Studies are revealing new insights into the impact of the gut microbiome on the response to immunotherapy in many cancers


Illustration of bacteria in the human gut. Credit: Daryl Lega, National Human Genome Research Institute, National Institutes of Health

Two studies led by the University of Texas MD Anderson Cancer Center that shed new light on the potential of the gut microbiome as a targeted biomarker for improving responses to immunotherapy were presented today at the 2022 American Society of Clinical Oncology (ASCO) annual meeting.

The results include the first report of gut microbiome Correlations with immunotherapy response in newly diagnosed glioblastoma patients and a study identifying the link between gut microbiome fingerprints, immune cells in the tumor microenvironment and immune checkpoint response in melanoma, non-small cell lung cancer (NSCLC) and sarcoma.

Gut microbiome fingerprints associated with immunotherapy response to glioblastoma (Abstract 2006)

Immunotherapy has so far had limited success against glioblastoma, the most common and serious form of brain cancer. A new study shows that distinct gut microbiome fingerprints were present in patients who survived longer versus shorter after treatment with immune checkpoint inhibitors.

A phase I/II clinical trial (NCT 03174197) validating atzolizumab (an anti-PD-L1) in combination with temozolomide and radiotherapy in newly diagnosed glioblastoma patients who previously reported modest activity, with median overall survival (OS) 18 months and median progression-free survival of 10.6 months. The trial was designed with correlative studies to better understand the mechanisms underlying resistance to immune checkpoint inhibitor therapy, including stool collection for gut microbiome analysis, a novel approach to glioblastoma.

“Although the addition of atezolizumab Standard chemotherapy and radiotherapy did not improve the survival of patients with newly diagnosed glioblastoma, and correlative studies have given us insights into which patients may respond better than expected to immune checkpoint inhibitor therapy,” said lead author and principal investigator Shiao-B. Withers, MD, associate professor of neuro-oncology.” β€œThe challenge for immune checkpoint inhibitor therapy in glioblastoma is that there are select patients who respond, and we need to better understand what characterizes these patients so that we can design our own treatment strategies.” “

The study included 45 stool samples collected from patients in the study before (26 samples) and after (19 samples) treatment. The researchers analyzed gut microbiome composition and categorized the results by OS, and found clear differences between the core (pre-treatment) microbiomes of patients with shorter versus longer survival.

The population enrolled in clinical trials was representative for the incidence of glioblastoma: 68% men, 87% non-Hispanic whites and a mean age of 57.8. Results from whole exosome and RNA sequencing on tumor tissue samples consistent with known genetic features of glioblastoma, including EGFR mutations associated with OS and low IDH1 mutations associated with higher OS.

“We found distinct bacteria enriched in patients with long versus short survival, which is new enough to warrant further investigation of this observation from a small sample size,” Withers said. “I think these findings may help add to the excitement of immune checkpoint inhibitor therapy because it shows that we still have a lot to learn about the gut microbiome and its potential role in response to immune checkpoint inhibitor treatment in glioblastoma.”

As a result of this study, several clinical trials of . have been conducted glioblastoma VMD Anderson now routinely includes stool sample collection to enable correlative studies of the gut microbiome.

Gut microbiome associated with increased immune cell infiltration into the tumor microenvironment and response to immunotherapy across cancer types (Abstract 2511)

Recent research led by MD Anderson has identified associations between induced immune checkpoint responses, B cells and tertiary lymphoid structures (TLS) in the tumor microenvironment. In this study, the researchers built on previous work, found more consolidated evidence for these new biomarkers of response and determined the relationship between the gut microbiota, B cells, and TLS across three types of cancer: melanoma, NSCLC, and sarcoma.

“If these findings are confirmed, we hope that we can target cells in the tumor microenvironment with microbiome-guided therapies to increase B cells and tertiary lymphoid structures in tumors and enhance responses to immune checkpoint blockade,” said lead author Elise. Nassif, MD, Postdoctoral Fellow in Surgical Oncology. Nassif received the Conquer Cancer Foundation’s GlaxoSmithKline Oncology Award of Merit for the abstract.

The research team pulled data from three randomized phase II clinical trials of the new immune checkpoint blockade led by MD Anderson designed with similar sample collection and timing protocols: NCT02519322 (melanoma; 23 patients), NCT03158129 (NSCLC; 33 patients) and NCT02301039 (sarcoma); 17 patients). A total of 22 cancer patients responded to treatment, based on the main pathological response criteria.

When team members analyzed gut microbiome signatures and transcriptome data, they found that high pre-treatment levels of Ruminococcus were associated with response across cancer types. High levels of B-cell infiltration and TLS formation in surgery (after immunotherapy) have also been associated with response across cancer types.

Longitudinal data showed that B cells and TLS increased over the course of the cycle Immunotherapy treatment in responders, but not in non-responders, and that this increase correlated with a gut microbiome signature that included high levels of Ruminococcus at baseline. B-cells and TLS were unchanged in patients with low staphylococcal levels prior to treatment.

“The goal should be to learn something from every patient, especially for rare diseases,” said lead researcher Christina Rowland, assistant professor of surgical oncology. “This study shows that we can really learn a lot from very small numbers of patients in well-designed clinical trials, even across multiple diseases, and that is critical to making great strides in cancer care.”

Preoperative immunotherapy is associated with improved survival for soft tissue sarcoma

more information:
Abstract 2006: Shiao-Pei S. Weathers et al, Correlation of primary tumor genomics and gut microbiota with clinical outcome in newly diagnosed glioblastoma (GBM) treated with ezolizumab in combination with temozolomide (TMZ) and radiation. (2022)

Abstract 2511: Elise F Nassif, Identification of intestinal microbial signatures associated with B cells and tertiary lymphocyte (TLS) structures in the tumor microenvironment (TME) in response to immune checkpoint blockade (ICB). (2022)

Submitted by the University of Texas MD Anderson Cancer Center

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