# Mechanism-rooted therapeutic strategies for immune-related toxicities induced by checkpoint inhibitors

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $352,047

## Abstract

PROJECT SUMMARY/ABSTRACT
Although immune checkpoint inhibitors (ICIs) are revolutionizing cancer treatment, they are associated with
life- or organ-threatening complications, termed immune-related adverse events (irAEs). Steroids, the first-line
of treatment for irAEs, significantly abrogate the anti-tumor efficacy of ICIs; however, our knowledge of the
mechanisms and signs that underpin the onset and progression of irAEs is very limited. Furthermore,
commonality and individuality of altered immunity between irAEs have never been characterized. Our clinical
and translational studies have revealed significant impact of combined ICI therapy (cytotoxic T lymphocyte-
associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) inhibitors) on the severity of
arthritis-irAE, -colitis-irAE, and -pneumonitis-irAE compared to PD-1 inhibitor monotherapy. Notably, T helper
(Th)17 cell signatures were significantly enhanced in arthritis-irAE synovial fluid, colitis-irAE colon, and
pneumonitis-irAE bronchoalveolar lavage. In parallel, our lab has developed arthritis-irAE, colitis-irAE and
pneumonitis-irAE murine models recapitulating patients’ clinical settings. Importantly, like in humans, Th17 cell
signatures were enriched in the inflamed tissue of mice with ICI-induced arthritis (synovium), colitis (colon),
and pneumonitis (lung) after combined ICI-therapy and correlated with irAE disease severity. Interestingly,
arthritis-prone mice developed arthritis after receiving fecal microbial transplant (FMT) from combined ICI
arthritis donor mice, notably with enhanced Th17 cell signatures. We also observed that blockade of Th17-
related cytokines, interleukin (IL)-6 and tumor necrosis factor alpha (TNFα), may pinpoint irAE immunity while
preserving/enhancing the anti-tumor efficacy of ICI therapy in humans and mice. Further understanding of
mechanisms underlying irAEs may lead to identification of common and valid biomarkers predicting
development and/or reflecting severity of irAEs as well as to new steps in their treatment. Therefore, we
propose to uncover shared and distinct cellular/molecular mechanism(s) underpinning irAEs (arthritis-
irAE, colitis-irAE, and pneumonitis-irAE) development as well as establish efficient therapeutic
strategies. Here, in Aim 1, we will identify the cellular and molecular mechanisms and therapeutic targets by
utilizing our novel preclinical murine models of irAEs including arthritis, colitis, and pneumonitis. In addition,
cellular, phenotypic, and transcriptomic analysis of biospecimens from cancer patients with arthritis-irAE,
colitis-irAE or pneumonitis-irAE will help to uncover common or unique immunopathogenesis mechanisms
between different irAEs. In Aim 2, we will develop optimal strategies for treatment of irAEs while preserving
anti-tumor immunity by utilizing melanoma tumor model in mice with irAEs. The implications from this work will
be significant and will help to: 1) discover mechanisms universally or dis...

## Key facts

- **NIH application ID:** 10861932
- **Project number:** 5R01CA284684-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Roza Insafetdinovna Nurieva
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $352,047
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10861932

## Citation

> US National Institutes of Health, RePORTER application 10861932, Mechanism-rooted therapeutic strategies for immune-related toxicities induced by checkpoint inhibitors (5R01CA284684-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10861932. Licensed CC0.

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