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Fecal Transplant Overcomes Resistance to Immunotherapy

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For some patients with advanced melanoma whose conditions had stopped responding to immunotherapy, response was restored after treatment with fecal transplants.

The material for the fecal transplants was obtained from patients who were experiencing a response to immunotherapy with the anti-PD-1 agent, pembrolizumab.

The fecal transplants “changed the gut microbiome and reprogrammed the tumor microenvironment to overcome resistance” to the immunotherapy, say researchers reporting a proof-of-concept study in Science.

The trial included 15 patients who received a fecal transplant and were then treated with pembrolizumab.

Six of the 15 experienced a restored response.

One patient experienced a complete response; two experienced partial responses, one of which was ongoing in the absence of treatment after 2 years; and among three patients, disease was stable past 1 year.

One of the patients with stable disease again experienced disease progression after taking antibiotics for a soft tissue infection. Response resumed after a second transplant from their donor.

All six patients had been experiencing disease progression prior to the fecal transplant.

“The likelihood that the patients treated in this trial would spontaneously respond to a second administration of anti-PD-1 immunotherapy is very low, so any positive response should be attributable to the administration of fecal transplant,” senior author Hassane Zarour, MD, a cancer immunologist and professor at the University of Pittsburg, Pittsburgh, Pennsylvania, said in a press release.

“Our findings show that a single FMT [fecal microbiota transplant] administered colonoscopically together with PD-1 blockade successfully colonized the gut of responders and reprogrammed the tumor microenvironment to overcome primary resistance to anti-PD-1,” say investigators led by Diwakar Davar, MD, a medical oncologist and assistant professor at the University of Pittsburgh.

After transplant, the gut microbiome of the patients with restored responses was much like that of their donors. There was an increase in bacteria associated with CD8+ T-cell activation and with strong response to immune checkpoint inhibition, including bacteria of phyla Firmicutes and Actinobacteria. In these patients, levels of circulating and intertumoral interleukin-8, an immunosuppressive cytokine that interferes with PD-1 blockade, were decreased. In addition, there were other cellular and biochemical changes that favored response.

Similar Findings With Nivolumab

“This is an excellent study,” said Erez Baruch, MD, PhD, a researcher and internal medicine resident at the University of Texas Health Science Center, Houston, Texas, when asked for comment.

He led a similar but smaller study that was reported in Science in December 2020. In that study, 3 of 10 patients with metastatic melanoma whose conditions had stopped responding to checkpoint inhibition experienced a restored response to nivolumab after fecal transplants from melanoma patients who had experienced complete and durable responses.

“The fact that two completely different cancer centers using different anti-PD-1 agents for reinduction reached the same clinical findings emphasizes the key role of the gut microbiota in immunotherapy. The two clinical trials validate each other,” Baruch told Medscape Medical News.

The findings support the increasing realization in oncology that the gut microbiome affects the response to immunotherapy and that altering the microbiome might improve long-term response rates, which currently are not quite 40% in cases of advanced melanoma.

It’s a hot topic, Baruch commented. Multiple clinical trials are in the works that will combine anti-PD-1 therapy with FMT for skin cancer and other malignancies. Investigators are looking for predictors of response and the particular bacterial species in play, in part so that they can be delivered in pill form some day.

“A lot of further lab work is required to understand exactly why some patients respond and why others do not. Samples collected in the trials will feed the lab work, and findings from the lab work will refine the trials. The circle will continue until the mechanisms of action are fully unmasked,” Baruch said.

Donors Were Responders

The material for the fecal transplants used in the pembrolizumab study came from seven donors, all of whom experienced response to pembrolizumab treatment for advanced melanoma. For four of the seven donors, the response was complete. The remaining three patients showed a partial response. The median progression-free survival (PFS) was 56 months.

The FMT success was unrelated to whether the material came from donors who had complete or partial responses, the researchers note.

In the trial, the patients whose conditions had stopped responding received pembrolizumab 200 mg at the time of transplant then every 3 weeks until progression or intolerable toxicity. Among the six responders, median PFS and overall survival was 14 months. A patient who had experienced a complete response died shortly after transplant from unrelated complications of spinal stenosis surgery. Among the entire cohort, median PFS was 3 months, and median overall survival was 7 months.

Adverse events were common but were of low grade except for grade 3 fatigue, which occurred in two patients, and peripheral motor neuropathy that required hospitalization, which occurred in one patient. The neuropathy resolved upon reintroduction of pembrolizumab.

The study was funded by the National Cancer Institute and by Merck, the maker of pembrolizumab. Davar, Zarour, and two other investigators have numerous ties to industry, among them research and/or consulting relationships with Merck and Bristol-Myers Squibb, maker of nivolumab. Baruch has disclosed no relevant financial relationships.

Science. Published online February 5, 2021. Abstract

M. Alexander Otto is a physician assistant with a master’s degree in medical science, and an award-winning medical journalist who has worked for several major news outlets before joining Medscape, including McClatchy and Bloomberg. He is an MIT Knight Science Journalism fellow. Email: [email protected]

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