Abstract
Abstract 6496: Methylseleninic acid enhances anti-FN14 CAR-T cell effector function and redirects cytotoxicity against TGF-β-rich kidney, prostate, and brain tumors
Cancer research (Chicago, Ill.), Vol.86(7_Supplement), pp.6496-6496
04/03/2026
DOI: 10.1158/1538-7445.AM2026-6496
Abstract
Background:
Clear cell renal cell carcinoma (ccRCC), metastatic castration-resistant prostate cancer (mCRPC), and glioblastoma (GBM) are treatment-refractory tumors marked by high TGF-β1, a master suppressor of antitumor immunity and antigen presentation. Pharmacologic methylseleninic acid (MSA) potently inhibits TGF-β1, PD-L1, and VEGF without significant off-target toxicity. FN14, the TWEAK receptor and a metastasis driver, is selectively overexpressed in these malignancies, making it a high-specificity CAR-T target.
Methods:
We developed second-generation anti-FN14 CARs with CD28 or 4-1BB costimulation and CD3ζ signaling and lentivirally transduced them into human CD4+/CD8+ T cells. Cytotoxicity against FN14+ ccRCC, mCRPC, GBM lines and patient-derived tumors was measured using LDH release and xCELLigence assays. Effector function was assessed by intracellular cytokines, phenotyping, and multiplex analysis. MSA was tested at physiologic concentrations to evaluate effects on CAR-T viability, metabolism, function, and tumor susceptibility.
Results:
Anti-FN14 CAR-T cells mediated rapid, antigen-specific lysis across all tumor types, achieving >50% specific lysis at an E:T ratio of 1:1. MSA (2.5-5 µM) reduced tumor PD-L1 and TGF-β by >40% and improved CAR-T metabolic activity, enhancing IL-2 and IFN-γ secretion. Manufacturing CAR-T cells with MSA (2.5 µM) increased cytotoxicity and persistence versus controls (p < 0.01). MSA’s effects were dose- and schedule-dependent at clinically compatible concentrations without detectable off-target toxicity.
Conclusion:
MSA augments anti-FN14 CAR-T cytotoxicity, metabolic fitness, and sustained effector function by suppressing tumor-derived TGF-β1 and PD-L1 and directly enhancing CAR-T activity. As a clinically relevant TGF-β1 inhibitor and active seleno-L-methionine metabolite, MSA represents a readily translatable strategy to reduce CAR-T exhaustion and improve efficacy in TGF-β-rich solid tumors.
Details
- Title: Subtitle
- Abstract 6496: Methylseleninic acid enhances anti-FN14 CAR-T cell effector function and redirects cytotoxicity against TGF-β-rich kidney, prostate, and brain tumors
- Creators
- Gloria B. Kim - Mayo Clinic in ArizonaObed B. Amissah - Mayo Clinic in ArizonaCasey R. Ager - Mayo Clinic in ArizonaYousef Zakharia - Mayo Clinic in ArizonaYoucef M. Rustum - Roswell Park Comprehensive Cancer Center
- Resource Type
- Abstract
- Publication Details
- Cancer research (Chicago, Ill.), Vol.86(7_Supplement), pp.6496-6496
- DOI
- 10.1158/1538-7445.AM2026-6496
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Publisher
- AMER ASSOC CANCER RESEARCH
- Language
- English
- Date published
- 04/03/2026
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9985153160302771
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