dstock07734
2 weeks ago
See the roundtable participants? Can you find anyone working on mRNA stuff? I can find several of them who are familiar with DC vaccine.
https://www.fda.gov/vaccines-blood-biologics/workshops-meetings-conferences-biologics/cell-and-gene-therapy-roundtable-06052025
FDA Cell and Gene Therapy Roundtable
June 5, 2025
Roundtable Participants
Jeff Allen, PhD
Present and CEO
Friends of Cancer Research
Ron Bartek
Co-founder and President
Friedreich's Ataxia Research Alliance
Allyson Berent, DVM, DACVIM
Chief Scientific Officer
Foundation for Angelman Syndrome Therapeutics
Co-Director
Angelman Syndrome Biomarker and Outcome Measure
Catherine Bollard, MBChB, MD
Senior Vice President and Chief Research Officer
Director, Center for Cancer and Immunology Research
Professor of Pediatrics and Immunology
Children's National and The George Washington University
Thomas Cahill, MD, PhD
Founder and Managing Partner
Newpath Partners
Andrew M. Cameron MD, PhD
Director
Department of Surgery
The Johns Hopkins University School of Medicine
Paula Cannon, PhD
Distinguished Professor of Microbiology and Immunology
Keck School of Medicine
University of Southern California
Terence R. Flotte, MD
Professor, Provost, Dean of UMass Chan Medical School
President, American Society of Gene and Cell Therapy
Charles A. Gersbach, PhD
John W. Strohbehn Distinguished Professor
Department of Biomedical Engineering
Director, Center for Advanced Genomic Technologies
Duke University
Bambi Grilley, RPh, CCRC, CCRP, CIP, RAC
Director, Clinical Research and Early Product Development
Center for Cell and Gene Therapy
Professor, Pediatrics
Baylor College of Medicine
Chief Regulatory Officer
International Society for Cell & Gene Therapy
Timothy Hunt, JD
Chief Executive Officer
Alliance for Regenerative Medicine
Carl H. June, MD
Richard W. Vague Professor in Immunotherapy
Department of Pathology and Laboratory Medicine
Director Center for Cellular Immunotherapies
Director, Parker Institute for Cancer Immunotherapy
Perelman School of Medicine
University of Pennsylvania
Smilow Center for Translational Research
Donald B. Kohn, MD
Distinguished Professor:
- Microbiology, Immunology and Molecular Genetics
- Pediatrics, Hematology/Oncology
- Molecular and Medical Pharmacology
University of California, Los Angeles
Brett Kopelan, MA
Executive Director
The Dystrophic Epidermolysis Bullosa Research Association of America
David Liu, PhD
Richard Merkin Professor and Director of the Merkin Institute for Transformative Technologies in Healthcare
Director of the Chemical Biology and Therapeutic Sciences Program
Core Institute Member and Vice-Chair of the Faculty, Broad Institute
Investigator, Howard Hughes Medical Institute
Thomas Dudley Cabot Professor of the Natural Sciences and Professor of Chemistry & Chemical Biology, Harvard University
Jayme Locke MD, MPH
Vice President, Medical Development Xenotransplantation
United Therapeutics
Crystal Mackall, MD
Ernest and Amelia Gallo Family Professor of Pediatrics and Medicine
Founding Director, Stanford Center for Cancer Cell Therapy
Director of the Parker Institute for Cancer Immunotherapy
Stanford University
Rachel McMinn, PhD
Founder and CEO
Neurogene
Sean J. Morrison, PhD
Investigator, Howard Hughes Medical Institute
Director, Children's Research Institute at UT Southwestern
University of Texas Southwestern Medical Center
Dallas, Texas
Chair of Public Policy Committee
International Society for Stem Cell Research
Terry Pirovolakis
CEO & Founder
Elpida Therapeutics
Vinayak Prasad, MD, MPH
Director
Center for Biologics Evaluation and Research
U.S. Food and Drug Administration
Michelle Rengarajan, MD, PhD
Physician-Scientist and Attending Endocrinologist
Massachusetts General Hospital
Instructor in Medicine
Harvard Medical School
Shengdar Q. Tsai, PhD
Associate Member, Department of Hematology, St. Jude Children's Research Hospital
Co-chair, Steering Committee of NIH Somatic Cell Genome Editing Consortium
Fyodor Urnov, PhD
Professor of Molecular Therapeutics at University of California, Berkeley
Scientific Director at Innovative Genomics Institute
Nicole Verdun, MD
Super Office Director
Office of Therapeutic Products
Center for Biologics Evaluation and Research
U.S. Food and Drug Administration
jondoeuk
2 weeks ago
Tumors don't have chance to adapt if DCs can present hundreds of tumor-associated antigens to immune system.
Cancer cells can mutate in real time to evade treatment as well [1,2]. In this, 17% innately have HLA LOH [3], but other papers put it (much) higher.
Also, many TAAs are self-antigens. As a result of negative selection, to prevent autoimmunity, any T-cell that is able to target a TAA will express a TCR with a low affinity. But TCRs with high affinity (for TAAs) are required for efficient antitumour immunity [4]. This is why ADAP (and other companies) do what they do.
The current issue is that with massive t-cell infiltration into tumor site comes tumor-associated macropahges which can be depleted by CSF1R inhibitor.
CD163hi macrophages are resistant to CSF-1(R) targeted therapies, and drive both primary and secondary immune resistance. We know that clinical trials testing CSF-1(R) targeted therapies have shown poor results to date, and that CSF-1R+ macrophages can be positively associated with response [5].
The CD163hi macrophage issue is so minor in comparison of massive and sustainable t-cell infiltration triggered by DCVax-L.
High frequency of CD163hi macrophages correlates with higher risk of relapse, predicts poor response to ICI, and poor survival across different (sub)types of cancer.
CD163hi macrophages were also infiltrating two progressing lesions in the patient I talked after she received tens of billions of TCR-T cells (plus an anti-PD-1).
Refs:
1 https://www.nejm.org/doi/full/10.1056/NEJMoa1609279
2 https://aacrjournals.org/cancerimmunolres/article/10/8/932/707173/Adoptive-Cellular-Therapy-with-Autologous-Tumor
3 https://aacrjournals.org/cancerdiscovery/article/11/2/282/2772/Somatic-HLA-Class-I-Loss-Is-a-Widespread-Mechanism
4 https://academic.oup.com/cei/article/180/2/255/6422173
5 https://jitc.bmj.com/content/10/5/e003890
jondoeuk
3 weeks ago
You should know that CD163 only accounts for small population and they cannot suppress massive number of t-cells.
Based on the literature CD163hi macrophages are able to suppress T-cells.
In this paper, two HLA-matched patients with metastatic pancreatic ductal adenocarcinoma were treated with a TCR-T cell therapy (the TCRs came from a patient who responded to TIL therapy) [1].
In one patient, who had lung mets only, experienced a durable partial response after receiving 16.2 billion TCR-T cells. Looking into why therapy was more successful, one reason was due to the phenotype of the T-cells (CD45RO+CD103+CD69+CD49a+, so memory and tissue-resident).
However, after about a year, she showed slow progression. Dr. Tran has gone on to give more info at different medical/scientific conferences. She got a second infusion of TCR-T cells (that were more potent) plus an anti-PD-1. Looking at efficacy, at three months she had stable disease (~25% reduction by RECIST) and a six month scan showed stable disease as well. There were regressions of some lesions, but when comparing the scans (three months vs. six months) there was some growth in other lesions. At time they were thinking about the next steps.
Looking at two progressing lesions, the first genetically expressed the HLA and targeted antigen. It contained transduced T-cells as well, with the cells preferentially expressing TIM3, TIGIT, CD25 and IL7RA, suggestive of antigen encounter. It also displayed a high infiltration of non-transduced T-cells and CD163hi macrophages, often intimately co-localised with each other, both with the transduced and non-transduced T-cells.
As for the second progressing lesion (smaller), it contained a neutrophil infiltrate as well as CD163hi macrophages. Based on this, they are trying to further characterise what (neo)antigens might be recognised by the non-transduced T-cells in one of the progressing lesions. In addition, undertaking single-cell transcriptomics of infusion products and peripheral blood samples, and deeper molecular studies on tumour sections.
Merck makes the collaboration with Moderna look so real just like Merck signed the deal with Daiichi on three ADCs.
The first deal was in 2016. Under the terms of the agreement, MRK made an upfront cash payment to MRNA of $200 million. That was expanded in 2017 and amended in 2018, before MRK exercised its option to jointly develop and commercialise MRNA's vaccine in 2022. For the latter, MRK paid MRNA $250 million upfront. Now additional trials are planned.
Targeting for several neoantigens may have efficacy for a certain percentage of hot tumors.
MRNA's vaccine encodes up to 34 patient-specific neoantigens.
But it lacks of efficacy in treating cold tumors.
Autogene cevumeran (which encodes up to 20 patient-specific neoantigens), jointly developed by BNTX and RHHBY's Genentech, continues to show poly-specific T-cell responses and delayed tumour recurrence in patients with resected pancreatic ductal adenocarcinoma [2].
Based on the data, a randomised PhII trial is ongoing. Other randomised PhII trials, including in adjuvant CRC are ongoing as well.
If I am not mistaken, the trials between Merck and Moderna only target hot tumor.
So far, but MRNA's CEO has talked about testing the vaccine in ''cold'' tumours, including resected pancreatic ductal adenocarcinoma.
Refs:
1 https://www.nejm.org/doi/full/10.1056/NEJMoa2119662
2 https://www.nature.com/articles/s41586-024-08508-4
axelvento
3 weeks ago
On May 14, 2025 - Merck & Co., Inc. filed a 13F-HR form disclosing ownership of 2,308,190 shares of Moderna, Inc. (US:MRNA) valued at $65,437,186 USD as of March 31, 2025. The entity filed a previous 13F-HR on February 14, 2025 disclosing 2,308,190 shares of Moderna, Inc.. This represents a change in shares of 0.00% during the quarter. The current value of the position is $61,305,526 USD.
https://fintel.io/so/us/mrna/merck
it's written on the wall
axelvento
4 weeks ago
What we know about the safety, efficacy of mRNA vaccines amid recent scrutiny
Infectious disease experts told ABC News that mRNA and mRNA vaccines have been studied for decades, the vaccines are safe and effective, and that the shots were instrumental in saving lives during the COVID-19 pandemic.
“Here’s the bottom line: mRNA vaccines for COVID, according to estimates from Yale School of Public Health, saved 3.2 million lives,” Dr. Peter Hotez, a professor of pediatrics and molecular virology at Baylor College of Medicine in Houston, told ABC News.
“So instead of 1.2 million Americans who lost their life because of COVID, it would have been a 4.4 million,” he added. “So, I think it's unfortunate that anti-vaccine activists target mRNA vaccines like they do, but it is a good technology.”
https://abcnews.go.com/Health/safety-efficacy-mrna-vaccines-amid-recent-scrutiny/story?id=122068940
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