Summary: The researchers say the gut microbiome may be a viable targetable biomarker for improving immunotherapy responses in people with glioblastoma and a range of other cancers.
Source: MD Anderson Cancer Center
Two studies from the University of Texas MD Anderson Cancer Center that shed new light on the potential of the gut microbiome as a targetable biomarker to improve responses to immunotherapy were presented today at the annual meeting. 2022 from the American Society for Clinical Oncology (ASCO).
Findings include the first report of gut microbiome associations with immunotherapy response in newly diagnosed glioblastoma patients and a study that identified a link between gut microbiome signatures, immune cells in the microenvironment of tumor and checkpoint blockade immune response in melanomanon-small cell lung cancer (NSCLC) and sarcoma.
Gut microbiome signatures associated with immunotherapeutic response in glioblastoma
Immunotherapy has so far had limited success against glioblastoma, the most common and aggressive form of brain cancer. A new study demonstrated that distinct gut microbiome signatures were present in patients with longer or shorter survival after treatment with immune checkpoint inhibitors.
A phase I/II clinical trial (NCT 03174197) studying atezolizumab (anti-PD-L1) in combination with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma have previously reported modest activity, with a median overall survival (OS) of 18 months and a 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 treatment, including stool collection to analyze the gut microbiome, a new approach for glioblastoma.
“Although adding atezolizumab to standard radiation therapy and chemotherapy did not improve the survival of patients with newly diagnosed glioblastoma, the correlative studies gave us insight into which patients might better respond than expected to immune checkpoint inhibitor therapy,” said senior author and principal investigator Shiao-Pei Weathers, MD, associate professor of neuro-oncology.
“The challenge with 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 tailor our treatment strategies.”
The study included 45 stool samples taken from study patients before (26 samples) and after (19 samples) treatment. The researchers analyzed the composition of the gut microbiome and categorized the results by OS, finding distinct differences between the baseline (before treatment) microbiomes of patients with shorter versus longer survival.
The clinical trial enrollment population was representative of glioblastoma incidence: 68% male, 87% non-Hispanic Caucasian, and a median age of 57.8 years. Results of whole exosome and RNA sequencing on tumor tissue samples aligned to known genomic features of glioblastoma, including EGFR mutations associated with lower OS and HDI1 mutations associated with higher OS.
“We found distinct enriched bacteria in patients with long or short survival, which is novel enough to warrant further investigation of this observation from a small sample,” Weathers said.
“I think these findings may help increase the excitement for immune checkpoint inhibitor therapy, as they show that we still have a lot to learn about the gut microbiome and its potential role in response to immune checkpoint inhibitor therapy. immune checkpoint in glioblastoma.”
As a result of this study, many glioblastoma clinical trials at MD Anderson now routinely include the collection of stool specimens to enable correlative studies of the gut microbiome.
The study was supported by Genentech and the MD Anderson Rare Tumor Initiative. Weathers reports research funding from Genentech.
Gut microbiome associated with increased immune cell infiltration into the tumor microenvironment and response to immunotherapy for all cancer types
Recent research led by MD Anderson has identified associations between neoadjuvant immune checkpoint blocking responses and B cells and tertiary lymphoid structures (TLS) in the tumor microenvironment.
In this study, the researchers built on previous work, finding further unifying evidence for these new response biomarkers and identifying a relationship between gut microbes, B cells and TLS in three types of cancer: melanoma, NSCLC and sarcoma.
“If these results are confirmed, we hope we can target cells in the tumor microenvironment with microbiome-directed therapies to augment B cells and tertiary lymphoid structures in tumors and to improve responses to checkpoint blockade. immune,” said lead author Elise. Nassif, MD, postdoctoral fellow in surgical oncology. Nassif received the GlaxoSmithKline Oncology Endowed Merit Award from the Conquer Cancer Foundation for the abstract.
The research team extracted data from three phase II randomized clinical trials of neoadjuvant immune checkpoint blockade led by MD Anderson and designed with similar protocols for sample collection and timing: NCT02519322 (melanoma; 23 patients), NCT03158129 (NSCLC; 33 patients) and NCT02301039 (sarcoma; 17 patients). A total of 22 patient cancers responded to treatment, based on the primary pathological response criteria.
When team members analyzed gut microbiome signatures and transcriptome data, they found that high levels of preprocessing of Ruminococcus were associated with response to all types of cancer. High levels of B-cell infiltration and TLS formation at surgery (after immunotherapy) have also been associated with response in all cancer types.
Longitudinal data showed that B cells and TLS increased during immunotherapy treatment in responders, but not in non-responders, and that this increase correlated with a gut microbiome signature that included elevated levels of Ruminococcus at the baseline. B cells and TLS did not change in patients with low levels of Ruminococcus before treatment.
“The ideal should be to learn something from every patient, especially for rare diseases,” said lead author Christina Roland, MD, associate professor of surgical oncology.
“This study shows that we can really learn a lot from a very small number of patients in well-designed clinical trials, even for multiple diseases, and that’s essential for making big advances in cancer care.”
Funding: The study was supported by Bristol Myers Squibb. Nassif has no conflicts of interest to disclose.
About this brain cancer and microbiome research news
Original research: Results will be presented at the annual meeting of the American Society of Clinical Oncology
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