Fecal microbiota transplant may overcome resistance to anti-PD-1 therapy for solid cancers
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Key takeaways:
- Interactions between “good bugs” and “bad bugs” within the gut microbiota affect treatment outcomes.
- Incorporating FMT along with anti-PD-1 inhibitors could help patients overcome resistance.
CHICAGO — Fecal microbiota transplantation that contains effective microbiota may overcome resistance to anti-PD-1 therapy among patients with advanced solid cancers, according to data presented at ASCO Annual Meeting.
“In addition, we have discovered a new strain of Prevotella merdae that exhibits promising evidence as a potential causative bacteria responsible for the therapeutic effects of FMT [fecal microbiota transplantation],” Sook Ryun Park, MD, PhD, of the department of oncology at Asan Medical Center in Seoul, South Korea, said during a presentation.
Background and methodology
Despite data showing the gut microbiome to be a key regulator of the immune system during immunotherapy, the effect of modifying the gut microbiome in patients with cancer refractory to immunotherapy remains unknown.
Researchers conducted a prospective, single-arm clinical trial to assess the efficacy of FMT plus anti-PD-(L)1 therapy among patients with advanced solid cancers refractory to PD-(L)1 inhibitors.
Donor eligibility criteria included being aged older than 18 years, having histologically confirmed solid tumors, passing serologic and stool screening tests for FMT, and having an ongoing durable complete or partial response per RECIST v1.1 for at least 6 months with anti-PD-(L)1 monotherapy for unresectable or metastatic solid tumors.
Among the six donors, four had hepatocellular carcinoma, one had gastric cancer and one had esophageal squamous cell carcinoma.
Among the 13 recipients (median age, 60 years; range, 38-76; 76.9% men), five had esophageal squamous cell carcinoma, four had gastric cancer and four had hepatocellular carcinoma. All had confirmed disease progression on nivolumab (Opdivo, Bristol Myers Squibb) monotherapy following primary (46.2%) or secondary resistance (53.8%).
FMT had been performed using colonoscopy, followed by continuation or reintroduction of anti-PD-(L)1 until acceptable toxicity or disease progression.
Results
Five patients achieved stable disease and one achieved partial response after FMT, for a disease control rate of 46.2% and objective response rate of 7.7%.
Recipient No. 7, who had metastatic hepatocellular carcinoma with primary resistance to nivolumab, achieved the partial response after a second FMT from donor No. 5.
Researchers observed clinical response to be accompanied by an increase in levels of cytotoxic T cells in the blood and tumor microenvironment and immune cytokines.
The relative abundance of a new species derived from donor No. 5 showed 97% whole genome nucleotide sequence similarity with Prevotella sp. Marseille-P4119.
Upon isolation of the species from feces of recipient No. 7, preclinical experiments revealed that treatment with the species activated human CD4- and CD8-positive T cells and suppressed tumor growth.
The combination treatment also appeared to reduce the tumor volume more than with anti-PD-1 alone.
“These findings suggest the significance of considering the intricate interplay between ‘good bugs’ and ‘bad bugs’ within the gut microbiota in treatment outcomes,” Park said. “To validate and confirm these findings, further research is definitely necessary.”
Perspective
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Diana Hanna, MD
The gut microbiome impacts carcinogenesis and the tumor microenvironment, including across gastrointestinal cancers. Prior studies demonstrated the feasibility and efficacy of modulating the microbiome through fecal transplantation to promote response to anti-PD-1 therapy in patients with melanoma.
At ASCO, Park and colleagues presented data from a single-arm, prospective study of 13 patients with metastatic HCC, gastric cancer and esophageal squamous cell cancer who had primary or secondary resistance to nivolumab.
The investigators are to be commended for their efforts in demonstrating the preliminary clinical benefit in this difficult-to-treat population. Interestingly, none of the four recipients who received FMT from the donor with the best clinical outcome — a durable complete lasting over 6 years — derived long-term benefit: three had continued progressive disease and one had short-lived stable disease. Similarly, two recipients from the same donor had significantly different responses, including one durable partial response and one short-duration stable disease. Researchers attributed the discrepancies between outcomes to differences in Prevotella levels, but multiple tumor and patient-based characteristics are likely at play here. Furthermore, patients who derived clinical benefit received multiple FMTs by colonoscopy and the feasibility of widescale application of this approach remains uncertain.
Several questions remain, including the optimal dosing, timing, type and duration of antibiotics, and potential adverse effects of repeated antibiotic exposure.
The microbiome has been an integral partner in facilitating response to immune checkpoint inhibitors. We are only now beginning to appreciate its implications, and studies such as this one will guide future microbiome interventions and perhaps define a new strategy for treatment beyond progression for carefully selected patients. Indeed, identifying the specific therapeutic bacterial species for the individual patient and the right donors and recipients is still in its infancy.
The interplay between the microbiome and other variables — including antibiotic use and selection, cytotoxic agents, biologics, radiation and tumor molecular profile — will be challenging to discern, but contextualizing FMT across these parameters will be important. Measuring and maintaining a favorable balance between treatment-enhancing and tumor-promoting bacteria will require frequent, standardized monitoring using noninvasive assays. As the gut microbiome is shaped by diet, ongoing studies are also assessing the potential of nutritional interventions to enhance the clinical benefit of immunotherapy.
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Park SR, et al. Abstract 105. Presented at: ASCO Annual Meeting 2023; June 2-6, 2023: Chicago.
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