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ASCO Presenter Proposes Gut Microbiome Profiling in Checkpoint Blockade Response Trials

NEW YORK (GenomeWeb) – Researchers with ties to a new cancer-focused microbiome company are looking to bring microbiome profiling to clinical trials of response to cancer immunotherapy drugs, according to a presentation at the American Society of Clinical Oncology annual meeting in Chicago this week.

The interest in such trials is stemming from the team's preliminary evidence hinting at gut microbiome differences in a small group of melanoma patients who did or did not respond to checkpoint blockade immunotherapy treatment, Jennifer Wargo explained during her presentation in a developmental therapeutics session at the meeting.

Wargo is a surgical oncology and genomic medicine researcher at the University of Texas MD Anderson Cancer Center. She is also cofounder and clinical science advisor for the cancer immunotherapy-focused microbiome profiling company MicrobiomeDX, which was incorporated and registered in Texas this past February.

The company's web site says MicrobiomeDX "works with clinical trial investigators to deliver subject gut microbiome profile analysis and clinical implications in pursuit of the link between the microbiome and cancer immunotherapy response."

Wargo noted that the tumor genome, epigenome, immune system infiltration of the tumor, broader immune activity, and more may affect response to immunotherapy. Pointing to prior studies on the potential role of the microbiome in carcinogenesis and/or response to stem cell transplantation, she argued that there appears to be a rationale for exploring microbiome influences on immunotherapy response.

She and her colleagues set out to compare the composition and diversity of microbes in the mouth and gut in 233 individuals with metastatic melanoma treated with checkpoint blockade immunotherapy — most often with treatment targeting PD-1.

The team collected oral samples from all of the patients at baseline and after treatment, while stool samples for evaluating the gut microbiome over time before and after treatments were available for a subset of the study participants. With these samples, the group used 16S ribosomal RNA sequencing to assess gut microbe members in the mouth and gut.

The researchers also profiled molecular features in the individuals' tumors, along with their immune cell repertoire, using a combination of whole-genome sequencing, immunohistochemistry, flow cytometry, cytokine profiling, and/or gene expression analyses.

When they focused on baseline samples from 105 individuals treated with anti-PD-1 treatment and samples collected 12 weeks into treatment, the investigators saw signs that those responding to treatment tended to have higher microbial diversity in the gut, though oral microbiome diversity was comparable between responders and non-responders.

The team also saw differences in representation by specific types of bugs in the gut that appeared to coincide with response or lack of response to the anti-PD-1 treatment. Some bacteria were found at enhanced levels in responders, Wargo said, including those from the Clostridiales order. Other microbes, such as the Bacteroidales order bacteria, turned up more frequently in non-responder gut microbiomes.

The researchers' subsequent experiments suggested that checkpoint blockade response tends to be marked by more robust immune infiltration of tumors, enhanced CD8+ T cell density, and other immune profile differences. And again, Wargo reported, there seemed to be some microbes that were more common in the gut when these response-related immune features were present in the metastatic melanoma patients.

She noted that the team is continuing to investigate potential microbiome-immunotherapy response interactions, as well as potential mechanisms that may contribute to this process, in the hopes of unearthing microbiome-based strategies — such as fecal transplantation or dietary interventions — to enhance treatment response.

Commenting on the study during an abstract discussion panel at the same ASCO session, University of California, Los Angeles hematology and oncology expert Antoni Ribas called the current data "exploratory," but said the results support the notion that there may be some connection between the microbiome and immunotherapy response. Even if that interaction is not found to be causal, he explained that the microbiome could theoretically serve as a surrogate of immune activity.

In April, Wargo's team secured a three-year $750,000 innovative research grant from Stand Up to Cancer to study interactions between the immune system and microbes in the gut, along with strategies for potentially altering the gut microbiome to boost response to immunotherapy treatments.

Last month, a team of investigators led by Silvia Formenti at the Weill Medical College of Cornell University submitted information to Clinical Trials.gov on a proposed trial of ipilimumab and radiation followed by nivolumab and a decreased dose of ipilimumab in advanced non-small cell lung cancer patients who have progressed on one or more treatments in the past. While the study's main endpoint would be increased survival in the patient group, the team noted that it plans to look for potential associations between treatment response and the microbiome in the lung cancer patients over several years, if possible.

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