Fecal microbiota transplant increases survival in metastatic colorectal cancer treatment

In a recent study published in e-clinical medicineresearchers are evaluating the use of fecal microbiota transplantation to increase the efficacy of anti-programmed cell death protein 1 (PD-1) therapy for patients with microsatellite-stable metastatic colorectal cancer.

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

background

Colorectal cancer is one of the three most prevalent forms of cancer worldwide and, as a result, is the leading cause of cancer-related deaths. Current standard first- and second-line treatments for metastatic colorectal cancer include epidermal growth factor (EGF) or vascular endothelial growth factor (VEGF) receptor-targeted therapies and fluorouracil-based chemotherapy. Includes a combination of treatments. However, third-line treatments are still lacking, and existing treatments often have low efficacy and high rates of adverse events.

Immune checkpoint inhibitors have significantly improved therapeutic efficacy in a variety of cancers and are particularly recommended for the treatment of tumors with microsatellite instability and mismatch repair defects, such as colorectal cancer. However, most metastatic colorectal cancers have a microsatellite-stable or mismatch repair-proficient phenotype, making immune checkpoint inhibitors less effective.

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

About research

This study was a single-arm, open-label study to evaluate the safety and efficacy of fecal microbiota transplantation in combination with fruquintinib, a small molecule tyrosine kinase inhibitor of the VEGF receptor, and tislelizumab, a monoclonal antibody. It was a phase II clinical trial. PD-1 inhibitor. This combination was investigated as a third-line treatment option for microsatellite-stable metastatic colorectal cancer.

Patients 18 years and older with advanced or metastatic colorectal cancer who were intolerant to or had progressed to second-line chemotherapy were included in the study. Eligible patients were required to have adequate renal, hepatic, and hematologic function and at least one measurable tumor. Polymerase chain reaction (PCR) assays, immunohistochemistry, and next-generation sequencing were used to confirm microsatellite stability.

Individuals with another concomitant cancer, autoimmune disease, history of immunotherapy or organ transplantation, factors that affect oral drug absorption, and individuals prescribed systemic immunosuppressive therapy were excluded from the study. After the natural microbiota depletion phase, fecal microbiota transplantation was performed using patient-customized orally administered fecal capsules along with orally administered fruquintinib and intravenously administered tislelizumab.

Progression-free survival was the primary endpoint, and secondary endpoints were overall response rate, duration of response, disease control rate, clinical benefit rate, and overall survival. An independent radiologist assessed tumor response. Treatment continued until the participant withdrew consent, an unacceptable level of toxicity was observed, the study was completed, the investigator decided to terminate the study, or the participant died. .

Fecal and peripheral blood samples were collected serially to analyze the gut microbiota and exploratory biomarker levels. We analyzed the gut microbiota using pyrosequencing of 16S ribosomal deoxyribonucleic acid (rDNA) amplicons from genomic DNA extracted from stool samples. To explore potential biomarkers, sequencing of T cell receptors from peripheral blood mononuclear cells (PBMCs) was performed.

research result

Combination treatment of fecal microbiota transplantation with tislelizumab and fruquintinib was found to be manageably safe and improved survival in patients with microsatellite stable metastatic colorectal cancer. More specifically, this intervention increased mean progression-free survival by 9.6 months, mean overall survival by 13.7 months, and improved overall response and disease control rates by 20% and 95%, respectively. did.

Gut microbiome analysis also showed that the post-treatment microbiome composition was relatively enriched with bacteria belonging to this family. Lachnospiraceae, is known to be advantageous for immunotherapy.There are abundant bacteria belonging to Bifidobacterium Families that increase immune tolerance were also found to be reduced after treatment.

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

conclusion

Fecal microbiota transplantation in combination with fruquintinib and tislelizumab had manageable side effects. Importantly, this therapeutic approach significantly improved overall survival and progression-free survival in patients with microsatellite stable metastatic colorectal cancer.