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Using organoids to model gastrointestinal toxicities associated with immune checkpoint blockade

Award Number: R21CA312872
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/10/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Using organoids to model gastrointestinal toxicities associated with immune checkpoint blockade - Project Summary Here we propose developing a patient-derived intestinal organoid system to model intestinal toxicity associated with immune checkpoint inhibitors (ICIs) used to treat cancer. Monoclonal antibodies targeting immune checkpoint receptors PD-1 and CTLA-4 have revolutionized immuno-oncology by harnessing the power of the immune system to fight solid tumors. Although ICI therapy has improved the survival of patients with metastatic cancer, treatments are limited by the development of immune-related adverse events (irAEs). While only 20% of patients with solid tumors respond to ICI therapy, irAEs can occur in over 85% of ICI-treated patients and are a frequent indication for stopping cancer therapy and immunosuppressing patients with corticosteroids that can suppress tumor immune responses. Colitis is the most common, severe irAE and occurs in up to 45% of patients on dual PD-1/CTLA-4 blockade. We recently showed that in patients with irAE colitis (irColitis), the colon mucosa has expanded CD8 tissue-resident memory (TRM) T cells that upregulate a unique, human-specific transcriptional program (GZMB, IL26, IL17A, CXCL13), IL17AHi and CXCL13Hi CD4 T cell effectors, T regulatory cells, CIQAHi macrophages, inflammatory VCANHi monocytes, and interferon-induced epithelial damage predicted to alter epithelial barrier and absorptive functions. While traditional 3D epithelial organoid cultures can model interferon- related epithelial signatures, they lack the complex immune components that define human irColitis. Here we will develop a holistic model of irColitis using intestinal air-liquid interface (ALI) organoid cultures, which preserve heterogeneous epithelial and immune components from human colon mucosa. In this proposal, we will test the hypothesis that patient-derived intestinal ALI organoids stimulated with ICI therapy support the upregulation of cytotoxic CD8 TRM T cell gene programs and can be used to model irColitis treatment with various immunosuppressive therapies repurposed from inflammatory bowel disease (IBD). Aim 1 will determine if colon ALI organoids from healthy individuals have sufficient components to support ICI-induced activation of intestinal CD8 TRM T cells as seen in the colon mucosa of patients with irColitis. Aim 2 establishes methods to derive colon ALI organoids from patients with irColitis to determine how well cytotoxic CD8 TRM T cell features are retained in cultures and to assess the efficacy of IBD therapies (anti-TNFa, anti-IL12/23, anti-IL23) in ameliorating immune activation. This work is enabled by a collaboration with the Oregon Health & Science University Gastrointestinal Immune Toxicity Clinic, which expedites that clinical care and research enrollment of patients with suspected irColitis. At the conclusion of these experiments, we will have established a human experimental system that will advance the mechanistic understanding of irColitis, identify new irAE treatments that do not interfere with tumor immunity, and improve preclinical ICI testing to enable the development of safer and less toxic therapies to treat patients with cancer.


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 = $510,510 )
2026	2026	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Treatment Research	001	1	7/21/2026	NEW	$109,395
2026	2026	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Treatment Research	000	1	7/10/2026	NEW	$401,115
														Subtotal = $510,510

Grand Total All Awards = $510,510

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Using organoids to model gastrointestinal toxicities associated with immune checkpoint blockade

Award Number: R21CA312872

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/10/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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