Fecal microbiota transplantation boosts survival in metastatic colorectal cancer treatment

By Dr. Chinta SidharthanReviewed by Benedette Cuffari, M.Sc.Nov 15 2023

In a recent study published in eClinicalMedicine, researchers assess the use of fecal microbiota transplantation to enhance the efficacy of anti-programmed cell death protein 1 (PD-1) therapy for patients with microsatellite stable metastatic colorectal cancer.

Study: Fecal microbiota transplantation plus tislelizumab and fruquintinib in refractory microsatellite stable metastatic colorectal cancer: an open-label, single-arm, phase II trial (RENMIN215). Image Credit: Peakstock / Shutterstock.com

Background

Colorectal cancer is one of the three most prevalent forms of cancer throughout the world and, as a result, a major cause of cancer-related mortality. The current standard first- and second-line treatments for metastatic colorectal cancer include therapies targeting epidermal growth factor (EGF) or vascular endothelial growth factor (VEGF) receptors combined with fluorouracil-based chemotherapy. However, there remains a lack of third-line treatments, with existing options often associated with low efficacy and a high rate of adverse events.

Immune checkpoint inhibitors have significantly improved the treatment effectiveness for various cancers and have been specifically recommended for the treatment of tumors with high microsatellite instability or mismatch repair deficiency, including colorectal cancers. However, most metastatic colorectal cancers are of the microsatellite stable or mismatch-repair proficient phenotype, for which immune checkpoint inhibitors are less effective.

Based on previous observations that the gut microbiota can improve immune responses, fecal microbiota transplantation has been explored to enhance treatment efficacy by reprogramming the tumor microenvironment in colorectal cancer.

About the study

The present study was a single-arm, open-label, phase II clinical trial to evaluate the safety and efficacy of combining fecal microbiota transplantation with fruquintinib, which is a small-molecule tyrosine kinase inhibitor of VEGF receptors, and tislelizumab, a monoclonal antibody PD-1 inhibitor. This combination was explored as a third-line treatment option for microsatellite stable metastatic colorectal cancers.

Patients above the age of 18 with progressive or metastatic colorectal cancer and an intolerance to or progression despite second-line chemotherapy were included in the study. The included patients were required to have adequate renal, hepatic, and hematological function and at least one measurable tumor. Polymerase chain reaction (PCR) assay, immunohistochemistry, and next-generation sequencing were used to confirm microsatellite stability.

Individuals with another concomitant cancer, autoimmune disease, a history of immunotherapy or organ transplantation, any factors that would impact the absorption of oral drugs, and those prescribed systemic immunosuppressive therapy were excluded from the study. After a phase of native microbiota depletion, fecal microbiota transplantation was conducted using orally administered stool capsules that were customized to the patient, along with orally administered fruquintinib and intravenously administered tislelizumab.

Progression-free survival was the primary endpoint, whereas overall response rate, duration of response, disease control rate, clinical benefit rate, and overall survival were secondary outcomes. Independent radiologists assessed tumor responses. The treatment was continued until the participant withdrew consent, unacceptable levels of toxicity were observed, the study was completed, the investigator decided to terminate the study, or the participant died.

Fecal and peripheral blood samples were serially collected to analyze the gut microbiome and exploratory biomarker levels. Pyrosequencing of the 16S ribosomal deoxyribonucleic acid (rDNA) amplicon from genomic DNA extracted from the stool samples was used to analyze the gut microbiome. T-cell receptor sequencing from peripheral blood mononuclear cells (PBMCs) was conducted to explore potential biomarkers.

Study findings

The combination treatment of fecal microbiota transplantation with tislelizumab and fruquintinib was found to be manageably safe and resulted in improved survival in patients with microsatellite stable metastatic colorectal cancer. More specifically, the intervention resulted in a 9.6-month increase in mean progression-free survival and a 13.7-month increase in mean overall survival, as well as 20% and 95% higher overall response and disease control rates, respectively.

The gut microbiome analyses also showed that post-treatment microbiome compositions had a relatively greater abundance of bacteria belonging to the family Lachnospiraceae, which are known to be favorable for immunotherapy. The abundance of bacteria belonging to the Bifidobacterium family, which increases immune tolerance, was also found to be lower after treatment.

The toxicity profile of this combination treatment was manageable, and significant antitumor activity was observed.

Conclusions

Fecal microbiota transplantation combined with fruquintinib and tislelizumab had manageable adverse reactions. Importantly, this treatment approach significantly increased overall and progression-free survival rates in patients with microsatellite stable metastatic colorectal cancer.