Fecal microbiota transplants may improve the effectiveness of immunotherapy in patients with gastrointestinal cancers, according to a recent study published by Kim et al in Cell Host & Microbe.
Background
Although immune checkpoint inhibitors have revolutionized cancer treatment, many patients may not respond to therapy or develop immunotherapy resistance after an initial response. Emerging evidence has indicated that the gut microbiota play a crucial role in modulating the immune system and can significantly impact the efficacy of these therapies.
Previous research has reported that fecal microbiota transplants could overcome resistance to immune checkpoint inhibitors in some patients with melanoma, Nonetheless, the potential for fecal microbiota transplants to overcome resistance in other advanced solid tumors has not yet been explored.
Study Methods and Results
In the small, proof-of-concept clinical trial, the researchers analyzed the efficacy of fecal microbiota transplants in 13 patients with metastatic solid tumors—4 of whom had gastric cancer, 5 of whom had esophageal cancer, and 4 of whom had hepatocellular carcinoma—who underwent treatment with immune checkpoint inhibitors and were resistant to the PD-1 inhibitor nivolumab.
The 5 fecal microbiota transplant donors, who also had gastric cancer, esophageal cancer, or hepatocellular carcinoma, had achieved complete or partial response for at least 6 months following treatment with nivolumab or pembrolizumab. The fecal microbiota transplants were delivered via colonoscopy after the recipients had received antibiotics to tamp down their own microbiotas.
The researchers discovered that 46.2% (n = 6) of the patients who had previously shown resistance to immune checkpoint inhibitors benefited from receiving fecal microbiota transplants from donors who had previously responded to treatment.
“One of the most surprising results was from a [patient with] hepatocellular carcinoma who initially showed no response to the first [fecal microbiota transplant] and continued to experience cancer progression. However, after switching the donor for the second [transplant], the patient exhibited remarkable tumor shrinkage,” revealed co–senior study author Sook Ryun Park, MD, PhD, of the Asan Medical Center at the University of Ulsan College of Medicine in Seoul, South Korea. “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 [fecal microbiota transplant] response, we could not predict whether the treatment would be effective,” she continued.
The researchers then examined which specific strains of bacteria were most likely to affect whether patients benefited from fecal microbiota transplants combined with immune checkpoint inhibitors. They identified a novel bacterial strain that helped to improve fecal miocrbiota transplant efficacy, known as Prevotella merdae Immunoactis. The researchers also determined that two strains that had a detrimental impact on transplant efficacy: Lactobacillus salivarius and Bacteroides plebeius.
Conclusions
This findings demonstrated the potential benefits of fecal microbiota transplants in clinical settings beyond melanoma.
“This research highlights the complex interplay between beneficial and detrimental bacteria within the gut microbiota in determining treatment outcomes,” emphasized co–senior study author Hansoo Park, MD, PhD, of the Gwangju Institute of Science and Technology in South Korea. “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,” he added.
The researchers plan to continue assessing the newly identified bacterial strains and other strains with the goal of developing novel strategies to boost immunotherapy effectiveness by altering the gut microbiota.
“By examining the complex interactions within the microbiome, we hope to identify optimal microbial communities that can be used to enhance cancer treatment outcomes. This comprehensive approach will help us understand how the microbial ecosystem as a whole contributes to therapeutic success,” underscored Dr. Hansoo Park.
The researchers acknowledged the challenges of adopting fecal microbiota transplants as part of standard treatment on a broad scale, including the lack of standardized protocols and regulatory guidelines, the potential risks of transmitting pathogens, and logistical issues surrounding large-scale manufacturing and distribution of fecal microbiota transplant products.
“Developing efficient and cost-effective methods for production and distribution is necessary for widespread adoption. Addressing these challenges through comprehensive research and careful planning will be essential for integrating [fecal microbiota transplants] into the standard of care for cancer treatment,” concluded Dr. Sook Ryun Park.
Disclosure: The research in this study was supported by grants from the Asan Institute for Life Sciences, Asan Medical Center, and National Cancer Centre in Korea; the GIST Research Institute; the Bio and Medical Technology Development Program from Ministry of Science; and the ICT of the Korean Government. For full disclosures of the study authors, visit sciencedirect.com.
