FMT May Combat Immune Checkpoint Inhibitor Resistance in Advanced Solid Cancers

New research is calling attention to the impact of fecal microbiota transplant (FMT) on resistance to immune checkpoint inhibitors in advanced solid cancers, highlighting its effectiveness in combination with anti-PD-1 inhibitors for the treatment of gastrointestinal cancers.¹

Results showed treatment with FMT and continued nivolumab induced sustained microbiota changes and clinical benefits in 6 of 13 patients, achieving an objective response rate of 7.7% and a disease control rate of 46.2%. Further analysis identified specific strains of bacteria associated with better or worse responses.¹

“This research highlights the complex interplay between beneficial and detrimental bacteria within the gut microbiota in determining treatment outcomes,” Hansoo Park, MD, PhD, assistant professor at Gwangju Institute of Science and Technology, said in a press 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.”

To evaluate the potential of FMT in overcoming resistance to anti-PD-(L)1 inhibitors in patients with advanced solid cancers refractory to these inhibitors, investigators conducted a prospective, single-arm, and single-center study assessing the combination of FMT and an anti-PD-(L)1 inhibitor. The trial enrolled patients with metastatic solid-tumor cancers who were resistant to nivolumab, including 4 with gastric cancer, 5 with esophageal squamous cell carcinoma, and 4 with hepatocellular carcinoma. It also included 6 FMT donors who had gastrointestinal cancer but showed complete or partial response for ≥ 6 months after treatment with nivolumab or pembrolizumab.¹

FMT procedures were conducted via colonoscopy followed by the continuation or reintroduction of an anti-PD-(L)1 inhibitor administered at the standard dose and schedule until either unacceptable toxicity or disease progression occurred. Investigators collected sequential samples of blood, stool, and tumor biopsies both before and after FMT, carrying out response assessment every 6-8 weeks.¹

All patients were treated with a combination of nivolumab with FMT, which involved continuing nivolumab treatment after failure to prior nivolumab therapy. The median cycle of nivolumab after FMT was five cycles (range, 1–27). Of the 13 recipients, 7 received subsequent FMTs from the same (n = 4) and/or different donors (n = 4) after the first FMT.¹

Investigators noted 7 (53.8%) patients experienced ≥ 1 treatment-related adverse event, all of which were either grade 1 or 2, except for 1 patient who experienced grade 3 immune-related gastritis. The most common treatment-related adverse events were skin pruritus (n = 5), followed by skin rash (n = 2) and hypothyroidism (n = 2).¹

Treatment with FMT in conjunction with continued nivolumab induced sustained microbiota changes and clinical benefits in 6 of 13 patients, with 1 partial response and 5 stable diseases, achieving an objective response rate of 7.7% and a disease control rate of 46.2%. Specifically, investigators highlighted treatment response in recipient 7, whose microbial compositions closely resembled those of the respective donor as early as 1 day after both the first and second FMT procedures and persisted for 282 days following receipt of the second FMT.¹

Evaluation of systemic immune changes with the response to FMT combined with nivolumab in recipient 7 revealed a gradual increase in CD8+ T cells and CD8+CCR7−CD27− terminal effector T (Tte) cells, and a decrease in CD4+CD25+CD127−CCR4+ regulatory T (Treg) cells from baseline. At 23 weeks post-second FMT, Tte cells increased by 255% and Treg cells decreased by 81%, correlating with recipient 7’s clinical response and more pronounced after the second FMT.¹

Elevated levels of IFN-γ, TNF-α, IL-2, IL-7, IL-15, and IL-6 after the second FMT also correlated with the clinical response. Additionally, 4 weeks after the second FMT, investigators pointed out recipient 7 showed a significant increase in tumor-infiltrating cytotoxic T cells (from 14 to 361 cells/mm2) and MHC-II+ M1 macrophages (from 25 to 174 cells/mm2), while the number of CD4+FOXP3+CD8−CD20− Treg cells remained low.¹

Comparative genomic analysis of isolated P. merdae from recipient 7’s stool sample revealed a potential distinction, as the average nucleotide identity with P. merdae sp. Marseille-P4119 was 97.41%. Phylogenetic analysis identified more than 1980 single-nucleotide polymorphisms in conserved markers, indicating significant dissimilarity from the reference genome of P. merdae sp. Marseille-P4119 and suggesting the discovery of a new strain, which investigators designated as P. merdae Immunoactis and speculated contributed to the favorable clinical and immune response in recipient 7 after the second FMT. Further analysis revealed Lactobacillus salivarius and Bacteroides plebeius may inhibit T cell activation, potentially impairing the efficacy of FMT and anti-PD-1 inhibitors, and their ratio to P. merdae Immunoactis has clinical implications, including survival likelihood.¹

“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 concluded.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 transplantation improves anti-PD-1 inhibitor efficacy in unresectable or metastatic solid cancers refractory to anti-PD-1 inhibitor. Cell Host & Microbe. doi:https://doi.org/10.1016/j.chom.2024.06.010}
2. ^{Cell Press. In clinical trial, fecal matter transplant helped half of patients with gastrointestinal cancers overcome resistance to immunotherapy treatment. EurekAlert! July 25, 2024. Accessed July 25, 2024. https://www.eurekalert.org/news-releases/1051759}