17 Dec ASH 2025: Roswell Park Study Identifies Mechanism of CAR T-cell resistance in B-cell lymphoma
Dr. Davila
MedicalResearch.com Interview with:
Marco Davila, MD, PhD
Hematologist/Oncologist,
Senior Vice President and Associate Director for Translational Research at
Roswell Park Comprehensive Cancer Center (Buffalo, NY) – study senior author
Dr. Stone
Co-author Meredith Stone, PhD
Assistant Director for Cell Therapy Translation
in Dr. Davila’s lab at Roswell Park – presenting author
MedicalResearch.com: What is the background for this study?
Response: While CD19-targeted CAR T cell therapy has garnered clinical success and FDA approval for the treatment of large B cell lymphoma, approximately half of patients suffer from primary resistance or relapse. Increasing evidence suggests that resistance mechanisms are supported by the tumor microenvironment (TME). Cytokines secreted by CAR T cells can remodel the TME, determining the phenotype and function of other immune cells.
MedicalResearch.com: What are the main findings?
Response: Here, we demonstrated that interferon-gamma (IFNγ) derived from CAR T cells drove inducible nitric oxide synthase (iNOS) expression in tumor-associated macrophages, reprogramming them into a suppressive phenotype that inhibited CAR T cell activity. Mechanistically, these immunoregulatory macrophages impaired CAR T metabolic function and altered the proteome of CAR T cells to reduce protein synthesis and promote apoptosis. In laboratory studies, inhibition of iNOS reversed these changes and extended survival in preclinical models treated with CD19-targeted CAR T cells. Serum from patients whose cancers failed to respond to CAR T therapy reprogrammed macrophages to an immunoregulatory phenotype that inhibited CAR T cell function, highlighting the translational relevance of our work.
MedicalResearch.com: What should readers take away from your report?
Response: Our study identifies CAR T cell-derived IFNγ as a key determinant of macrophage-mediated immunosuppression in the TME. Targeting the IFNγ-iNOS axis may mitigate macrophage-driven resistance, relieve immunosuppression, and enhance therapeutic efficacy of CAR T cells in LBCL.
MedicalResearch.com: What recommendations do you have for future research as a results of this study?
Response: Future studies should assess the therapeutic potential of genetic or pharmacologic interventions that modulate IFNγ signaling in CAR T cells. Comparative studies of IFNγ deletion versus blockade will be needed to successfully modulate immune regulation while preserving anti-tumor function. Moreover, the timing, dosage, and patient subset most likely to benefit from targeting the IFNγ pathway warrant evaluation, including biomarker-guided approaches.
Disclosures: Dr. Davila discloses the following:
Adaptive Biotechnologies, Research Funding
Adicet, Consultancy (Includes expert testimony)
Adicet, Research Funding
BMS, Consultancy (Includes expert testimony)
Incyte, Research Funding
MyeloidTx, Consultancy (Includes expert testimony)
CRISPR, Patents & Royalties
CRISPR, Research Funding
Kite/Gilead, Research Funding
CARGO, Consultancy (Includes expert testimony)
Bellicum, Consultancy (Includes expert testimony)
Bellicum, Research Funding
Atara, Patents & Royalties
Novartis, Research Funding
Capstan, Consultancy (Includes expert testimony)
Citation: ASH 2025 abstract
Davila M, Lee SB, Kang YP, Boucher J, Mandula J, Roselli E, Chang D, Jimenez R, Kotani H, Reid K, Vazquez-Martinez J, Beatty N, Goala P, Sierra-Mondragon R, Liu M, Koomen J, Nguyen J, Hussaini M, Shaw T, Wang X, Faramand R, Jain M, Locke F, Rodriguez P, Sailer C, McSain S, Hamid S, Tariq M, Wang J, Abraham-Miranda J. CAR T cell-driven induction of iNOS in tumor-associated macrophages promotes CAR T cell resistance in B cell lymphoma. Res Sq [Preprint]. 2025 Mar 31:rs.3.rs-3481746. doi: 10.21203/rs.3.rs-3481746/v1. PMID: 40235478; PMCID: PMC11998770.
https://pubmed.ncbi.nlm.nih.gov/40235478/
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Last Updated on December 17, 2025 by Marie Benz MD FAAD