Early-Phase Trial Indicates Potential of Fecal Microbiota Transplant in Overcoming Resistance to Immune Checkpoint Inhibitors

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An early-phase clinical trial (NCT04264975) suggests that patients with cancer who have shown prior resistance to treatment with immune checkpoint inhibitors (ICIs) may benefit from fecal microbiota transplants (FMTs) from donors who previously responded to treatment.^1,2 The study, published in Cell Host & Microbe, noted the significance of the gut microbiome in affecting immune responses as well as patient response to ICIs.

“This research highlights the complex interplay between beneficial and detrimental bacteria within the gut microbiota in determining treatment outcomes,” co-corresponding author Hansoo Park of Gwangju Institute of Science and Technology, Gwangju, South Korea, said in a press release. “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.”³

Although ICIs that target the CTLA-4 and PD-1/PD-L1 pathways have revolutionized the treatment of a variety of cancers, their impact is not universal across all cancer types. Further, most patients who initially showed a response to ICIs may experience disease progression resulting from secondary resistance, according to the study authors.

“Although recent research has progressed in elucidating predictive biomarkers, understanding resistance mechanisms in immuno-oncology, and improving treatment outcomes by combining ICIs with other therapies, overcoming primary and secondary resistance remains significantly challenging,” the study authors wrote. “The gut microbiome has emerged as a key player in shaping immune responses and affecting the efficacy of ICIs. Studies have shown that the presence of specific commensals in patient stool samples correlates with clinical response to ICIs.”¹

The authors noted that prior small clinical trials have indicated FMTs may help overcome resistance to ICIs in some patients with melanoma; however, the potential of FMTs to overcome this resistance in other advanced solid cancers has yet to be evaluated. For the current study, investigators analyzed the potential of FMT to overcome resistance to anti-PD-L1 inhibitors in patients with advanced solid cancers refractory to ICIs, as well as to determine the specific commensal bacteria that play a causal role in the efficacy of both types of treatments.

The prospective, single-arm, single-center trial enrolled 13 patients with metastatic solid tumor cancers with resistance to Opdivo (nivolumab). Four of the patients had gastric cancer, five had esophageal cancer, and four had hepatocellular carcinoma. All of the patients showed confirmed disease progression on Opdivo monotherapy, with six showing primary resistance and seven showing secondary resistance.

FMTs were collected from six donors with gastric cancer, esophageal cancer, and hepatocellular carcinoma (HCC), who previously achieved a complete or partial response for at least six months following treatment with Opvdio or Keytruda (pembrolizumab). FMTs were administered via colonoscopy after patients received antibiotics. Of the 13 patients, one patient with HCC achieved a partial response and five showed stable disease, which translates to a 7.7% response rate and 46.2% disease control rate.

“One of the most surprising results was from a hepatocellular carcinoma patient 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,” co-corresponding author Sook Ryun Park, of Asan Medical Center at the University of Ulsan College of Medicine in Seoul, South Korea, said in the release. “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.”³

Investigators found a novel bacterial strain that helped boost the efficacy of FMT—Prevotella merdae Immunoactis—as well as two strains that showed a negative impact on the efficacy of FMT—Lactobacillus salivarius and Bacteroides plebeius. In the release, the study authors said they will continue evaluating bacteria strains to develop better methods that improve the efficacy of immunotherapies via altering of the gut microbiota.

“In conclusion, our findings suggest the potential of FMT to boost responsiveness to ICIs in advanced solid tumors, extending beyond melanoma,” the study authors wrote. “By comparing responses among patients, we identified P. merdae Immunoactis as an effective strain, contrasting with the ineffective B. plebeius and L. salivarius. Our analysis of the IFN-γ signaling pathway elucidated the mechanisms of immune modulation by these strains. This study not only demonstrates the broad applicability of FMT in enhancing immunotherapy efficacy but also opens new paths for targeted microbial interventions in cancer treatment.”¹

References

1. Kim Y, et al. Fecal microbiota transplantation improves anti-PD-1 inhibitor efficacy in unresectable or metastatic solid cancers refractory to anti-PD-1 inhibitor. Cell Host & Microbe. Published July 25, 2024. DOI: https://doi.org/10.1016/j.chom.2024.06.010

2. Phase 2 clinical trial for FMT with anti-PD1 antibody treatment. ClinicalTrials.gov. July 1, 2024. https://www.ncbi.nlm.nih.gov/bioproject/1130324

3. In clinical trial, fecal matter transplant helped half of patients with gastrointestinal cancers overcome resistance to immunotherapy treatment. News release. Cell Press. Published July 25, 2024. Accessed July 25, 2024. https://www.eurekalert.org/news-releases/1051759