Nature Medicine | Safety and Mechanistic Study of Fecal Microbiota Transplantation Combined with Immunotherapy in Metastatic Renal Cell Carcinoma

This study reveals the critical role of the gut microbiome in modulating the efficacy and toxicity of immune checkpoint inhibitors, providing actionable biomarkers and intervention targets for optimizing personalized treatment strategies in mRCC patients, suggesting that future clinical trials should integrate microbiome monitoring and functional assessment.

 

Literature Overview

The article titled 'Fecal microbiota transplantation plus immunotherapy in metastatic renal cell carcinoma: the phase 1 PERFORM trial,' published in Nature Medicine, systematically investigates the safety, preliminary efficacy, and potential mechanisms of combining healthy donor fecal microbiota transplantation (FMT) with immune checkpoint inhibitors (ICI) in treatment-naïve patients with metastatic renal cell carcinoma (mRCC). Through integrative multi-omics analysis, the study reveals associations between microbiome functional engraftment and both antitumor responses and immune-related adverse events (irAEs), offering high-quality clinical evidence for microbiome-based interventions in cancer immunotherapy.

Background Knowledge

Responses to immune checkpoint inhibitors (ICI) in metastatic renal cell carcinoma (mRCC) are highly heterogeneous and often accompanied by immune-related adverse events (irAEs), limiting their long-term use. Although ICI significantly improves survival in some patients, most discontinue treatment within five years due to disease progression or toxicity. Current understanding of how the gut microbiome regulates antitumor immunity remains insufficient, particularly lacking clinical data on microbiome-targeted interventions in mRCC. Furthermore, challenges persist in selecting effective and safe FMT donors and predicting treatment response and toxicity. This study focuses on evaluating the safety of an encapsulated FMT product, LND101, in combination with standard ICI regimens, and explores the dynamic relationships among microbiome engraftment, metabolic functions, and host immune responses, aiming to identify microbial features predictive of efficacy and toxicity, thereby providing a mechanistic foundation for next-generation microbiome-assisted immunotherapy.

 

 

Research Methods and Experiments

The study employed a single-center, open-label phase 1 clinical trial design (PERFORM, NCT04163289), enrolling 20 treatment-naïve mRCC patients who received oral encapsulated FMT from healthy donors (LND101) in combination with standard ICI regimens (primarily ipilimumab/nivolumab). High-throughput shotgun metagenomic sequencing of fecal samples was performed, along with longitudinal monitoring of plasma metabolomics, cytokines, and peripheral blood immune phenotypes, to systematically assess associations between microbiome engraftment, functional changes, and clinical outcomes. Microbiome dynamics were quantified using metrics such as α-diversity, β-diversity, strain engraftment rates, and enzyme functional annotations (EC numbers), combined with RECIST v1.1 to evaluate objective response rate (ORR) and progression-free survival (PFS).

Key Conclusions and Perspectives

• Fifty percent of patients experienced grade 3 irAEs, but no severe FMT-related toxicities were observed, indicating that LND101 combined with ICI is tolerable in mRCC and supports further investigation.
• The objective response rate reached 50% (9/18), including two complete responses, suggesting that FMT may enhance ICI efficacy, particularly within specific microbial contexts.
• Responders were less likely to experience grade 3 irAEs (11% vs 89%) and exhibited significantly higher gut microbiome α-diversity, indicating a positive correlation between microbial diversity and treatment tolerance.
• Patients tolerant to toxicity showed durable donor strain engraftment and transfer of functional metabolic pathways, particularly enrichment of short-chain fatty acid-producing bacteria such as Faecalibacterium prausnitzii, suggesting that the implantation of anti-inflammatory microbial functions may protect against irAEs.
• Segatella copri was significantly expanded in patients experiencing grade 3 irAEs, especially those receiving ipilimumab/nivolumab, and its abundance >10 CPM predicted toxicity, identifying S. copri as a potential biomarker for toxicity.
• Source tracking revealed that S. copri primarily originated from donors, underscoring the importance of donor screening; its enrichment correlated with pro-inflammatory enzymatic activities (e.g., branched-chain amino acid transaminase), revealing potential pathogenic mechanisms.
• Metabolomic analysis showed that patients without severe toxicity maintained higher levels of immunomodulatory metabolites such as L-histidine, L-cysteine, and stearoylcarnitine, indicating a systemic association between metabolic homeostasis and resistance to toxicity.
• Immune phenotyping revealed that patients without grade 3 irAEs exhibited sustained increases in CD38+ Treg cells and elevated CD56++CD16− NK cells, suggesting activation of immune tolerance mechanisms.

Research Significance and Prospects

This study provides important clinical evidence for combination strategies in mRCC, demonstrating that FMT can be safely combined with ICI and may improve both efficacy and safety by reshaping the gut microbiome. The identification of S. copri as a driver of toxicity suggests that future donor screening should exclude individuals with high abundance of this bacterium, and patients should be monitored for its dynamics post-FMT. Additionally, Faecalibacterium prausnitzii and specific metabolites (e.g., L-histidine) may serve as potential protective biomarkers to guide personalized interventions.

From a drug development perspective, the findings support the development of 'next-generation' microbiome therapies based on specific bacterial strains or metabolites, rather than non-selective FMT. For example, designing synthetic microbial consortia containing F. prausnitzii or their metabolic products as adjuvants could more safely and effectively enhance ICI responses. Furthermore, small-molecule inhibitors or phage therapies targeting S. copri or its pro-inflammatory metabolic pathways warrant exploration.

In terms of clinical monitoring, it is recommended to incorporate metagenomic surveillance into ICI treatment pathways for dynamic risk stratification. Future phase 2 trials should stratify patients based on microbiome features to validate the efficacy-enhancing effects of FMT and explore optimal timing, dosing, and sequencing of FMT with ICI.

 

 

Conclusion

This study establishes the safety of fecal microbiota transplantation combined with immunotherapy in metastatic renal cell carcinoma and, for the first time, reveals deep associations between microbiome functional engraftment and clinical outcomes. Through integrative multi-omics analysis, it not only identifies S. copri as a driver of toxicity but also discovers links between F. prausnitzii and specific metabolites with reduced toxicity and improved response, providing actionable biomarkers for clinical translation. From bench to bedside, these findings advance the paradigm shift from 'non-selective' FMT toward 'precision microbiome intervention.' In the future, donor screening based on microbiome functional profiles, dynamic patient monitoring, and the development of synthetic consortia or metabolite-based replacement therapies hold promise for building safer and more effective personalized immunotherapy strategies. This study introduces the microbiome dimension into the mRCC care framework, marking a foundational step toward the new era of 'microbiome-guided cancer immunotherapy.'

 

Ricardo Fernandes, Behnam Jabbarizadeh, Adnan Rajeh, Michael S Silverman, and Saman Maleki Vareki. Fecal microbiota transplantation plus immunotherapy in metastatic renal cell carcinoma: the phase 1 PERFORM trial. Nature Medicine.