Fecal Microbiota Transplants May Enhance Immunotherapy Efficacy in GI Cancers

Hansoo Park, MD, PhD, MS

Fecal microbiota transplantations (FMTs) were shown to boost the activity of immunotherapy in patients with multiple types of gastrointestinal (GI) cancers, according to findings from a non-randomized, prospective clinical trial (NCT04264975) published in Cell Host & Microbe.¹

Results from the proof-of-concept study demonstrated that 13 patients with anti-PD-1-refractory metastatic gastric cancer (n = 4), esophageal squamous cell carcinoma (ESCC; n= 5), and hepatocellular carcinoma (HCC; n= 4) who received a PD-1 inhibitor with FMT from a donor who responded to an anti-PD-1 agent, achieved an objective response rate (ORR) of 7.7% and a disease control rate of 46.2%. Additionally, FMT treatment displayed sustained microbiota changes and clinical benefit in 6 patients as 1 patient experienced a partial response and 5 experienced stable disease; of those who achieved stable disease, 4 had ESCC and 1 had HCC.

“This research highlights the complex interplay between beneficial and detrimental bacteria within the gut microbiota in determining treatment outcomes,” Hansoo Park, MD, PhD, MS, of Gwangju Institute of Science and Technology in Gwangju, South Korea, said in a news release.² “While the connection between gut microbiota and immune response to cancer therapy has been a growing area of interest, our study provides concrete evidence and new avenues for improving treatment outcomes in a broader range of cancers.”

The prospective, single-arm, single-center study was divided into categories of donors and recipients. Donors needed to have experienced a durable complete or partial response per RECIST 1.1 criteria for a minimum of 6 months following anti-PD-(L)1 monotherapy for the treatment of unresectable or metastatic solid tumors. Recipients were required to have experienced disease progression during anti-PD-(L)1-based monotherapy or combination therapy.¹

Part 2 of the trial, which was the proof-of-concept of FMT therapy portion, enrolled patients receiving immunotherapy for solid cancers. Eligible donors did not have a history of exposure to HIV or hepatitis virus within past year, communicable disease, history of inflammatory bowel disease, or household members with active GI infection, among other criteria. Recipients could not have contraindications for colonoscopy, including suspected bowel perforation, acute diverticulitis, or fulminant colitis.³

Oral antibiotics were administered to recipients for 5 days prior to the first FMT to eliminate the native gut microbiota. FMT was administered via colonoscopy, followed by the PD-(L)-1 inhibitor given at the standard dose and schedule until disease progression or unacceptable toxicity. All patients were treated with nivolumab (Opdivo) as the PD-(L)-1 inhibitor and the primary end point was ORR.^1,3

Patients were recruited between January 2019 and August 2020; at baseline the median age was 60 years (range, 38-76). The median number of prior lines of systemic therapy received was 10 (range, 4-34). All patients experienced confirmed disease progression following nivolumab monotherapy with 46.2% displaying primary resistance and 53.8% secondary resistance. All patients had microsatellite stable tumors and 53.8% had a PD-L1 combined positive score of at least 1.¹

Additional findings from the study showed that 1 patient with HCC who initially experienced progressive disease achieved a PR following FMT with continued immunotherapy treatment. Eight weeks after the second FMT, the patient achieved a 30.5% reduction in tumor size, eventually experiencing a maximum reduction of 47.7% from baseline before first FMT.

“One of the most surprising results was from a patient [with HCC] who initially showed no response to the first FMT and continued to experience cancer progression. However, after switching the donor for the second FMT, the patient exhibited remarkable tumor shrinkage,” Sook Ryun Park, MD, PhD, of Asan Medical Center at the University of Ulsan College of Medicine in Seoul, South Korea, said in the news release.² “Both donors were long-lasting, good responders to anti-PD-1 inhibitors, but because we did not yet know the causative bacteria responsible for the FMT response, we could not predict whether the treatment would be effective.”

In terms of safety, 53.8% of patients experienced at least 1 any-grade treatment-related adverse effect (TRAE); all TRAEs were grade 1 or 2 aside from 1 patient who experienced grade 3 immune-related gastritis. The most common any-grade TRAEs consisted of skin pruritus (38.5%), skin rash (15.4%), and hypothyroidism (15.4%). The median number of nivolumab cycles following FMT was 5 (range, 1-27), with 7 patients receiving subsequent FMTs from the same and/or different donors after the first FMT.

“By examining the complex interactions within the microbiome, we hope to identify optimal microbial communities that can be used to enhance cancer treatment outcomes,” Park said in the news release.² “This comprehensive approach will help us understand how the microbial ecosystem as a whole contributes to therapeutic success.”

References

1. Kim Y, Kim G, Kim S, et al. Fecal microbiota transplantationimprovesanti-PD-1 inhibitor efficacy in refractory unresectable or metastatic solid cancers refractory to anti-PD-1 inhibitor. Cell Host Microbe. Published online July 25, 2024. doi:10.1016/j.chom.2024.06.010
2. In clinical trial, fecal matter transplant helped half of patients with gastrointestinal cancers overcome resistance to immunotherapy treatment. News release. Cell press. July 25, 2024. Accessed July 25, 2024. https://www.eurekalert.org/news-releases/1051759
3. Utilization of microbiome as biomarkers and therapeutics in immuno-oncology. ClinicalTrials.gov. Updated February 17, 2020. Accessed July 25, 2024. https://clinicaltrials.gov/study/NCT04264975