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Fecal microbiota transplant in melanoma patients helps anti-PD-1 therapy work

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Science
Reuters Health - 11/02/2021 - Certain melanoma patients who don't respond to anti-programmed cell death protein 1 (PD-1) therapy may become responsive after receiving a fecal microbiota transplant, a small study suggests.

Researchers followed 15 patients who were primary refractory to anti-PD-1 therapy and received treatment with fecal microbiota transplant (FMT) derived from a single donor, along with pembrolizumab therapy. Participants received another treatment with pembrolizumab every three weeks until they could no longer tolerate the toxicity or they experienced disease progression.

Six of the 15 patients who had previously not responded to pembrolizumab or nivolumab appeared to benefit from FMT, with either tumor reduction or long-term disease stabilization. One of the six patients had an ongoing partial response to FMT after two years and is still being followed, while an additional four patients are still in treatment and have not had disease progression for more than one year.

"We think that FMT in primary anti-PD1 resistant melanoma patients induced clinical response to continued anti-PD1 treatment in patients that had an immunological ability to respond to the treatment but with an unfavorable gut microbiota composition that prevented a successful clinical response," said Dr. Giorgio Trinchieri, chief of the Laboratory of Integrative Cancer Immunology at the National Cancer Institute in Bethesda, Maryland.

This unfavorable microbiota composition was corrected by the fecal microbiota transplant (FMT) with an improved balance between bacteria favoring or opposing anti-PD1 efficacy, Dr. Trinchieri, one of the senior authors of the study, said by email.

"A single FMT delivered by colonoscopy induced long lasting perturbation of microbiota composition in all patients that responded to anti PD1 after FMT and in many that had progressive disease," Dr. Trinchieri added.

Most bacteria and bacterial genes that were present in the donor but not in the patients colonized the recipient gut efficiently and persistently unless the patients were treated with antibiotics, Dr. Trinchieri noted. After FMT, the microbiota composition reflected the colonization with donor-specific bacteria, but also FMT-induced changes in gut ecology resulting in altered abundance of different taxa of either donor or recipient origin.

Participants in the study tolerated treatment well, though some of the patients experienced minor side effects that were associated with pembrolizumab, including fatigue.

Collectively, the study findings show that FMT and anti-PD-1 changed the gut microbiome and reprogrammed the tumor microenvironment to overcome resistance to anti-PD-1 in a subset of PD-1 advanced melanoma, the study team concludes in Science.

Based on the study findings, the researchers suggest that larger clinical trials should be conducted to confirm the results and identify biological markers that could eventually be used to select patients who are most likely to benefit from treatments that alter the gut microbiome.

"These findings will serve as a strong rationale to expand on translational research efforts to precisely identify the microbes responsible for the observed clinical and immunological effects, determine the mechanisms of actions, and also find out whether these clinical results can also be obtained in other cancers," said co-senior author of the study, Dr. Hassane Zarour, co-leader of the Cancer Immunology and Immunotherapy Program at the University of Pittsburgh Medical Center Hillman Cancer Center in Pennsylvania.

"Such findings will hopefully lead to novel microbiome-based therapies of cancer, for which a consortium of microbes can be given in pills in addition to anti-PD-1 antibodies to cancer patients," Dr. Zarour said by email.

Melanoma therapies, and the field of immunotherapy and immune-reshaping therapies as a whole, are rapidly evolving, and clinicians should consider referring patients to academic medical centers for access to these types of therapies, said Dr. Pauline Funchain, director of melanoma medical oncology and genomics at the Taussig Cancer Institute at Cleveland Clinic, in Ohio.

"We know that changes in the microbiome are correlated with many autoimmune disease states such as inflammatory bowel disease and rheumatoid arthritis," Dr. Funchain, who wasn't involved in the study, said by email.

"These studies imply that the immune system may not work properly due to a 'bad start' in the gut," Dr. Funchain said. "It makes sense that for those who do not respond to immunotherapy because their immune system was dysfunctional, some proportion may benefit from more robust immune interaction, or 'training,' with FMT."

SOURCE: https://bit.ly/3tJy1b3 and https://bit.ly/3jCV2aY Science, online February 5, 2021.

By Lisa Rapaport



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