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Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients
Diwakar Davar1, Amiran K Dzutsev2, John A McCulloch2
1Department of Medicine and UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Abstract:
Anti-programmed cell death protein 1 (PD-1) therapy provides long-term clinical benefits to patients with advanced melanoma. The composition of the gut microbiota correlates with anti-PD-1 efficacy in preclinical models and cancer patients. To investigate whether resistance to anti-PD-1 can be overcome by changing the gut microbiota, this clinical trial evaluated the safety and efficacy of responder-derived fecal microbiota transplantation (FMT) together with anti-PD-1 in patients with PD-1-refractory melanoma. This combination was well tolerated, provided clinical benefit in 6 of 15 patients, and induced rapid and durable microbiota perturbation. Responders exhibited increased abundance of taxa that were previously shown to be associated with response to anti-PD-1, increased CD8+ T cell activation, and decreased frequency of interleukin-8-expressing myeloid cells. Responders had distinct proteomic and metabolomic signatures, and transkingdom network analyses confirmed that the gut microbiome regulated these changes. Collectively, our findings show that FMT and anti-PD-1 changed the gut microbiome and reprogrammed the tumor microenvironment to overcome resistance to anti-PD-1 in a subset of PD-1 advanced melanoma.
Insights
Fecal microbiota transplantation (FMT) combined with anti-programmed cell death protein 1 (PD-1) therapy shows promise for treating advanced melanoma resistant to anti-PD-1. This approach altered gut bacteria and reprogrammed the tumor microenvironment, benefiting some patients.
Area of Science:
- Oncology
- Immunology
- Microbiome Research
Background:
- Anti-programmed cell death protein 1 (PD-1) therapy is crucial for advanced melanoma treatment.
- Gut microbiota composition influences anti-PD-1 therapy efficacy.
- Mechanisms of resistance to anti-PD-1 therapy remain a significant clinical challenge.
Purpose of the Study:
- To evaluate the safety and efficacy of combining fecal microbiota transplantation (FMT) with anti-PD-1 therapy in patients with PD-1-refractory melanoma.
- To investigate if modulating the gut microbiota can overcome resistance to anti-PD-1 treatment.
- To understand the impact of FMT on the tumor microenvironment and host immune response.
Main Methods:
- A clinical trial involving patients with PD-1-refractory melanoma receiving responder-derived FMT alongside anti-PD-1 therapy.
- Assessment of treatment safety and clinical benefit.
- Analysis of gut microbiota composition, CD8+ T cell activation, myeloid cell populations, and proteomic/metabolomic signatures.
- Transkingdom network analyses to elucidate microbiome-host interactions.
Main Results:
- The combination therapy was well-tolerated.
- Clinical benefit was observed in 6 out of 15 patients.
- FMT induced rapid and durable changes in gut microbiota composition.
- Responders showed increased CD8+ T cell activation and decreased interleukin-8-expressing myeloid cells.
- Distinct proteomic and metabolomic profiles were identified in responders, regulated by the gut microbiome.
Conclusions:
- Fecal microbiota transplantation combined with anti-PD-1 therapy is a safe and potentially effective strategy for a subset of patients with advanced melanoma resistant to anti-PD-1.
- This combination therapy can alter the gut microbiome and reprogram the tumor microenvironment, overcoming treatment resistance.
- Microbiome modulation represents a promising avenue for enhancing immunotherapy outcomes in cancer patients.
