# NIH grant: Using organoids to model gastrointestinal toxicities associated with immune checkpoint blockade (1R21CA312872-01) — retained record

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NIH grant 1R21CA312872-01: Using organoids to model gastrointestinal toxicities associated with immune checkpoint blockade
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Molly  Thomas. Award: $401115.
Start: 2026-07-10T00:00:00.
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.
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