor burden was a median of38.2% of blasts. None of the patients had undergone a prior allogeneic hematopoieticstem cell transplant.

Allpatients developed cytokine release syndrome (CRS), 4 of which were grade 3 and1 was grade 4. All cases were manageable and resolved with treatment andsupportive care. None of the patients developed neurotoxicity.

The completeremission (CR)/CR with incomplete hematologic recovery was 100%. By day 28, 4patients achieved a CR with negative for minimal residual disease (MRD) and 3of these patients remained MRD negative up to day 161. One patient achieved CRbut was MRD positive, and relapsed by day 29.

Peak CART-cell expansion in peripheral blood occurred between week 1 and 2.

As the first-in-human, universal CAR T-cell therapy for adult relapsed/refractory T-ALL, Dr Wang said, GC027 has demonstrated superior clinical efficacy and induced deep response in patients with acceptable safety profile. She added that trial enrollment is ongoing.

Reference

Wang X, Li S, Gao L, et al. Clinical safety and efficacy study of TruUCAR GC027: The first-in-human, universal CAR-T therapy for adult relapsed/refractory T-cell acute lymphoblastic leukemia (r/r T-ALL). Presented at: American Association for Cancer Research (AACR) Virtual Annual Meeting I; April 27-28, 2020. Abstract CT052.

This article originally appeared on Cancer Therapy Advisor

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First-in-Human Universal CAR-T Therapy Found Active in Relapsed/Refractory T-ALL - Oncology Nurse Advisor

Alessandra de Oliveira Pinheiro,1 Valria M Lara,1 Aline F Souza,1 Juliana B Casals,2 Fabiana F Bressan,1 Paulo Fantinato Neto,1 Vanessa C Oliveira,1 Daniele S Martins,1 Carlos E Ambrosio1

1Department of Veterinary Medicine, Faculty of Animal Science and Food Engineering, University of So Paulo, Pirassununga, So Paulo, Brazil; 2Private Veterinary Practice, Pirassununga, So Paulo, Brazil

Correspondence: Carlos E AmbrosioDepartment of Veterinary Medicine, Faculty of Animal Science and Food Engineering, University of So Paulo, FZEA- Av. Duque de Caxias Norte, 225, ZMV, Pirassununga 13635-900, So Paulo, BrazilTel +55 19 3565-4113 Email ceambrosio@usp.br

Purpose: Amniotic membrane stem cells have a high capacity of proliferation, cell expansion, and plasticity, as well as immunomodulatory properties that contribute to maternal-fetal tolerance. Owing to the lack of research on human amniotic membrane at different gestational stages, the canine model is considered ideal because of its genetic and physiological similarities. We aimed to characterize the canine amniotic membrane (CAM) cell lineage in different gestational stages and evaluate the expression of immunomodulatory genes.Materials and Methods: Twenty CAMs from early (20 30 days) (n=7), mid- (31 45 days) (n=7), and late gestation (46 63 days) (n=6) stages were studied. The cell features were assessed by cell viability tests, growth curve, colony-forming units, in vitro differentiation, cell labeling for different immunophenotypes, and pluripotent potential markers. The cells were subjected to RT-PCR and qPCR analysis to determine the expression of IDO, HGF, EGF, PGE2, and IL-10 genes.Results: CAM cells exhibited a fibroblastoid morphology and adherence to plastic with an average cell viability of 78.5%. The growth curve indicated a growth peak in the second passage and we obtained an average of 138.2 colonies. Osteogenic, chondrogenic, and adipogenic lineages were confirmed by in vitro differentiation assays. Cellular immunophenotyping experiments confirmed the presence of positive mesenchymal markers (CD90 and CD105) and the low or negative expression of hematopoietic markers (CD45 and CD34). Qualitative analysis of the immunomodulatory functions indicated the expression of the IDO, HGF, EGF5, and PGE2 genes. When stimulated by interferon-gamma, CAM cells exhibited higher IDO levels throughout gestation.Conclusion: The CAMs from different gestational stages presented features consistent with mesenchymal stem cell lineage; better results were observed during the late gestation stage. Therefore, the gestational stage is a key factor that may influence the functionality of therapies when using fetal membrane tissues from different periods of pregnancy.

Keywords: canine stem cells, immunomodulation, fetal annexes

This work is published by Dove Medical Press Limited, and licensed under a Creative Commons Attribution License.The full terms of the License are available at http://creativecommons.org/licenses/by/4.0/.The license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Characterization and Immunomodulation of Canine Amniotic Membrane Stem | SCCAA - Dove Medical Press

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that new data from its oncology program will be presented at the 2020 American Society of Clinical Oncology (ASCO20) Virtual Scientific Program from May 29-31. More than 80 abstracts in nearly 20 types of solid tumors and blood cancers have been accepted across Mercks broad cancer portfolio and investigational pipeline, including KEYTRUDA, Mercks anti-PD-1 therapy; LENVIMA (in collaboration with Eisai); LYNPARZA (in collaboration with AstraZeneca); and MK-6482 (formerly PT2977), an investigational, oral hypoxia-inducible factor-2 alpha (HIF-2) inhibitor.

Despite the challenges we all face due to the COVID-19 pandemic, Merck remains fully committed to supporting the cancer community and to advancing important scientific research from our clinical program, said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. The data to be presented at this years ASCO demonstrate how our deep and diverse oncology portfolio continues to show meaningful outcomes for patients in new tumor types and stages of disease, while long-term survival data for KEYTRUDA in non-small cell lung cancer, renal cell carcinoma and melanoma further support its important role in these types of cancer.

Key abstracts including late-breakers, oral sessions, and select poster discussions and posters to be presented at ASCO include:

Merck Investor Event

Merck will hold a virtual investor event in conjunction with the ASCO20 Virtual Scientific Program on Tuesday, June 2 at 2 p.m. ET. Details will be provided at a date closer to the event at http://investors.merck.com/home/default.aspx.

Details on Abstracts Listed Above, Additional Presentations and Key Abstracts with Mercks Collaboration Partners

KEYTRUDA

Breast Cancer

Bladder Cancer

Classical Hodgkin Lymphoma

Colorectal Cancer

Lung Cancer

Renal Cell Carcinoma

Prostate Cancer

Melanoma

Ovarian Cancer

Head and Neck Cancer

KEYTRUDA plus LENVIMA (in collaboration with Eisai)

Hepatocellular Carcinoma

Renal Cell Carcinoma

Endometrial Cancer

LYNPARZA (in collaboration with AstraZeneca)

Ovarian Cancer

MK-6482

Renal Cell Carcinoma

About KEYTRUDA (pembrolizumab) Injection, 100 mg

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

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,200 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications

Melanoma

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

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

Non-Small Cell Lung Cancer

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

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

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

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

Small Cell Lung Cancer

KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Head and Neck Squamous Cell Cancer

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

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

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

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

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

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

Microsatellite Instability-High (MSI-H) Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

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

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Cervical Cancer

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

Hepatocellular Carcinoma

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

Merkel Cell Carcinoma

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

Renal Cell Carcinoma

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

Endometrial Carcinoma

KEYTRUDA, in combination with LENVIMA, is indicated for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.

Selected Important Safety Information for KEYTRUDA

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients with various cancers receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%). Pneumonitis occurred in 8.2% (65/790) of NSCLC patients receiving KEYTRUDA as a single agent, including Grades 3-4 in 3.2% of patients, and occurred more frequently in patients with a history of prior thoracic radiation (17%) compared to those without (7.7%). Pneumonitis occurred in 6% (18/300) of HNSCC patients receiving KEYTRUDA as a single agent, including Grades 3-5 in 1.6% of patients, and occurred in 5.4% (15/276) of patients receiving KEYTRUDA in combination with platinum and FU as first-line therapy for advanced disease, including Grades 3-5 in 1.5% of patients.

Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-Mediated Hepatitis (KEYTRUDA) and Hepatotoxicity (KEYTRUDA in Combination With Axitinib)

Immune-Mediated Hepatitis

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hepatotoxicity in Combination With Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA alone. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed.

Immune-Mediated Endocrinopathies

KEYTRUDA can cause adrenal insufficiency (primary and secondary), hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Adrenal insufficiency occurred in 0.8% (22/2799) of patients, including Grade 2 (0.3%), 3 (0.3%), and 4 (<0.1%). Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC (16%) receiving KEYTRUDA, as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.

Monitor patients for signs and symptoms of adrenal insufficiency, hypophysitis (including hypopituitarism), thyroid function (prior to and periodically during treatment), and hyperglycemia. For adrenal insufficiency or hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 adrenal insufficiency or hypophysitis and withhold or discontinue KEYTRUDA for Grade 3 or Grade 4 adrenal insufficiency or hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

Immune-Mediated Nephritis and Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.

Immune-Mediated Skin Reactions

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Other Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barr syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use.

Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 (26%) developed graft-versus-host disease (GVHD) (1 fatal case) and 2 (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (1 fatal case). Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptorblocking antibody before transplantation. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions.

In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.

Increased Mortality in Patients With Multiple Myeloma

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

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions

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Merck to Present New Data from its Broad Oncology Portfolio and Pipeline at the ASCO20 Virtual Scientific Program - Business Wire

CAMBRIDGE, Mass.--(BUSINESS WIRE)--AVROBIO, Inc. (Nasdaq: AVRO) and Magenta Therapeutics (Nasdaq: MGTA) today announced a research and clinical collaboration agreement to evaluate the potential utility of MGTA-117, Magentas novel targeted antibody-drug conjugate (ADC) for conditioning patients before they receive one of AVROBIOs investigational lentiviral gene therapies.

The collaboration will combine AVROBIOs leadership in lentiviral gene therapies with Magentas expertise in ADC-based conditioning and is expected to further the two companies shared mission to enable patients to live free from disease. Under the collaboration, AVROBIO and Magenta will jointly evaluate MGTA-117 in conjunction with one or more of AVROBIOs investigational gene therapies. Magenta will retain all commercial rights to MGTA-117. AVROBIO will retain all commercial rights to its gene therapies and will be responsible for the clinical trial costs related to the evaluation of MGTA-117 with AVROBIOs gene therapies.

This agreement with Magenta springs from our strategic focus on maintaining technology leadership in gene therapy, said Geoff MacKay, AVROBIOs president and CEO. AVROBIO has always led by investing early in technological innovations that further the field of lentiviral gene therapy, such as plato, our proprietary platform designed to optimize the safety, potency and durability of our investigational lentiviral gene therapies. Were continually assessing new technologies that could be complementary to our plato platform to sustain our cutting-edge advantage and continue to evolve platos capabilities.

We believe targeted ADCs represent the next generation of medicines to prepare patients for gene therapy or transplant in a targeted, precise way. AVROBIOs investigational gene therapies complement our platform as well as our focus and commitment to patients. This partnership will allow Magenta to validate our conditioning platform in lentiviral gene therapy applications, said Jason Gardner, D.Phil., president and chief executive officer, Magenta Therapeutics. Weve selected ADCs as the preferred modality for our conditioning programs, as we believe they offer the most promising option for more patients. We have optimized our ADCs for gene therapy and transplant settings and look forward to collaborating with AVROBIO to evaluate MGTA-117 in specific gene therapy settings. Magenta will continue to develop MGTA-117 in other diseases, including blood cancers and genetic diseases.

MGTA-117, Magentas most advanced conditioning program, is a CD117-targeted antibody engineered for the transplant setting and conjugated to amanitin, a toxin in-licensed from Heidelberg Pharma. It is designed to precisely deplete only hematopoietic stem and progenitor cells and has shown high selectivity, potent efficacy, wide safety margins and broad tolerability in non-human primate models, suggesting that it may be capable of clearing space in bone marrow to support long-term engraftment and rapid recovery in humans. Magenta plans to complete IND-enabling studies this year.

AVROBIO currently uses a personalized conditioning regimen with precision dosing of busulfan, an extensively validated conditioning agent generally considered to be the gold standard for ex vivo lentiviral gene therapy, based on decades of general use and administration to hundreds of patients treated with lentiviral gene therapy candidates. The treating clinician uses therapeutic drug monitoring (TDM) to evaluate how quickly the patient metabolizes busulfan and adjusts the dose regimen accordingly with the goal of achieving the optimum result. AVROBIO has reported early clinical data with this precision conditioning regimen with TDM in its own clinical trials, adding to a body of data that suggest busulfan can effectively clear space in the patients bone marrow, where stem cells engraft, produce generations of daughter cells carrying the therapeutic gene and make the functional protein the patient needs to maintain cellular health.

About AVROBIO

Our mission is to free people from a lifetime of genetic disease with a single dose of gene therapy. We aim to halt or reverse disease throughout the body by driving durable expression of functional protein, even in hard-to-reach tissues and organs including the brain, muscle and bone. Our clinical-stage programs include Fabry disease, Gaucher disease and cystinosis and we also are advancing a program in Pompe disease. AVROBIO is powered by the plato gene therapy platform, our foundation designed to scale gene therapy worldwide. We are headquartered in Cambridge, Mass., with an office in Toronto, Ontario. For additional information, visit avrobio.com, and follow us on Twitter and LinkedIn.

About Magenta Therapeutics

Magenta Therapeutics is a clinical-stage biotechnology company developing medicines to bring the curative power of immune system reset through stem cell transplant to more patients with autoimmune diseases, genetic diseases and blood cancers. Magenta is combining leadership in stem cell biology and biotherapeutics development with clinical and regulatory expertise, a unique business model and broad networks in the stem cell transplant world to revolutionize immune reset for more patients. Magenta is based in Cambridge, Mass. For more information, please visit http://www.magentatx.com. Follow Magenta on Twitter: @magentatx.

AVROBIO Forward-Looking Statements

This press release contains forward-looking statements, including statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements may be identified by words and phrases such as aims, anticipates, believes, could, designed to, estimates, expects, forecasts, goal, intends, may, plans, possible, potential, seeks, will, and variations of these words and phrases or similar expressions that are intended to identify forward-looking statements. These forward-looking statements include, without limitation, statements regarding our business strategy for and the potential therapeutic benefits of our prospective product candidates, the design, commencement, enrollment and timing of ongoing or planned clinical trials, clinical trial results, product approvals and regulatory pathways, anticipated benefits of our gene therapy platform including potential impact on our commercialization activities, timing and likelihood of success, the expected benefits and results of our implementation of the plato platform in our clinical trials and gene therapy programs, the expected safety profile of our investigational gene therapies, and the potential and expected benefits of MGTA-117, Magentas investigational antibody-drug conjugate, including the ability of MGTA-117 to deplete hematopoietic stem and progenitor cells in order to clear space in bone marrow to support long-term engraftment in humans, as well as MGTA-117s potential application to AVROBIOs investigational gene therapies. Any such statements in this press release that are not statements of historical fact may be deemed to be forward-looking statements. Results in preclinical or early-stage clinical trials may not be indicative of results from later stage or larger scale clinical trials and do not ensure regulatory approval. You should not place undue reliance on these statements, or the scientific data presented.

Any forward-looking statements in this press release are based on AVROBIOs current expectations, estimates and projections about our industry as well as managements current beliefs and expectations of future events only as of today and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to, the risk that any one or more of AVROBIOs product candidates will not be successfully developed or commercialized, the risk of cessation or delay of any ongoing or planned clinical trials of AVROBIO or our collaborators, the risk that AVROBIO may not successfully recruit or enroll a sufficient number of patients for our clinical trials, the risk that AVROBIO may not realize the intended benefits of our gene therapy platform, including the features of our plato platform, the risk that AVROBIO may not realize the intended benefit of MGTA-117 with respect to AVROBIOs investigational gene therapies, the risk that our product candidates or procedures in connection with the administration thereof will not have the safety or efficacy profile that we anticipate, the risk that prior results, such as signals of safety, activity or durability of effect, observed from preclinical or clinical trials, will not be replicated or will not continue in ongoing or future studies or trials involving AVROBIOs product candidates, the risk that we will be unable to obtain and maintain regulatory approval for our product candidates, the risk that the size and growth potential of the market for our product candidates will not materialize as expected, risks associated with our dependence on third-party suppliers and manufacturers, risks regarding the accuracy of our estimates of expenses and future revenue, risks relating to our capital requirements and needs for additional financing, risks relating to clinical trial and business interruptions resulting from the COVID-19 outbreak or similar public health crises, including that such interruptions may materially delay our development timeline and/or increase our development costs or that data collection efforts may be impaired or otherwise impacted by such crises, and risks relating to our ability to obtain and maintain intellectual property protection for our product candidates. For a discussion of these and other risks and uncertainties, and other important factors, any of which could cause AVROBIOs actual results to differ materially and adversely from those contained in the forward-looking statements, see the section entitled Risk Factors in AVROBIOs most recent Annual or Quarterly Report, as well as discussions of potential risks, uncertainties and other important factors in AVROBIOs subsequent filings with the Securities and Exchange Commission. AVROBIO explicitly disclaims any obligation to update any forward-looking statements except to the extent required by law.

Magenta Therapeutics Forward Looking Statements

This press release may contain forward-looking statements and information within the meaning of The Private Securities Litigation Reform Act of 1995 and other federal securities laws, including, without limitation, statements regarding the research and clinical collaboration agreement between Magenta and AVROBIO, including the timing, progress and success of the collaboration contemplated under the agreement, the successful evaluation MGTA-117 in conjunction with one or more of AVROBIOs investigational gene therapies under the agreement, the anticipated cost allocation and other commercial terms under the agreement, Magentas strategy and business plan, as well as the future development, manufacture and commercialization between AVROBIO and Magenta. The use of words such as may, will, could, should, expects, intends, plans, anticipates, believes, estimates, predicts, projects, seeks, endeavor, potential, continue or the negative of such words or other similar expressions can be used to identify forward-looking statements. The express or implied forward-looking statements included in this press release are only predictions and are subject to a number of risks, uncertainties and assumptions, including, without limitation, risks set forth under the caption Risk Factors in Magentas most recent Annual Report on Form 10-K, as updated by Magentas most recent Quarterly Report on Form 10-Q and its other filings with the Securities and Exchange Commission, as well as risks, uncertainties and assumptions regarding the impact of the COVID-19 pandemic to Magentas business, operations, strategy, goals and anticipated timelines, including, without limitation, Magentas ongoing and planned preclinical activities, ability to initiate, enroll, conduct or complete ongoing and planned clinical trials, timelines for regulatory submissions and financial position. In light of these risks, uncertainties and assumptions, the forward-looking events and circumstances discussed in this press release may not occur and actual results could differ materially and adversely from those anticipated or implied in the forward-looking statements. You should not rely upon forward-looking statements as predictions of future events. Although Magenta believes that the expectations reflected in the forward-looking statements are reasonable, it cannot guarantee that the future results, levels of activity, performance or events and circumstances reflected in the forward-looking statements will be achieved or occur. Moreover, except as required by law, neither Magenta nor any other person assumes responsibility for the accuracy and completeness of the forward-looking statements included in this press release. Any forward-looking statement included in this press release speaks only as of the date on which it was made. We undertake no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events or otherwise, except as required by law.

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AVROBIO and Magenta Therapeutics Announce Collaboration to Evaluate Targeted Antibody-Drug Conjugate as a Potential Conditioning Regimen for...

Lineage Cell Therapeutics, Inc. (NYSE American and TASE: LCTX), a clinical-stage biotechnology company developing novel cell therapies for unmet medical needs, today announced that updated results from a Phase I/IIa study of its lead product candidate, OpRegen, a retinal pigment epithelium (RPE) cell transplant therapy currently in development for the treatment of dry age-related macular degeneration (AMD), were published online via the ARVOLearn platform as part of the 2020 Association for Research in Vision and Ophthalmology (ARVO) Meeting. The presentation entitled, "Phase I/IIa Clinical Trial of Human Embryonic Stem Cell (hESC)-Derived Retinal Pigmented Epithelium (RPE, OpRegen) Transplantation in Advanced Dry Form Age-Related Macular Degeneration (AMD): Interim Results" (Abstract # 3363764), was presented by Christopher D. Riemann, M.D., Vitreoretinal Surgeon and Fellowship Director, Cincinnati Eye Institute (CEI) and University of Cincinnati School of Medicine. Dr. Riemanns presentation is available on the Media page of the Lineage website. Lineage will also host a live call with Dr. Riemann, on Monday, May 11, 2020 at 5:00 p.m. ET/2:00 p.m. PT to further discuss the results of treatment with OpRegen. Interested parties can access the call on the Events and Presentations section of Lineages website.

"This update is significant as it builds on our earlier reports of gains in visual acuity and provides a more comprehensive picture of treatment with OpRegen for dry AMD, with meaningful improvements in the progression of geographic atrophy, visual acuity, and reading speed observed in our first Cohort 4 patient and first Orbit SDS with thaw-and-inject formulation dosed patient," stated Brian M. Culley, Lineage CEO. "As dry AMD is a slow and progressive disease, it takes many months to observe changes to retinal anatomy or visual acuity. With the benefit of longer follow-up, we now can report that some OpRegen treated patients are able to see better, have less growth in their area of GA, and are able to read faster, all of which represent significant enhancements to vision and quality of life metrics. In addition to these individual results, the pooled data continues to suggest a treatment effect in both visual acuity and GA progression. Notably, we also are reporting additional evidence that OpRegen cells remain present for at least 4 years and hope that longer follow-up periods will reinforce a growing body of evidence that OpRegen is well-tolerated and can provide sustained and clinically meaningful benefits with a single dose of RPE cells. Our near-term objective is to treat and monitor the final four patients in Cohort 4 of the current study and utilize these data to direct our clinical, regulatory, and partnership discussions. Our goal is to combine the best cell line, the best production process, and the best delivery system, to position OpRegen as the front-runner in the race to address the unmet need in the potential billion-dollar dry AMD market."

"As a principal investigator on the OpRegen clinical study, I am excited to present this most recent update, where all Cohort 4 patients treated with OpRegen had improved Best Corrected Visual Acuity up to one year or at their last visit, demonstrating a substantial treatment response," stated Christopher D. Riemann, M.D. "The pooled Cohort 4 data demonstrate a significant, greater than 10-letter sustained visual acuity improvement over the entire followup period. Reading center assessments of GA also suggest a reduction in GA progression in the OpRegen treated eye when compared to fellow eye in Cohort 4. I am encouraged by the results observed in patients treated to date with OpRegen and I look forward to dosing patients in this study at CEI."

KOL Call Information and Webcast

Lineage will host a conference call with Dr. Riemann, on Monday, May 11, 2020 at 5:00 p.m. ET/2:00 p.m. PT to further discuss the results following treatment with OpRegen. A live webcast of the conference call will be available online in the Events and Presentations section of Lineages website. Interested parties may also access the conference call by dialing (866) 888-8633 from the U.S. and Canada and (636) 812-6629 from elsewhere outside the U.S. and Canada and should request the "Lineage Cell Therapeutics Call". A replay of the webcast will be available on Lineages website for 30 days and a telephone replay will be available through May 19, 2020, by dialing (855) 859-2056 from the U.S. and Canada and (404) 537-3406 from elsewhere outside the U.S. and Canada and entering conference ID number 6597936.

Story continues

About Lineage Cell Therapeutics, Inc.

Lineage Cell Therapeutics is a clinical-stage biotechnology company developing novel cell therapies for unmet medical needs. Lineages programs are based on its robust proprietary cell-based therapy platform and associated in-house development and manufacturing capabilities. With this platform Lineage develops and manufactures specialized, terminally differentiated human cells from its pluripotent and progenitor cell starting materials. These differentiated cells are developed to either replace or support cells that are dysfunctional or absent due to degenerative disease or traumatic injury or administered as a means of helping the body mount an effective immune response to cancer. Lineages clinical programs are in markets with billion dollar opportunities and include three allogeneic ("off-the-shelf") product candidates: (i) OpRegen, a retinal pigment epithelium transplant therapy in Phase 1/2a development for the treatment of dry age-related macular degeneration, a leading cause of blindness in the developed world; (ii) OPC1, an oligodendrocyte progenitor cell therapy in Phase 1/2a development for the treatment of acute spinal cord injuries; and (iii) VAC2, a cancer immunotherapy of antigen-presenting dendritic cells in Phase 1 development for the treatment of non-small cell lung cancer. For more information, please visit http://www.lineagecell.com or follow the Company on Twitter @LineageCell.

Forward-Looking Statements

Lineage cautions you that all statements, other than statements of historical facts, contained in this press release, are forward-looking statements. Forward-looking statements, in some cases, can be identified by terms such as "believe," "may," "will," "estimate," "continue," "anticipate," "design," "intend," "expect," "could," "plan," "potential," "predict," "seek," "should," "would," "contemplate," project," "target," "tend to," or the negative version of these words and similar expressions. Such statements include, but are not limited to, statements relating to Lineages objectives with respect to OpRegen. Forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause Lineages actual results, performance or achievements to be materially different from future results, performance or achievements expressed or implied by the forward-looking statements in this press release, including risks and uncertainties inherent in Lineages business and other risks in Lineages filings with the Securities and Exchange Commission (the SEC). Lineages forward-looking statements are based upon its current expectations and involve assumptions that may never materialize or may prove to be incorrect. All forward-looking statements are expressly qualified in their entirety by these cautionary statements. Further information regarding these and other risks is included under the heading "Risk Factors" in Lineages periodic reports with the SEC, including Lineages Annual Report on Form 10-K filed with the SEC on March 12, 2020 and its other reports, which are available from the SECs website. You are cautioned not to place undue reliance on forward-looking statements, which speak only as of the date on which they were made. Lineage undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law.

View source version on businesswire.com: https://www.businesswire.com/news/home/20200506005264/en/

Contacts

Lineage Cell Therapeutics, Inc. IR Ioana C. Hone(ir@lineagecell.com)(442) 287-8963

Solebury Trout IR Gitanjali Jain Ogawa(Gogawa@troutgroup.com)(646) 378-2949

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Lineage Cell Therapeutics Reports New Data With OpRegen for the Treatment of Dry AMD With Geographic Atrophy - Yahoo Finance

VANCOUVER, Washington, May 04, 2020 (GLOBE NEWSWIRE) -- CytoDyn Inc. (OTC.QB: CYDY), (CytoDyn or the Company"), a late-stage biotechnology company developing leronlimab (PRO 140), a CCR5 antagonist with the potential for multiple therapeutic indications, today announced that the Company is expecting enrollment completion for its 75 patient, Phase 2 double blinded, placebo controlled, randomized study by the end of this month.

CytoDyn has submitted a request to the FDA to grant expanded access, also known as compassionate use, to make leronlimab available for patients not eligible for participation in two ongoing clinical trials for coronavirus infections. Many severe and critically-ill patients, who have received off-label immunomodulatory treatments for COVID-19, are excluded from participation in the Companys Phase 2b/3 clinical trial and could potentially benefit from access to leronlimab under a compassionate use program.

There are 49 COVID-19 patients who have enrolled for treatment with leronlimab through eIND. Four out of 11 critically ill patients with a multitude of pre-existing conditions survived after treatment, and of the next 38 patients, many were extubated, improved, or were discharged.

Nader Pourhassan, Ph.D., President and Chief Executive Officer of CytoDyn said, We are very excited about the continuing positive responses from eIND patients following their treatment with leronlimab. We are equally excited about the prospects for patients should the FDA grant access to leronlimab under the compassionate use program. During this past Saturday, we had to overcome many obstacles for two patients who desperately wanted leronlimab. One patient was in the same hospital that enrolled the first 11 patients and the second was a VIP patient in Los Angeles. Under the compassionate use program, we could avoid and quickly overcome this type of stress and turmoil which was very difficult for the patients, their families, the physicians, and CytoDyn. The daughter of a patient who was on a machine used for severe heart and lung failure contacted us directly and expressed her immense gratitude believing leronlimab saved her mothers life. These are amazing times for us at CytoDyn; with the opportunity to wake up every day with the potential of saving somebodys life. For sure, I could never have imagined such an incredible honor.

About Coronavirus Disease 2019CytoDyn is currently enrolling patients in two clinical trials for COVID-19, a Phase 2 randomized clinical trial for mild-to-moderate COVID-19 population in the U.S. and a Phase 2b/3 randomized clinical trial for severe and critically ill COVID-19 population in several hospitals throughout the country.

SARS-CoV-2 was identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China. The origin of SARS-CoV-2 causing the COVID-19 disease is uncertain, and the virus is highly contagious. COVID-19 typically transmits person to person through respiratory droplets, commonly resulting from coughing, sneezing, and close personal contact. Coronaviruses are a large family of viruses, some causing illness in people and others that circulate among animals. For confirmed COVID-19 infections, symptoms have included fever, cough, and shortness of breath. The symptoms of COVID-19 may appear in as few as two days or as long as 14 days after exposure. Clinical manifestations in patients have ranged from non-existent to severe and fatal. At this time, there are minimal treatment options for COVID-19.

About Leronlimab (PRO 140) and BLA Submission for the HIV Combination TherapyThe FDA has granted a Fast Track designation to CytoDyn for two potential indications of leronlimab for deadly diseases. The first as a combination therapy with HAART for HIV-infected patients and the second is for metastatic triple-negative breast cancer.Leronlimab is an investigational humanized IgG4 mAb that blocks CCR5, a cellular receptor that is important in HIV infection, tumor metastases, and other diseases, including NASH.Leronlimab has completed nine clinical trials in over 800 people, including meeting its primary endpoints in a pivotal Phase 3 trial (leronlimab in combination with standard antiretroviral therapies in HIV-infected treatment-experienced patients).

In the setting of HIV/AIDS, leronlimab is a viral-entry inhibitor; it masks CCR5, thus protecting healthy T cells from viral infection by blocking the predominant HIV (R5) subtype from entering those cells. Leronlimab has been the subject of nine clinical trials, each of which demonstrated that leronlimab could significantly reduce or control HIV viral load in humans. The leronlimab antibody appears to be a powerful antiviral agent leading to potentially fewer side effects and less frequent dosing requirements compared with daily drug therapies currently in use. We would like to provide an update that the Biologics License Application (BLA) for Leronlimab as a Combination Therapy for Highly Treatment Experienced HIV Patients will be considered completed after the clinical datasets are submitted on May 11, 2020. The clinical datasets are updated to address FDA comments for mock datasets from March 12 and March 20, 2020. After the BLA submission is considered completed, FDA makes a filing decision and sets a PDUFA goal date. CytoDyn has Fast Track designation and a rolling review previously assigned by the FDA and plans to request a priority review for the BLA. A priority review designation means the FDAs goal is to take action on the marketing application within six months of receipt (compared with 10 months under standard review).

In the setting of cancer, research has shown that CCR5 may play a role in tumor invasion, metastases, and tumor microenvironment control. Increased CCR5 expression is an indicator of disease status in several cancers. Published studies have shown that blocking CCR5 can reduce tumor metastases in laboratory and animal models of aggressive breast and prostate cancer. Leronlimab reduced human breast cancer metastasis by more than 98% in a murine xenograft model. CytoDyn is, therefore, conducting aPhase 1b/2 human clinical trial in metastatic triple-negative breast cancer and was granted Fast Track designation in May 2019.

The CCR5 receptor appears to play a central role in modulating immune cell trafficking to sites of inflammation. It may be crucial in the development of acute graft-versus-host disease (GvHD) and other inflammatory conditions. Clinical studies by others further support the concept that blocking CCR5 using a chemical inhibitor can reduce the clinical impact of acute GvHD without significantly affecting the engraftment of transplanted bone marrow stem cells. CytoDyn is currently conducting a Phase 2 clinical study with leronlimab to support further the concept that the CCR5 receptor on engrafted cells is critical for the development of acute GvHD, blocking the CCR5 receptor from recognizing specific immune signaling molecules is a viable approach to mitigating acute GvHD. The FDA has granted orphan drug designation to leronlimab for the prevention of GvHD.

About CytoDynCytoDyn is a late-stage biotechnology company developing innovative treatments for multiple therapeutic indications based on leronlimab, a novel humanized monoclonal antibody targeting the CCR5 receptor. CCR5 appears to play a critical role in the ability of HIV to enter and infect healthy T-cells.The CCR5 receptor also appears to be implicated in tumor metastasis and immune-mediated illnesses, such as GvHD and NASH. CytoDyn has successfully completed a Phase 3 pivotal trial with leronlimab in combination with standard antiretroviral therapies in HIV-infected treatment-experienced patients. CytoDyn completed the filing of its BLA in April 2020 to seek FDA approval for leronlimab as a combination therapy for highly treatment experienced HIV patients. CytoDyn is also conducting a Phase 3 investigative trial with leronlimab as a once-weekly monotherapy for HIV-infected patients. CytoDyn plans to initiate a registration-directed study of leronlimab monotherapy indication. If successful, it could support a label extension. Clinical results to date from multiple trials have shown that leronlimab can significantly reduce viral burden in people infected with HIV with no reported drug-related serious adverse events (SAEs). Moreover, a Phase 2b clinical trial demonstrated that leronlimab monotherapy can prevent viral escape in HIV-infected patients; some patients on leronlimab monotherapy have remained virally suppressed for more than five years. CytoDyn is also conducting a Phase 2 trial to evaluate leronlimab for the prevention of GvHD and a Phase 1b/2 clinical trial with leronlimab in metastatic triple-negative breast cancer. More information is atwww.cytodyn.com.

Forward-Looking StatementsThis press releasecontains certain forward-looking statements that involve risks, uncertainties and assumptions that are difficult to predict. Words and expressions reflecting optimism, satisfaction or disappointment with current prospects, as well as words such as believes, hopes, intends, estimates, expects, projects, plans, anticipates and variations thereof, or the use of future tense, identify forward-looking statements, but their absence does not mean that a statement is not forward-looking. Forward-looking statements specifically include statements about leronlimab, its ability to have positive health outcomes, the possible results of clinical trials, studies or other programs or ability to continue those programs, the ability to obtain regulatory approval for commercial sales, and the market for actual commercial sales. The Companys forward-looking statements are not guarantees of performance, and actual results could vary materially from those contained in or expressed by such statements due to risks and uncertainties including: (i)the sufficiency of the Companys cash position, (ii)the Companys ability to raise additional capital to fund its operations, (iii) the Companys ability to meet its debt obligations, if any, (iv)the Companys ability to enter into partnership or licensing arrangements with third parties, (v)the Companys ability to identify patients to enroll in its clinical trials in a timely fashion, (vi)the Companys ability to achieve approval of a marketable product, (vii)the design, implementation and conduct of the Companys clinical trials, (viii)the results of the Companys clinical trials, including the possibility of unfavorable clinical trial results, (ix)the market for, and marketability of, any product that is approved, (x)the existence or development of vaccines, drugs, or other treatments that are viewed by medical professionals or patients as superior to the Companys products, (xi)regulatory initiatives, compliance with governmental regulations and the regulatory approval process, (xii)general economic and business conditions, (xiii)changes in foreign, political, and social conditions, and (xiv)various other matters, many of which are beyond the Companys control. The Company urges investors to consider specifically the various risk factors identified in its most recent Form10-K, and any risk factors or cautionary statements included in any subsequent Form10-Q or Form8-K, filed with the Securities and Exchange Commission. Except as required by law, the Company does not undertake any responsibility to update any forward-looking statements to take into account events or circumstances that occur after the date of this press release.

CYTODYN CONTACTSInvestors: Dave Gentry, CEORedChip CompaniesOffice: 1.800.RED.CHIP (733.2447)Cell: 407.491.4498dave@redchip.com

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FDA Approves 54 Emergency INDs for Leronlimab Treatment of Coronavirus CytoDyn Requests Compassionate Use from FDA for COVID-19 Patients Not Eligible...

Cheyenne Braganza has an entire floor to herself in her dorm building at the University of Vermont.

Her roommate is home in Massachusetts, gone with almost all 10,000-plus UVM undergraduates. The Burlington school told them in mid-March to stay away after spring break rather than return and risk spreading the COVID-19 virus.

Cheyenne Braganza, a sophomore at the University of Vermont, is a native of Kenya. She is among a handful of students remaining on the Burlington campus that stopped hosting in-person classes in mid-March.(Photo: COURTESY)

Braganza is among about 140 international students who, because of COVID-19-related travel complications, remain on campus. She has plenty of peace and quiet in her suite as she and students on-campus and at home continue their studies online in the last few days of final exams.

The solitude is great for doing school work, said the native of Nairobi, Kenya. The sophomore studying molecular genetics has a bathroom to herself, a glorious feeling for a college student. She can play music as loud as she wants.

But its isolating.

It gets lonely because I finished my work for the day and theres not much to do, said Braganza, who turns 21 in June. Her boyfriend, mother, father and brother are seven time zones away in Kenya. She talks with them on the phone during the day, but at night when her school work is done, her loved ones back home have gone to bed and the campus is forest-quiet Braganza feels forsaken.

Cheyenne Braganza of Nairobi, Kenya, says she gets a lot of work done but often feels lonely as one of only a few students remaining on campus at the University of Vermont.(Photo: COURTESY)

She finds comfort in socially-distant interactions with dining-hall workers and students she sees on meal runs. She takes solace in her work, which includes watching videos of scientists performing lab work before calculating data derived from that to write her own reports.

Braganzas career goals are timely. She dreams of doing medical research and running her own lab.

I dont want to treat patients. I want to do more-groundbreaking work, like research on vaccines, she said. Ive always had a passion for research.

More personal stories: How Vermonters are facing life in the coronavirus era

Contact Brent Hallenbeck at (802) 660-1844 or bhallenbeck@freepressmedia.com. Follow Brent on Twitter at http://www.twitter.com/BrentHallenbeck.

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A floor to herself: UVM international student remains on campus - Burlington Free Press

The Association for Molecular Pathology (AMP) today published consensus recommendations designed to support the design, validation, and interpretation of clinical genotyping tests for the prediction of warfarin response.

The new warfarin genotyping guideline offers a two-tier categorization of alleles that are recommended for inclusion in clinical PGx genotyping assays. Using criteria such as allele frequencies in different populations and ethnicities, the availability of reference materials and other technical considerations, the AMP PGx Working Group recommended a minimum set of alleles and their defining variants that should be included in all clinical warfarin sensitivity genotyping testswhat the guideline defines as Tier 1 PGx variant alleles.

The AMP PGx Working Groupdeveloped the guideline with organizational representation from the College of American Pathologists (CAP) and the Clinical Pharmacogenetics Implementation Consortium (CPIC). The team also defined a Tier 2 list of optional alleles that do not currently meet one or more of the criteria for inclusion in Tier 1. AMP said the recommendations were meant to be a reference guide and not a restrictive listand that it intends to update these recommendations as new data and/or reference materials become available.

Common benign variants in high linkage disequilibrium (LD) with established functional variant(s) are not currently being considered for inclusion as Tier 1 or Tier 2 variant alleles in routine clinical PGx genotyping panels, the Working Group added.

Guideline recommendations have been published in a manuscript, Recommendations for Clinical Warfarin Sensitivity Genotyping Allele Selection: A Joint Recommendation of the Association for Molecular Pathology and College of American Pathologists, that was released online ahead of publication inThe Journal of Molecular Diagnostics.

Clinical genotyping assays that help predict warfarin response and optimize a patients dosage requirements have enabled some of the earliest success stories of this precision medicine era, said Victoria M. Pratt, Ph.D., FACMG, Professor and Director of Pharmacogenetics and Molecular Genetics Laboratories, Indiana University School of Medicine, and AMP PGx Working Group Chair. Together, the AMP PGx Working Group defined a standard set of evidence-based recommendations that will help build on these past successes and improve phenotype prediction and test interpretation for all futurewarfarin sensitivity genotyping panels.

Earlier Recommendations

The AMP PGx Working Group previously developed recommendations for clinical CYP2C9 testing that were intended to be applied to CYP2C9-related medications including warfarin. Last year, the Working Group developed recommendations for clinical CYP2C9 testing that were intended to be applied to CYP2C9-related medications including warfarin.

Since then, the Working Group said, the discovery of additional well-characterized genes/alleles contributing to inter-individual variation in warfarin sensitivity created a need for a separate document addressing genes/alleles specifically related to warfarin sensitivity, including the CYP2C9 alleles.

CYP2C9 is a member of the CYP2C subfamily of the cytochrome P450 enzymes, and one of the most abundant and important drug metabolizing enzymes. It acts on approximately 15% of drugs in current clinical use, including ibuprofen and the blood thinner warfarin.As a result, it is currently included in the FDAs Table of Pharmacogenetic Biomarkers in Drug Labeling forseveral FDA-approved drugs.

According to the Working Group, clinicians have been able since 2010 to obtain CYP2C9 and VKORC1 genotypes and use either the FDA prescribing label or PGx dosing algorithms to define warfarin dose requirements for their patients. While experts have contributed to establishing high-quality genotype-based recommendations for warfarin14 and the accessibility of clinical PGx testing continues to increase, the diversity of available testing platforms and variants interrogated have led to inconsistencies in results among labs.

Although the initial CPIC guideline recommendations included variants that are more common among Caucasians and Asians, the updated 2017 guideline incorporated additional variants that are predictors of warfarin dose requirements in patients of African descent, the Working Group noted. In order to implement recommendations from the recent CPIC warfarin guideline, both the availability of self-reported ancestry and interrogation for specific alleles are therefore essential.

The Working Group recognizes that the benefit of genotype-guided dosing for warfarin to reduce under or over dosing episodes in patients from diverse ethnicities will not likely be realized unless testing panels account for appropriate clinical variants that are relevant for the ethnic groups to whom the test is offered, the Group added.

The new guideline on clinical warfarin sensitivity genotyping allele selection is the last in a series of three reports that are intended to facilitate testing and promote standardization for frequently usedpharmacogenetics (PGx)genotyping assays. The latest guideline builds on theearlier recommendations for clinicalCYP2C19andCYP2C9genotyping, according to AMP.

The recommendations should be implemented together with other clinical guidelines such as those issued by the CPIC, which focus primarily on the interpretation of PGx test results and therapeutic recommendations for specific drug-gene pairs.

AMP members are among the earliest adopters of pharmacogenetic testing in clinical settings, said AMP President Karen E. Weck, M.D., who is also a Professor of Pathology and Laboratory Medicine, Professor of Genetics and Director, Molecular Genetics and Pharmacogenomics at University of North Carolina Chapel Hill, and a PGx Working Group Member.This series of guidelines for common clinical PGx genotyping tests is another example of AMPs ongoing commitment to sharing our collective expertise with the broader laboratory community in order to improve professional practice and patient care.

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AMP Publishes Recommendations for Clinical Genotyping Tests to Predict Warfarin Response - Clinical OMICs News

DUBLIN--(BUSINESS WIRE)--The "2020 Global Infectious Disease Molecular Diagnostics Market for 100 Tests: US, Europe, Japan--Supplier Shares by Test, Volume and Sales Segment Forecasts, Competitive Strategies, Innovative Technologies, Instrumentation Review" report has been added to ResearchAndMarkets.com's offering.

This new seven-country study contains is designed to help current suppliers and potential market entrants identify and evaluate emerging opportunities in the infectious disease molecular diagnostics market during the next five years.

Report Highlights

Rationale

The infectious disease molecular diagnostics market is one of the most rapidly growing segment of the in vitro diagnostics industry. The next five years will witness significant developments in reagent systems and automation, as well as introduction of a wide range of new products that will require innovative marketing approaches. The rate of market penetration into routine clinical laboratories, however, will depend on the introduction of cost-effective and automated systems with amplification methods.

In order to successfully capitalize on the opportunities presented by the infectious disease molecular diagnostics market, many companies are already exploiting new molecular technologies as corporate strategic assets, managed in support of business and marketing strategies. Integrating new technology planning with business and corporate strategies will be one of the most challenging tasks for diagnostic companies during the next five years.

Geographic Coverage

Worldwide Market Overview

Market Segmentation Analysis

Product/Technology Review

Competitive Assessments

Opportunities and Strategic Recommendations

For more information about this report visit https://www.researchandmarkets.com/r/dr0itc

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2020 Insights on the Global Infectious Disease Molecular Diagnostics Market - Business and Technological Trends in Major Markets -...

Scientists at the Department of Infection and Immunity of the Luxembourg Institute of Health (LIH) revealed a novel mechanism through which the immune system can control autoimmunity and cancer. In the special focus of the researchers were regulatory T cells - a specific type of white blood cells that in general act as a brake on the immune system. The LIH research team led by Prof Dirk Brenner, FNR ATTRACT fellow and Head of Experimental & Molecular Immunology, revealed a mechanism that controls the function of regulatory T cells and determines the balance between autoimmunity and anti-cancer activity. In a preclinical model, the scientists further showed that the elucidation of the metabolic mechanism of a disease can lead to disease reduction by a rationally-designed diet that specifically addresses these metabolic alterations. This sets a new direction for future treatment of metabolic diseases. These findings, which were published today in the leading international journal Cell Metabolism, hold important implications for the development of personalised treatment options for autoimmune disorders and cancer.

"Our immune system is needed for a healthy body function and protects us from all kinds of infections. Particularly important in this respect are T cells, and specifically regulatory T cells. Although these represent only a small fraction of all T cells, they are crucial to keep our immune system in check" explains Prof Brenner. "If regulatory T cells are not functional, the immune system gets out of control and turns against its own body. This can lead to detrimental autoimmune diseases like multiple sclerosis, type I diabetes or arthritis. However, a highly reactive immune system can kill cancer cells very efficiently. This has led to the development of 'checkpoint inhibitors', specific drugs that unleash an immune system attack on cancer cells and which won the Nobel Prize in Medicine in 2018". The Luxembourgish scientists took this angle and revealed a novel mechanism by which this balance between an extreme or subdued immune reaction can be controlled by modifying regulatory T cell metabolism.

Initially, the researchers focused on how regulatory T cells cope with stress. Cellular stress can originate from the cells themselves, for example when they get activated and divide, but also from their environment, especially from nearby tumour cells. Free radicals called reactive oxygen species (ROS) are the molecular mediators of cellular stress. These are harmful for the cells and therefore need to be inactivated. "Free oxygen radicals are 'neutralised' by antioxidants and the major antioxidant in T cells is a molecule known as glutathione. We were surprised when we realised that regulatory T cells had about three times as much glutathione as other T cells. This pointed to an important function", says Henry Kurniawan, first author of the study and PhD student in Prof Brenner's group. Through a sophisticated genetic approach, the scientists removed a gene named 'glutamate cysteine ligase' (Gclc) only in a small population of regulatory T cells in mice. The Gclc gene is instrumental for glutathione production. Prof Brenner's team discovered that free radicals accumulated in these genetically altered regulatory T cells and that these cells lost their ability to act as a brake on the immune system. Strikingly, this led to a massive immune activation and a fatal autoimmune disease.

The team also found that the absence of glutathione in regulatory T cells increased serine metabolism massively. Serine is one of the 22 different amino acids that constitute the building blocks of proteins, which are in turn important for the structure and function of cells. No previous research group had studied the connection between glutathione, free radicals, serine and regulatory T cell function before. Prof Brenner's team characterised the metabolic alteration that led to the observed autoimmune disease in their mutant mice. Based on their findings, they designed a specific nutritional plan with the aim of correcting these disease-causing metabolic shifts. This dietary plan lacked both the amino acids serine and the closely related glycine. Interestingly, this engineered precision diet suppressed the severe autoimmunity and no disease developed. "Importantly, our study shows that the absence of only 2 out of 22 amino acids can cure a complex autoimmune disease. Therefore, elucidating the exact metabolic and molecular basis of a disease offers the possibility to correct these metabolic abnormalities through a special diet that is precisely adapted to the delineated disease mechanism. Our study might be a first step in the direction of the personalised treatment of metabolic diseases and autoimmunity", explains Prof Brenner.

"The relationship between glutathione, free radicals and serine can be used as a 'switch' to modulate immune cell activation. A higher immune cell activity is beneficial for cancer patients. We were intrigued by the idea of using our findings also to boost anti-tumor responses" he adds. Indeed, the team further showed that lower glutathione levels in regulatory T cells and the resulting rise in immune cell activation led to a significant tumour rejection, which might open up new therapeutic avenues for cancer treatment. "These astonishing results show the enormous potential of tweaking metabolism to prevent autoimmunity and target cancer. This could pave the way for the development of a new generation of immunotherapies," explains Prof Markus Ollert, Director of LIH's Department of Infection and Immunity. "The publication of these results in such a competitive and prestigious international journal is a momentous accomplishment not just for our department and institute, but for the entire Luxembourgish biomedical research community", he concludes.

In future projects, the researchers will use their findings to elaborate new approaches for therapeutic intervention. In that respect, the scientists have already proven that their delineated disease-controlling mechanism is also relevant in human regulatory T cells.

Due to its significance, the publication was selected by Cell Metabolism to be featured as the cover story of the May issue of the journal.

Involved research teams

Prof Dirk Brenner is the Deputy Head of Research & Strategy at LIH's Department of Infection and Immunity. He is Professor for Immunology & Genetics at the Luxembourg Center for Systems Biomedicine (LCSB) of the University of Luxembourg and Professor of Allergology at the University of Southern Denmark. He received a prestigious ATTRACT Consolidator grant from the Luxembourg National Research Fund (FNR), in 2015 to set up the Experimental & Molecular Immunology research group at LIH. The FNR-ATTRACT programme supports the national research institutions by expanding their competences in strategic research areas by attracting outstanding young researchers with high potential to Luxembourg.

The present study was performed in close collaboration with a national and international team and involved partners from LIH's Department of Infection and Immunity, LIH's Department of Oncology, the Braunschweig Integrated Center of Systems Biology (BRICS) of the Technische Universitt Braunschweig (Germany), the Helmholtz Centre for Infection Research (Germany), the Campbell Family Institute for Breast Cancer Research at the University of Toronto (Canada), the Institute for Medical Microbiology and Hospital Hygiene at the University of Marburg (Germany), the Department of Environmental Health Sciences at the Yale School of Public Health (USA), the Odense Research Center for Anaphylaxis (ORCA) of the Odense University Hospital (Denmark), the Department of Biomedical Genetics and Wilmot Cancer Institute of the University of Rochester Medical Center (USA), the Departments of Medical Biophysics and Immunology at the University of Toronto (Canada) and the University of Hong Kong (China).

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Fighting autoimmunity and cancer: The nutritional key - Science Codex

By Benjamin Mateus 5 May 2020

Without much fanfare, news reports on vaccines against the coronavirus have been focusing on ways to expedite vaccine development through human challenge trials. In a nutshell, such trials would deliberately infect healthy volunteers with the coronavirus after they received the experimental vaccine, to determine its efficacy.

Democratic Representative Bill Foster of Illinois, leading the effort with 34 other members of the House of Representatives, sent a letter to the Food and Drug Administration, stating, A more risk-tolerant development process is likely appropriate in the case of COVID-19 vaccine. The enormous human cost of the COVID-19 epidemic alters the optimization of the risk/benefit analysis.

Josh Morrison, a member of a supposed grass-roots effort, 1 Day Sooner, told Nature magazine, We want to recruit as many people as possible who want to do this, and pre-qualify them as likely to be able to participate in challenge trials would they occur. At the same time, we feel that the public policy decisions around challenge trials will be better informed if they highlight the voice of people interested in participating in such trials. According to the group, thousands from over 50 countries have volunteered.

Vaccine trials are notoriously lengthy, with optimistic estimates of 12 to 18 months to vaccine rollout. Much of the time in vaccine trials is spent in testing the safety and efficacy of a vaccine. These placebo-controlled phase-three trials, in which one group receives the vaccine and another a placebo, typically involve several thousands of participants who are followed long enough to assess differences in disease incidence.

Human challenge trials have been conducted over hundreds of years but are trials of last resort and conducted under special circumstances and much oversight. In the case of COVID-19, they were first raised in late March in a proposal published in the Journal of Infectious Diseases by authors Nir Eyal, Marc Lipstich, and Peter G. Smith. They wrote in their abstract, By replacing conventional phase-three testing of vaccine candidates [with human challenge trials], such trials may subtract months from the licensure process, making efficacious vaccines available more quickly.

The role of vaccines in global health cannot be understated. Smallpox was eradicated in 1977, the last case occurring in Somalia. Polio was eliminated in the United States in 1979. After a global campaign launched in 1994 by the United Nations Food and Agriculture Organization, rinderpest, a viral infection of cattle and domestic buffalo with near 100 percent lethality to livestock, was last confirmed in 2001 and declared eradicated in June 2011.

Measles, a virus for which only humans act as a host, killed 7 million to 8 million children annually until a decade of work led eventually to the development of a vaccine in 1963. Still, and despite an effective vaccine being available, measles infects more than half a million people across the globe, killing more than 140,000 people annually, mostly children under five years of age. Countries with the highest incidence include the Democratic Republic of Congo, Liberia, Madagascar, Somalia, and Ukrainethese five account for almost half of all cases worldwide.

The vaccination program in the United States, according to the CDC, has prevented more than 21 million hospitalizations and 732,000 deaths among children born in the last 20 years. Besides the morbidity and mortality associated with vaccinations, the economic benefits translate to $295 billion in direct costs and $1.38 trillion in total societal costs.

Efforts have been underway to develop a vaccine against the SARS-CoV-2 virus. Many see a vaccine as the only solution to the pandemic. With no pharmaceutical treatments that have shown clear mortality benefits, the present public health measures and supportive medical care remain essentially the only means by which to address the coronavirus and its impact on human populations.

According to the World Health Organization (WHO), there are currently six human trials in the race to develop a vaccine against SARS-CoV-2. Moderna, working in association with the NIAID, and INOVIO Pharmaceuticals are US-based trials, both in phase I. Moderna was the first to begin testing on humans in mid-March, building on its previous work on other coronaviruses. The University of Oxford, in Britain, is in phase I/II trial using a nonreplicating viral vector. The study is being led by Dr. Sarah Gilbert, who previously led work on Disease X, a hypothetical pathogen with pandemic potential adopted by the WHO on their shortlist of blueprint priority diseases. The other three trials are from ChinaCANSINO Biological, SINOVAC, and Beijing Institute of Biological Products. Seventy-seven other trials are in the preclinical evaluation stage.

In October 2016, the World Health Organization issued a statement on regulatory considerations for vaccine trials that pursue human challenge trials to expedite the development of these critical preventative treatments. They write, It is essential that challenge studies be conducted within an ethical framework in which truly informed consent is given. When conducted, human challenge studies should be undertaken with abundant forethought, caution, and oversight. The information to be gained should clearly justify the risks to human subjects.

The WHO notes that if a pathogen has a high case fatality rate and there are no existing therapies to prevent or diminish the impact of the disease and preclude death, then it would not be appropriate to consider such trials. Based on reports, they are planning to publish a response to proposed COVID-19 human challenge trials soon.

Authors Eyal et al., in regard to concerns about a human challenge trial for COVID-19, admit that it could be possible that any protection demonstrated from a vaccine in a human challenge study may not be replicated when the vaccine is used in the population at large.

Additionally, there is no attenuated SARS-CoV-2 virus that can help participants avoid the hazards associated with COVID-19, as was indicated in the WHOs guidance, nor is there a therapeutic that could safely reduce the mortality risk after the participants are infected. More concerning, they write, is that some vaccine constructs against coronavirus may induce more severe disease following infection, as has been reported in animal models of both SARS and MERS vaccine candidates. For this reason, they recommend challenging small groups sequentially to address this issue.

In support of the proposal, they state that these volunteers will have voluntarily consented to take these risks. They write, In the present case, the study would involve multiple tests of comprehension of all risks so that the decision is deeply informed and voluntary. These participants would be isolated in treatment facilities and given the best care possible.

They also justified the conduct of the trial on the grounds that 1) the study will only recruit healthy participants, 2) the vaccine likely will benefit some of those in the trial, 3) in the absence of a vaccine they are likely to be infected anyway, 4) only people with a high baseline risk of getting exposed should be recruited, 5) participants would be afforded the best available care, and 6) potentially some therapeutics may be available to ameliorate morbidity or mortality.

Dr. Beth Kirkpatrick, professor and chair of the Department of Microbiology and Molecular Genetics at the University of Vermont, who runs a human challenge trial unit, explained to STAT that human challenge models for COVID-19 do not exist. She said it would take upwards of two years to design and approve one, given all the ethical and regulatory constraints that they entail.

One of the primary considerations with such a human challenge trial is to establish appropriate endpoints for symptomsflu-like illness or pneumoniaand their implications for the efficacy of the vaccine. As yet, scientists are still puzzled over why some people become ill while others do not, and why symptomatic patients have a constellation of symptoms as compared to others. Additional concerns raised include if the data from such a study will translate to efficacy in all age categories, since the population being tested is young and healthy. Information about vaccine safety would also be compromised in these smaller trials.

The working class must treat with a great deal of skepticism the claimed benefits of such treatments and how such studies are being conducted, especially in the face of a pandemic with a novel coronavirus that at every turn has surprised and baffled scientists and researchers. Given the despair and upheavals caused by this pandemic, volunteers for these trials will likely come from among workers who are at the highest risk for contracting the infection because of the essential nature of their work.

That these human challenge trials are being vigorously supported by the political establishment is deeply concerning. The normal sentiments of mistrust, caution, and vigilance to protect the individuals involved seem absent. Ultimately, the race for vaccine development is rooted in capitalist relations which provide a tremendous profit incentive to the corporations that manufacture them, in addition to the general concern in ruling circles about promoting a back-to-work policy. The human challenge trials become a facilitator for both purposes.

The attempt to cut corners and expedite trials have already led to abject failures, which in the long run only delay the need to determine which therapeutics and vaccines will work and are inherently safe and which present adverse profiles. In the face of the frenzy and despair that is igniting social tensions, it becomes even more necessary to adhere rigorously to scientific principles. Even in desperate times, these principles will save time, life, and resources.

Featured statements on the coronavirus pandemic

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Human challenge trials are being pushed to develop a vaccine against the coronavirus - World Socialist Web Site

Scientists have identified an antibody in a lab that they say can prevent the novel coronavirus from infecting cells. The team hopes the antibody could be used to create treatments for COVID-19, the disease caused by the virus.

Since the coronavirus began infecting people in the central Chinese city of Wuhan late last year, more than 3.5 million people have been diagnosed with COVID-19, over a million have recovered and almost 248,000 have died, according to Johns Hopkins University.

The team, whose research was published in the journal Nature Communications, have been exploring whether what are known as monoclonal antibodies could help patients with COVID-19. Currently there is no vaccine or specific treatment for the disease. Monoclonal antibodies are a type of protein created in a lab which can bind to a specific substance in the body. These types of antibodies mimic how the immune system responds to a threat, and are used to treat some forms of cancer.

An antibody named 47D11 was found to bind to the spike protein which the novel coronavirus, known as SARS-CoV-2, uses to enter the body, and block it in a way that neutralizes the pathogen.

To carry out their study, the researchers used mice whose biology was tweaked to create antibodies similar to those found in humans. They injected the animals with spike proteins that the viruses which cause SARS, MERS, and some types of common cold use to invade cells. These viruses are members of the large coronavirus family of pathogens which also includes SARS-CoV-2, the bug which causes COVID-19. The mice produced 51 antibodies capable of neutralizing the spike protein of the injected coronaviruses. This stage of the research was done before SARS-CoV-2 first came to the attention of health officials in late 2019.

The team later watched to see if the antibodies would neutralize SARS-CoV-2 and SARS-CoV in lab samples, and found 47D11 did.

Co-author Berend-Jan Bosch, associate professor of the Utrecht University Infection and Immunity programme, explained in a statement that the research builds on work his team had done previously on antibodies which can target SARS-CoV, the virus which causes SARS.

"Using this collection of SARS-CoV antibodies, we identified an antibody that also neutralizes infection of SARS-CoV-2 [the COVID-19 virus] in cultured cells. Such a neutralizing antibody has potential to alter the course of infection in the infected host, support virus clearance or protect an uninfected individual that is exposed to the virus."

Co-author Frank Grosveld, Academy Professor of Cell Biology at the Erasmus Medical Center, Rotterdam, said: "This discovery provides a strong foundation for additional research to characterize this antibody and begin development as a potential COVID-19 treatment."

Experts not involved in the research welcomed the findings, but also pointed out the study's limitations.

Tony Carr, professor of molecular genetics in the Genome Damage and Stability Centre (GDSC) at the University of Sussex, said in a statement: "The block to infectivity is entirely based on cell culture work, but the previous literature supports the proposal that this reagent should be explored further as a potential treatment."

Penny Ward, visiting professor in Pharmaceutical Medicine at King's College London, said the antibody has the potential to be used to prevent and treat SARS-CoV-2 infection, "however without studying this in an animal model, it is not clear which of these approaches might be most efficient."

The findings would have been more robust if the team were able to show the antibody could prevent and treat COVID19 in animals, she said.

"It is not possible to conclude that the product will be effective in vivo in humans," said Ward.

Polly Roy, professor of virology at the London School of Hygiene and Tropical Medicine, said the data the team created is "very good," and highlighted they are well-known for their work on coronaviruses.

Gary McLean, professor in Molecular Immunology at London Metropolitan University, said: "Because it is not done in people and the antibody is not even found in people as far as we know there are limitations. However it is a nicely done study that could provide a potential biotherapeutic that could be used to treat COVID-19.

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The research complements separate projects looking at whether a century-old technique known as convalescent plasma therapy, where the blood from a person who has recovered from COVID-19 is inserted into a current patient in the hope it will help them beat the disease.

Professor Babak Javid, principal investigator at Tsinghua University School of Medicine, Beijing, and consultant in infectious diseases at Cambridge University Hospitals in the U.K., commented: "This is a very interesting study. One of the most widely touted experimental (though not yet proven) treatments for COVID is the use of convalescent plasma."

He said: "However, use of convalescent plasma is difficult to scale and make widely available as a treatment and has some potential safety concerns since it is a blood product. Therefore there has been intense scientific interest in identifying individual antibodies that can also neutralize SARS-CoV2. This is because we are able to manufacture large quantities of individual antibodies (known as monoclonal antibodies or mAbs) at scale as a pharmaceutical treatment for COVID. Monoclonal antibodies also don't have the safety concerns of administering blood products."

Simon Clarke, associate professor in Cellular Microbiology at the University of Reading, U.K., said in a statement: "Antibodies like this can be made in the lab instead of purified from people's blood and could conceivably be used as a treatment for disease, but this has not yet been demonstrated.

"While it's an interesting development, injecting people with antibodies is not without risk and it would need to undergo proper clinical trials."

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Antibody That Blocks Coronavirus From Infecting Cells Discovered by Scientists - Newsweek

The Covid-19 (coronavirus) pandemic is impacting society and the overall economy across the world. The impact of this pandemic is growing day by day as well as affecting the supply chain. The COVID-19 crisis is creating uncertainty in the stock market, massive slowing of supply chain, falling business confidence, and increasing panic among the customer segments. The overall effect of the pandemic is impacting the production process of several industries including Life Science, and many more. Trade barriers are further restraining the demand- supply outlook.

A biological computer is a special type of microcomputer that is specially designed for medical applications. It is an implantable device that is mainly used for various tasks like monitoring the bodys activities or including therapeutic effects, all at the molecular or cellular level. Biological computers are used to produce input and output, and software is composed of DNA, the material of genes, whereas DNA-manipulating enzymes are used as the hardware.

The biological computer market anticipated to grow as rising in the prevalence of cancer and an increase in demand for DNA or gene chips is some of the major factors driving the market growth. However, less awareness of this device is restraining the market growth. Nevertheless, an increase in healthcare expenditure and overall growth in the healthcare industry are influencing the market growth.

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Top Dominating Key Players:

1. Biometrix Technology Inc2. Emulate Inc.3. IBM4. Illumina, Inc.5. IndieBio6. Macrogen Corp7. Merck KGaA8. Microsoft9. Sequenom Inc.10. Thermofisher Scientific

The biological computers market is segmented on the basis of component, application and by end user. Based on component the market is segmented as hardware, software, input and output. On the basis of application the market is categorized as oncology, molecular genetics, nanobiotechnology and others. On the basis of end user the market is categorized as pharmaceutical & biotechnology companies, research centers, healthcare it companies, hospital & clinics and others.

The report provides a detailed overview of the industry including both qualitative and quantitative information. It provides overview and forecast of the in biological computers market based on various segments. It also provides market size and forecast estimates from year 2017 to 2027 with respect to five major regions, namely; North America, Europe, Asia-Pacific (APAC), Middle East and Africa (MEA) and South & Central America. The biological computers market by each region is later sub-segmented by respective countries and segments. The report covers analysis and forecast of 18 countries globally along with current trend and opportunities prevailing in the region.

The report analyzes factors affecting biological computers market from both demand and supply side and further evaluates market dynamics affecting the market during forecast period i.e., drivers, restraints, opportunities, and future trend. The report also provides exhaustive PEST analysis for all five regions namely; North America, Europe, APAC, MEA and South & Central America after evaluating political, economic, social and technological factors effecting the biological computers market in these regions.

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Ongoing Study Reveals Key Factors that Will Drive the Growth of Biological Computers Market During 2019-2027 - Cole of Duty

(CNN) A new genetic analysis of the virus that causes Covid-19 taken from more than 7,600 patients around the world shows it has been circulating in people since late last year, and must have spread extremely quickly after the first infection.

Researchers in Britain looked at mutations in the virus and found evidence of quick spread, but no evidence the virus is becoming more easily transmitted or more likely to cause serious disease.

"The virus is changing, but this in itself does not mean it's getting worse," genetics researcher Francois Balloux of the University College London Genetics Institute told CNN.

Balloux and colleagues pulled viral sequences from a giant global database that scientists around the world are using to share data. They looked at samples taken at different times and from different places, and said they indicate that the virus first started infecting people at the end of last year.

"This rules out any scenario that assumes SARSCoV-2 may have been in circulation long before it was identified, and hence have already infected large proportions of the population," Balloux's team wrote in their report, published in the journal Infection, Genetics and Evolution.

That is one piece of bad news. Some doctors had hoped the virus was circulating for many months and may have quietly infected many more people than has been reported. That would offer the hope that there might be some immunity already built up in some populations.

"Everyone was hoping for that. I was too," Balloux said.

Their findings pour cold water on such an idea. At the most, 10% of the global population has been exposed to the virus, Balloux estimated.

Many different studies have shown that the new coronavirus, often called SARS-CoV-2 by scientists, originated in a bat but had to have infected another animal before it jumped into humans. The first human cases were reported in Wuhan, China, last December.

Viruses make mistakes every time they replicate themselves, and these mutations can be used as what's called a molecular clock to track a virus through time and geography.

"Our results are in line with previous estimates and point to all sequences sharing a common ancestor towards the end of 2019, supporting this as the period when SARS-CoV-2 jumped into its human host," the team wrote.

"It's very recent," Balloux said. "We are really, really, really confident that the host jump happened late last year."

That's because viral samples taken from all corners of the globe show multiple mutations, and they are similar mutations. "Everything is everywhere," the team wrote.

"It has been introduced and introduced and introduced in almost all countries," Balloux added.

They also found genetic evidence that supports suspicions the virus was infecting people in Europe, the US and elsewhere weeks or even months before the first official cases were reported in January and February. It will be impossible to find the "first" patient in any country, Balloux said.

"All these ideas about trying to find a Patient Zero are pointless because there are so many patient zeros," he said.

Balloux's team's findings were reviewed by other experts, a process called peer review, before they were published in the journal. He said some reports by other teams, published online in what are called pre-print websites, may have drawn incorrect conclusions.

"All viruses naturally mutate. Mutations in themselves are not a bad thing and there is nothing to suggest SARS-CoV-2 is mutating faster or slower than expected. So far we cannot say whether SARS-CoV-2 is becoming more or less lethal and contagious," Balloux said.

Lane Warmbrod, an analyst at the Johns Hopkins Center for Health Security who has been tracking the reports on the genetics of the new coronavirus. She said more studies are needed in animals to demonstrate how changes in the genetics of the virus could make it more or less infectious or pathogenic.

"Just because these studies tell us these mutations are quickly spreading or becoming dominant doesn't mean anything except we know it happened. It doesn't actually tell us anything about what's happening biologically," Warmbrod told CNN.

Reports about mutations can be important for teams working on drugs and vaccines to fight the coronavirus. Vaccines, especially, need to target parts of the virus that are conserved that do not change much over time.

This story was first published on CNN.com, "Coronavirus quickly spread around the world starting late last year, new genetic analysis shows."

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Coronavirus quickly spread around the world starting late last year, new genetic analysis shows - CNN Philippines

The global Opthalmology Pacs market offers a thorough study of all the important aspects of the market. All the factors that are responsible for the growth of the global market are studied in this report. In addition to that, the factors causing hurdles in the path are also studied in the report. For the study of any market it is very important to study some factors such as market trends, revenue growth patterns market shares, demand and supply. In addition, it also covers political and social factors which is likely to affect the growth of the market. Production, market share, revenue rate, key regions and major vendors are some of the vital aspects analysed in the report.

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Global Opthalmology Pacs market is segmented based by type, application and region.

Based on Type, the market has been segmented into:

By End-Use, market is segmented into:

HospitalsAmbulatory Surgical Center (ASCS) & Specialty ClinicsOthersBy Type, market is segmented into:

Standalone PACSIntegrated PACSBy Delivery Model, market is segmented into:

Cloud/ web based modelsOn-premise modelsOthers

A systematized methodology is used to make a Report on the Global Opthalmology Pacs market. For the analysis of market on the terms of research strategies, these techniques are helpful. All the information about the Products, manufacturers, vendors, customers and much more is covered in research reports. Various important factors such as market trends, revenue growth patterns market shares and demand and supply are included in almost all the market research report for every industry. Adaptation of new ideas and accepting the latest trends are some the reasons for any markets growth. The Global Opthalmology Pacs market research report gives the deep understanding about the regions where the market is impactful. It also elaborates the big and small vendors working actively all over the globe. For the stakeholders seeking for new investment opportunities, this research report works as a guide as it offers the in-depth study of the global Opthalmology Pacs market.

The report includes market shares of global Opthalmology Pacs markets for global regions such as Europe, North America, Asia-Pacific, South America, and the Middle East & Africa. Some essential tools have been studied such as SWOT analysis, PESTEL analysis and Value chain analysis for the quantitative study of the market to help the participants to explain an overview of the global Opthalmology Pacs market. Furthermore, technological trends, innovations, governing an industry are some factors impacting the development of the market. All these developments would take the industry in the long term growth. Also, the report provides upcoming industry solutions for the global Opthalmology Pacs market.

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Opthalmology Pacs Market 2020 Analysis by Demand, Applications, End Users, Companies, Sales Prospects, Forthcoming Developments, Business...

A new treatment that helps to relieve coronavirus symptoms could be brought to market in three months' time if further trials go well, according to a researcher involved in the project.

"It's very early to say at this stage," said Dr.Fatima al-Kaabi, head of hematology and oncology at the Sheikh Khalifa Medical City in the United Arab Emirates.

"We've been happy that our initial safety results are promising, that's why we're heading into the next phase, of effectiveness of this treatment," she told CNBC's Hadley Gamble on Monday.

"If all ... went well and it worked well, then I would propose ... three months' time," she said, when asked how quickly the treatment, which was developed by doctors and researchersat the Abu Dhabi Stem Cell Center, could reach the market.

To date, there are no known vaccines or specific antiviral medicines against Covid-19.U.S. health officials say developing a vaccine will take at least 12 to 18 months.

The UAE has 14,163 cases and126 deaths due to the coronavirus, based on data from Johns Hopkins University.

The remedy uses a "minimally invasive" method where a Covid-19 patient's stem cells are extracted, activated and turned into a fine mist to be inhaled. This alleviates symptoms such as shortness of breath and possibly coughing, said Dr. al-Kaabi.

"It is hypothesized to have its therapeutic effect by regenerating lung cells and modulating the immune response to keep it from overreacting to the COVID-19 infection and causing further damage to healthy cells,"the UAE's ministry of health and preventionsaid a statement.

Some 73 patients with moderate to severe symptoms received this treatment, and all were "successfully treated and cured," the statement said, adding that none reported "immediate adverse effects." Around a quarter of these patients were intubated and in the intensive care unit.

The treatment was given along with "conventional medical intervention" and will not replace established protocols, according to the statement.

"We're hopeful," said Dr. al-Kaabi, noting that the results of further trials on the efficacy of the treatment will only be out a couple of weeks' time. "We've seen (a) favorable outcome."

Another treatment for the coronavirus, an antiviral drug from Gilead Sciences, has been in the spotlight following positive preliminary results from trials. America's Food and DrugAdministration granted the medicine emergency use authorization last week. That means doctors can administerremdesivir to patients hospitalized with Covid-19, even though the drug has not undergone the same FDA review as other treatments.

Separately, researchers cut short a study testing anti-malaria drug chloroquine as a potential Covid-19 treatment last month. The drug gained widespread international attention after two small studies published in France found the coronavirus infection cleared a lot faster for patients taking it when compared to a control group.

However, citing a high risk of death, scientists have now scrapped the trials, warning it should prompt some degree of skepticism from the public toward enthusiastic claims of the drug. President Donald Trump had touted chloroquine as a potential "game changer" in the fight against the virus.

CNBC'sBerkeley Lovelace Jr. andWilliam Feuer contributed to this report.

Read the original post:
Stem cell treatment in the UAE sees 'favorable' outcomes for coronavirus patients - CNBC

Korean researchers have found a signal transduction system that modulates the treatment of mesenchymal stem cells and immune control functions, opening the way for treating graft-versus-host disease treatment.

Mesenchymal stem cells divide into various cells, have immunomodulatory functions, and are the primary cell sources for stem cell therapy.

Graft-versus-host disease is a fatal disease that leads to death after an allogeneic blood transfusion or bone marrow transplantation. Although there are many clinical trials underway worldwide to treat the symptom, there are no applicable treatments besides alleviating symptoms with high-dose steroids.

The team, led by Professor Shin Dong-myeong of the Department of Biomedical Sciences at Asan Medical Center, discovered that the CREB1 (CAMP responsive element binding protein 1) signaling system activates the treatment and immune control functions of mesenchymal stem cells.

The team administered a therapeutic agent made by upgrading mesenchymal stem cells to graft-versus-host disease mice, and found that it alleviated anorexia symptoms and reduced the weight loss rate by 30 percent while increasing the survival rate by 30 percent.

When developing a cell therapy product, researchers have to cultivate the stem cells in vitro. Thus it is very likely that it will impair stem cell functions due to free radicals generated in the cells. To prevent the deterioration of stem cell function, it is necessary to improve the stem cell function in vitro culture, prevent stem cell oxidation, and increase the antioxidant capacity of the cell itself.

Until now, there was a lack of specific evidence and understanding of how stem cells regulate glutathione, an indicator of antioxidant capacity. Therefore, it was difficult to prevent stem cell dysfunction and oxidation.

Professor Shin's team developed experimental techniques that can monitor and quantify glutathione in real-time and confirmed that the CREB1 signaling system regulated the amount and activity of glutathione.

By activating the CREB1 signaling system, the team found that the process also activated nuclear factor erythroid 2-related factor 2 (NRF2) protein, which maintains the antioxidant capacity of mesenchymal stem cells and the increase of both the expression levels of peroxiredoxin-1 (PRDX1) and glutamate-cysteine ligase modifier subunit (GCLM) protein, which synthesize glutathione and are antioxidant activity indicators.

As a result, the team confirmed that its method was effective in treating the graft-versus-host disease.

"Based on this study, we have secured a technological foundation to advance stem cell treatment by controlling the antioxidant capacity of stem cells," Professor Shin said.

If this technology makes a high-purity and high-quality stem cell treatment, the team expects that it will be a step toward developing a graft-versus-host disease treatment and overcoming various intractable diseases such as nervous system diseases and inflammatory diseases with high medical demand, Shin added.

The results of the study were published in the journal, Science Advances.

corea022@docdocdoc.co.kr

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AMC to use stem cell therapy in treating graft-versus-host disease - Korea Biomedical Review

A group of UB researchers have published a paper that clarifies certain cellular mechanisms that could lead to improved outcomes in patients with globoid cell leukodystrophy, commonly known as Krabbe disease.

The paper, titled Macrophages Expressing GALC Improve Peripheral Krabbe Disease by a Mechanism Independent of Cross-Correction, was published May 5 in the journal Neuron.

The research was led by Lawrence Wrabetz and M. Laura Feltri. Wrabetz and Feltri head the Hunter James Kelly Research Institute and both are professors in the departments of Biochemistry and Neurology in the Jacobs School of Medicine and Biomedical Sciences at UB.

The institute is named for the son of former Buffalo Bills quarterback Jim Kelly. Hunter Kelly died at age 8 in 2005 from complications of Krabbe disease.

Krabbe disease is a progressive and fatal neurologic disorder that usually affects newborns and causes death before a child reaches the age of 2 or 3.

Traditionally, hematopoietic stem cell transplantation, also known as a bone marrow transplant, has improved the long-term survival and quality of life of patients with Krabbe disease, but it is not a cure.

It has long been assumed that the bone marrow transplant works by a process calledcross-correction, in which an enzyme called GALC is transferred from healthy cells to sick cells.

Using a new Krabbe disease animal model and patient samples, the UB researchers determinedthatin reality cross-correctiondoes not occur. Rather, the bone marrow transplant helps patients through a different mechanism.

The researchers first determined which cells are involved in Krabbe disease and by which mechanism. They discovered that both myelin-forming cells, or Schwann cells, and macrophages require the GALC enzyme, which is missing in Krabbe patients due to genetic mutation.

Schwann cells require GALC to prevent the formation of a toxic lipid called psychosine, which causes myelin destruction and damage to neurons. Macrophages require GALC to aid with the degradation of myelin debris produced by the disease.

The research showed that hematopoietic stem cell transplantation does not work bycross-correction, but by providing healthy macrophages with GALC.

According to Feltri, the data reveal that improvingcross-correctionwould be a way to makebone marrow transplants and other experimental therapies such as gene therapy more effective.

Bone marrow transplantation and other treatments for lysosomal storage disorders, such as enzyme replacement therapy, have historically had encouraging but limited therapeutic benefit, says study first author Nadav I. Weinstock, an MD-PhD student in the Jacobs School. Our work defined the precise cellular and mechanistic benefit of bone marrow transplantation in Krabbe disease, while also shedding light on previously unrecognized limitations of this approach.

Future studies, using genetically engineered bone marrow transplantation or other novelapproaches,may one day build on our findings and eventually bridge the gap for effectively treating patients with lysosomal disease, he continues.

UB investigators included Daesung Shin, research assistant professor at the Hunter James Kelly Research Institute; Nicholas Silvestri, clinical associate professor of neurology, Jacobs School; Narayan Dhimal, PhD student; Chelsey B. Reed, MD-PhD student; and undergraduate student Oliver Sampson.

Also participating in the research were Eric E. Irons, MD-PhD student, and Joseph T.Y. Lau, a distinguished faculty member from the Department of Molecular and Cellular Biology at Roswell Park Comprehensive Cancer Center.

The research was funded by multiple grants from the National Institutes of Health awarded to Weinstock, Shin, Wrabetz and Feltri, and also supported by Hunters Hope.

More here:
UB investigators uncover cellular mechanism involved in Krabbe disease - UB Now: News and views for UB faculty and staff - University at Buffalo...

People with cancer who contract the new coronavirus appear to have a greater risk for severe COVID-19 illness and death, but this may depend on their cancer stage and the type of treatment they are receiving, according to recent research. In fact, those with early-stage cancer may fare as well as people who have not had cancer.

Researchers from some of the earliest and hardest hit epicenters of the COVID-19 pandemic described outcomes among cancer patients with the coronavirus (officially known as SARS-CoV-2) during a special session the American Association for Cancer Research (AACR) virtual annual meeting last week. Soon after the conference, another group of researchers published an analysis of mortality among cancer patients in New York City.

Early reports from China, where the pandemic originated in late December, showed that older people, those with compromised immune systems and those with underlying health conditions are more susceptible to severe COVID-19. One study saw a death rate of 6% for people with cancermore than twice as high as the overall estimated COVID-19 mortality rate in China, but lower than the rates seen in people with diabetes (7%) or cardiovascular disease (11%).

Chemotherapy medications and some targeted therapies for cancer can cause neutropenia, a temporary depletion of immune system white blood cells that fight infection. People who receive bone marrow stem cell transplants or CAR-T therapy or for blood cancers typically receive strong chemotherapy to kill off existing blood cells and make room for the new ones. Conversely, immunotherapies such as checkpoint inhibitors and CAR-T therapy unleash natural or engineered T cells to fight cancer, which in some cases can trigger an excessive immune response that leads to harmful inflammation.

Two reports at the AACR meeting provided updates from China. Li Zhang, MD, PhD, of Tongji Medical College described outcomes among 28 cancer patients with COVID-19 in Wuhan, the initial epicenter of the pandemic.

Seven had lung cancer and the remainder had 13 other cancer types. Just over a third had Stage IV, or metastatic, cancer. Nearly 30% acquired the coronavirus at medical facilities. About half had severe disease, 10 patients required mechanical ventilators and eight diedmostly from acute respiratory distress syndromegiving a mortality rate of 29%.

Although three quarters had ever undergone surgery, radiation or chemotherapy, a majority had not received treatment recently. Only one person received radiation, three received chemotherapy, two received targeted therapy and one received immunotherapy within two weeks prior to their COVID-19 diagnosis. Recent cancer treatment was associated with a fourfold increased risk of severe outcomes. However, the single patient treated with a checkpoint inhibitor (for liver cancer) had mild COVID-19 and a short hospital stay.

Similarly, as part of his discussion of immunotherapy for cancer in the COVID-19 era, Paolo Ascierto, MD, of the National Tumor Institute in Naples, noted that just two out of 400 patients on immunotherapy at his institute tested positive for the coronavirus, they were asymptomatic and they recovered quickly, leading him to speculate that immunotherapy might somehow be protective against COVID-19.

Hongbing Cai, MD, of Zhongnan Hospital of Wuhan University, presented data on 105 cancer patients and 536 age-matched people without cancer at 14 hospitals in Hubei province who developed COVID-19. Results were also published in Cancer Discovery. Twenty-two had lung cancer, 13 had gastrointestinal cancers, 11 each had breast cancer and thyroid cancer, nine had blood cancers such as leukemia or lymphomawhich affect white blood cells that carry out immune responsesand six each had cervical and esophageal cancer.

In general, patients with cancer deteriorated more rapidly than those without cancer, Cais team reported. Cancer patients with COVID-19 were nearly three times more likely to have severe or critical illness (34%), be admitted to an intensive care unit ICU (19%) or be put on a ventilator (10%). Whats more, people with cancer were about twice as likely to die as COVID-19 patients without cancer (11% versus 5%, respectively).

People with blood cancers or lung cancer, as well as those with metastatic cancer, had a higher risk of severe events. Two thirds of the blood cancer patients and half of the lung cancer patients had such events. Among the lung cancer patients, 18% were put on ventilators and 18% died. In contrast, no one with breast, thyroid or cervical cancer required ventilators or died.

In particular, those with blood cancersmore than half of whom had severe immune suppressionhad about a 10-fold higher risk of severe events or death. Two thirds had severe symptoms, 22% were put on ventilators and 33% died. These patients all had a rapidly deteriorated clinical course once infected with COVID-19, the researchers wrote.

People with metastatic cancer had about a six-fold higher risk of severe events or death. But people whose cancer had not yet spread were not significantly more likely to have severe events or die than COVID-19 patients without cancer. People currently on cancer treatment and those with a history of cancer who had completed treatment were both at higher risk.

People who underwent surgery within the previous 40 days had higher rates of severe events, ICU admission, ventilator use and death, but this was not the case for those who received only radiation. In this study, unlike Zhangs and Asciertos, people treated with immunotherapy did not fare so well. Four of the six patients who recently received checkpoint inhibitors had critical symptoms and two died.

Based on our analysis, COVID-19 patients with cancer tend to have more severe outcomes when compared to the non-cancer population, the researchers wrote. Although COVID-19 is reported to have a relatively low death rate of 2% to 3% in the general population, patients with cancer and COVID-19 not only have a nearly three-fold increase in the death rate than that of COVID-19 patients without cancer, but also tend to have much higher severity of their illness.

In a related study, Marina Chiara Garassino, MD, of Fondazione IRCCS National Tumor Institute in Milan, presented the first data from the international TERAVOLT registry, which is collecting data about COVID-19 among people with lung cancer and other thoracic malignancies. She noted that TERAVOLT was registering around 70 new cases per week from around the world per week.

This population may be especially vulnerable to COVID-19 due to older age, lung damage, smoking and underlying health conditions, Garassino said. Whats more, the symptoms of COVID-19 overlap with lung cancer, making diagnosis very challenging.

Garassino described results from the first 200 cancer patients with COVID-19 in more than 20 countries. Non-small-cell lung cancer was the most common type, and nearly three quarters had metastatic disease. About 20% received only targeted therapy, 33% received chemotherapy alone and 23% received immunotherapy alone.

A majority (76%) were hospitalized, but most were not offered intensive care for COVID-19; just 9% were admitted to an ICU and 3% were put on ventilators. More than a third (35%) died, mostly due to COVID-19 rather than cancer. Specific types of cancer treatment were not significantly associated with an increased risk of death.

But not all studies have seen worse COVID-19 outcomes among people with cancer. Fabrice Barlesi, MD, PhD, and colleagues looked at 137 COVID-19 patients with cancer at Gustave Roussy, a cancer center near Paris. They had a variety of cancer types, with blood cancers and breast cancer being most common. Nearly 60% had active advanced disease while 40% were in remission or being treated with potentially curative therapy.

Within this group, 25% had worsening COVID-19 after admission, 11% were admitted to the intensive care unit (ICU) and 15% died. Again, people with blood cancers were more likely to have worse outcomes. Treatment with chemotherapy within the past three monthsbut not targeted therapy or immunotherapydoubled the likelihood of worsening disease. But this only applied to people with active or metastatic cancer, not those who had localized disease or were in remission.

The 15% death rate among people with cancer at Gustave Roussy was lower than the 18% rate for all COVID-19 patients in Paris and in France, Barlesi said. His team concluded that both incidence and outcomes of COVID-19 among cancer patients seem to be comparable to the population as a whole. However, people with blood cancers, those treated with chemotherapy and frail patients are at greater risk.

Discussing how to manage cancer patients during the COVID-19 pandemic, Cai recommended self-protective isolation, strict infection control in hospitals and shifting some medical services online.

With regard to cancer treatment, she said, clinicians need to develop individualized plans based on a patients tumor type and stage of disease. She added that postponing surgery, if appropriate, should be considered in areas with current outbreaks. Radiation therapy, she said, could go ahead according to existing treatment plans with intensive protection and surveillance. Whether people with early-stage cancer need to postpone their treatment remains an unanswered question, she said.

Click hereto read the abstracts from the AACR COVID-19 and cancer session.Learn about What People With Cancer Need to Know About the New Coronavirus.

Read more:
Cancer Patients With COVID-19 May Have Higher Risk of Severe Illness and Death - Cancer Health Treatment News