The gut microbiome enhances anti-PD-1 efficacy in a tumor-agnostic manner: results from a phase II trial of fecal microbiota transplantation and anti-PD-1 re-induction in MSI-H refractory cancers
Background: The gut microbiome has been associated with response to anti-PD‑1 therapy in melanoma, lung cancer, and kidney cancer. Small clinical trials combining gut microbiome modulation via fecal microbiota transplantation (FMT) and anti-PD‑1 therapy showed promising results in melanoma patients. However, the mechanisms driving the gut microbiome effect on anti-tumoral immunity remain elusive. Here, we address a fundamental mechanistic question: can the gut microbiome support anti-tumoral immunity in a tumor-agnostic manner.
Methods: We conducted a single-center clinical trial enrolling 15 patients with metastatic, anti-PD‑1 refractory microsatellite instability-high (MSI‑H), regardless of their primary cancer type. Responders were defined as an objective radiological response (RECIST) ≥6 months. Ten patients underwent antibiotic preconditioning prior to FMT via colonoscopy, followed by maintenance FMT via capsules. Five patients underwent FMT via colonoscopy only without antibiotic preconditioning. All 15 colonoscopy FMTs used a single donor, a metastatic MSI‑H colorectal cancer (CRC) patient who achieved a complete response (CR) on anti-PD‑1 therapy. In parallel, melanoma and CRC-bearing germ-free mice were treated with anti-PD‑1 and either FMT from the trial’s CR donor, FMT from a metastatic melanoma patient who did not respond to anti-PD‑1 therapy, or a bacterial consortium derived from the trial’s CR donor.
Results: Patients with the following MSI‑H cancer were enrolled in the trial: 10 CRC, two small bowel adenocarcinomas, one pancreatic adenocarcinoma, one endometrial adenocarcinoma, and one pineal brain tumor. The median number of previous treatments lines was three. Three out of 15 (20%) patients responded to treatment: one CRC patient achieved an ongoing CR >2 years, one small bowel adenocarcinoma patient achieved stable disease (SD) for 16 months, and one CRC patient achieved SD for 6 months. All responders had a primary anti-PD‑1 failure. No deaths were observed in the study. One grade 3⁄4 immune-related adverse event occurred: a patient with a history of immunotherapy-related colitis developed grade 3 hepatitis. The trial’s CR donor material enhanced anti-PD‑1 efficacy in melanoma and CRC-bearing mice, while a melanoma non-responder donor impaired anti-PD‑1 efficacy in these mice. Pending analyses include human and mouse stool metagenomics, human serum metabolomics, mouse gut and human and mouse tumor for spatial analysis and TCR-sequencing.
Conclusion: FMT and anti-PD1 re-induction enhanced efficacy in patients anti-PD‑1 refractory MSI‑H cancers. Our results suggest that the gut microbiome affects anti-tumoral immunity in a tumor-agnostic manner. Molecular profiling of clinical and pre-clinical samples is ongoing to unveil the mechanisms driving this effect.
Ethics approval:
This study involved human subjects as part of a clinical trial, which was approved by The University of Texas MD Anderson Cancer Center’s Institutional Review Board, approval number 2020 – 0186. The clinical trial was registered on ClinicalTrials.gov – NCT04729322. This study also included translational studies, which were approved by The University of Texas MD Anderson Cancer Center’s Institutional Review Board, approval number 10 – 0982.
Acknowledgment:
Dr. Overman was supported by: SPORE Grant P50CA221707, The University of Texas MD Anderson Cancer Center Moon Shots Program and Cancer Center Support Grant P30CA16672. Dr. Baruch was supported by the American Society of Clinical Oncology Conquer Cancer Young Investigator Award 2024YIA-5356050069.