# Adverse gut microbiome promotes resistance immune checkpoint inhibitors via chronic inflammation

> **NIH CA R00** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2026 · $248,658

## Abstract

Project summary/abstract
Immune checkpoint inhibitors (ICI) transformed oncological care for multiple cancers. Yet, 80% of ICI patients
will eventually fail therapy. Colossal efforts are invested in overcoming ICI resistance. A promising candidate
is the gut microbiome which was associated with ICI clinical outcomes. I led a seminal clinical trial in which the
gut microbiome of patients with ICI refractory metastatic melanoma was modulated via fecal microbiota
transplantation (FMT). FMT and ICI re-induction resulted in increased intra-tumoral infiltration of CD8+ T-cells
and objective clinical response rates of 30%. However, microbiome modulation remains far from wide clinical
use. While FMT showed consistent clinical efficacy, it is not feasible outside of major academic centers; and
some probiotics have been associated with a deleterious effect on ICI efficacy. Therapies that mimic the
microbiome effect on the immune system can enhance ICI efficacy while omitting FMT obstacles. However,
the development of such therapies is hindered since the mechanisms driving the gut microbiome's effect on
anti-tumoral immunity remain unknown. In this proposal, I will test the hypothesis that an adverse microbiome
induces a state of chronic inflammation that impedes ICI efficacy. FMT from donors with favorable microbiomes
promotes anti-tumoral immunity by disrupting the net inflammatory signaling; hence, attenuating inflammation
by direct immune re-programming can mimic the FMT effect. To test this, I propose the following research
plan. In Aim 1, I will determine the effect of microbial-induced inflammation on anti-tumoral immunity by
analyzing longitudinal stool, serum, gut, and tumor samples from a unique cohort of 33 patients with ICI-
refractory melanoma (n=20) and microsatellite-instability high cancers (MSI-H, n=13) who participated in
clinical trials of FMT and ICI re-induction (NCT03353402 and NCT04729322, respectively). Spatial
transcriptomics of gut and tumor samples w

## Key facts

- **NIH application ID:** 11478145
- **Project number:** 4R00CA296940-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Erez N Baruch
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** CA
- **Fiscal year:** 2026
- **Award amount:** $248,658
- **Award type:** 4N
- **Project period:** 2025-01-01T00:00:00 → 2028-12-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11478145

## Citation

> US National Institutes of Health, RePORTER application 11478145, Adverse gut microbiome promotes resistance immune checkpoint inhibitors via chronic inflammation (4R00CA296940-02). Retrieved via AI Analytics 2026-07-07 from https://api.ai-analytics.org/grant/nih/11478145. Licensed CC0.

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