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Mechanisms of BCMA CAR-T-mediated enteritis in multiple myeloma patients

Award Number: R01CA316736
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/12/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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Mechanisms of BCMA CAR-T-mediated enteritis in multiple myeloma patients - PROJECT SUMMARY/ABSTRACT Chimeric antigen receptor T cell (CAR-T) therapy that targets the B cell maturation antigen (BCMA), particularly the FDA-approved therapy cilta-cel, has led to durable responses for relapsed/refractory multiple myeloma. However, there is increasing awareness of emerging immune toxicities from cilta-cel, which directly impact both patient quality of life and survival. One such cilta-cel toxicity is CAR-T enteritis, which has been recently described in multi-institution case reports. While some patients respond to corticosteroids or TNF blockade, many cases are refractory to empiric immunosuppression, require total parental nutrition, or can be fatal. The refractoriness of BCMA CAR-T enteritis to standard interventions underscores a key unmet need: we lack precision targeted immunosuppression approaches because we do not understand its pathogenesis. It is unknown how CAR-T cells and other immune cell subsets interact to drive enteritis, whether these require on- target/off-tumor recognition of their cognate antigen, and the effector pathways that induce tissue damage. We hypothesize that BCMA CAR-T enteritis is caused by cytotoxic, tissue-infiltrating CAR-T clones that recognize their cognate BCMA and/or endogenous peptide-MHC antigens, within a permissive cellular niche of tissue- resident memory T cells (Trm) and epithelial states. Our research will employ single-cell and spatial multi-omics to analyze tissue and blood samples from BCMA CAR-T enteritis patients and controls, including patients with immune checkpoint inhibitor-induced enterocolitis and graft-versus-host disease. By characterizing the molecular and spatial signatures of both the BCMA CAR-T and endogenous immune and non-immune cells in inflamed duodenum, we will identify novel effector pathways as biomarkers and therapeutic targets. These pathways, and putative CAR-T antigenic targets, will be directly perturbed in autologous patient-derived organoid co-culture with BCMA CAR-T to validate their pathogenic contribution and provide an in vitro system to accelerate pre-clinical evaluation of new therapeutic strategies. The specific aims are: 1. Define pathogenic BCMA CAR-T programs and tissue interactions. 2. Determine requirements for antigen recognition and inflammatory pathways for epithelial injury. By integrating single-cell and spatial multi-omics with patient-derived organoid co-culture systems, this project will advance our fundamental understanding of the immune mechanisms in CAR-T enteritis, and lead to personalized therapeutic approaches that reduce morbidity and improve outcomes for patients.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $683,270 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Biology Research	000	1	8/12/2026	NEW	$683,270
														Subtotal = $683,270

Grand Total All Awards = $683,270

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Mechanisms of BCMA CAR-T-mediated enteritis in multiple myeloma patients

Award Number: R01CA316736

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/12/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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