The blend of bacteria in the digestive tract of metastatic melanoma patients is associated with disease progression or delay in patients treated with immunotherapy, researchers at The University of Texas MD Anderson Cancer Center report at the 2017 annual meeting of the American Society of Clinical Oncology.

Their study of fecal samples from 105 patients treated with immune checkpoint blockade indicates that certain characteristics of patients' microbiomes correlate with slower disease progression while other qualities are associated with rapid worsening of the disease.

"Greater diversity of bacteria in the gut microbiome is associated with both a higher response rate to treatment and longer progression-free survival," said study leader Jennifer Wargo, M.D., associate professor of Surgical Oncology at MD Anderson.

Wargo and colleagues also found that an abundance of specific bacteria also is associated with higher response rate and longer progression-free survival.

"The microbiome appears to shape a patient's response to cancer immunotherapy, which opens potential pathways to use it to assess a patient's fitness for immunotherapy and to manipulate it to improve treatment," said Wargo, who is also co-leader of the Melanoma Moon Shot™, part of MD Anderson's Moon Shots Program™ to reduce cancer deaths by accelerating development of therapies from scientific discoveries.

In collaboration with the Parker Institute for Cancer Immunotherapy (PICI), Wargo's team is developing the first immunotherapy-microbiome clinical trial, with a goal of launching it later this year.

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Researchers have found in recent years that single-celled organisms and viruses harbored in the human body outnumber the body's own cells. This microbiome plays a role in many regular functions, including the initial priming of the immune system and then its normal operation.

Longer progression-free survival

Patients in the study were treated with immune checkpoint inhibitors that block the activation of PD1, a protein on immune system T cells that halts immune response. The drugs' effect is to free the immune system to attack tumors.

The team found that patients with more varied types of bacteria in their digestive tract had longer median progression-free survival, defined at the time point where half of studied patients have their disease progress.

As a median time to follow-up of 242 days, the patient group with high microbiome diversity had not reached median PFS (more than half had not progressed), while those with intermediate diversity had median PFS of 232 days and those with lower diversity had median PFS of 188 days.

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Specific bacterial types also had an apparent effect. More than half of those with abundant F.prausnitzii had not reached median progression-free survival, while half of those with low abundance had their disease progress by 242 days.

An abundance of Bacteroidales was associated with more rapid disease progression, with patients at high abundance having median PFS of 188 days, while those with lower levels of the bacterium had median PFS of 393 days.

Research has shown that a persons' microbiome can be altered by diet, exercise, antibiotic use or, more recently, through transplantation of fecal material. Wargo cautions that there is much to understand about the relationship between the microbiome and cancer treatment and urges people not to attempt self-medication with probiotics and other methods.

Illuminating microbiome mechanisms

As they develop human clinical trials, Wargo and colleagues also are conducting lab and mouse model research to better understand the mechanisms that connect bacteria and the immune system. This will include a project funded by Stand Up to Cancer that involves fecal transplants from patients who responded to therapy and from non-responders into germ-free mice providing favorable and unfavorable microbiomes to study in detail.

The team conducted 16S rRNA sequencing, an analysis of the presence of 16S ribosomal RNA used to identify bacteria, to determine microbiome composition from fecal samples.

Whole genome sequencing and immune monitoring were conducted on the tumors after treatment and in some tumors before treatment. The immune profiling showed that responders to anti-PD1 treatment had significantly increased immune infiltrates in their tumors, including the presence of CD8+ killer T cells, correlated to the abundance of a specific bacterium.

Co-investigators on the study are Vancheswaran Gopalakrishnan, doctoral student at The University of Texas Health Science Center at Houston School of Public Health; Christine Spencer, Tatiana Karpinets, Ph.D., Robert Jenq, M.D., and Andrew Futreal, Ph.D., of Genomic Medicine; Miles Cameron Andrews, Ph.D., Alexandre Reuben, Ph.D., Jeffrey Lee, M.D., and Jeffrey Gershenwald, M.D., of Surgical Oncology; Michael Tetzlaff, Ph.D., M.D., and Alexander Lazar, M.D., Ph.D., of Pathology; Wen-Jen Hwu, M.D., Ph.D., Claudia Glitza, M.D., Ph.D., Hussein Tawbi, M.D., Ph.D., Sapna Patel, M.D., Michael Davies, M.D., Ph.D., and Patrick Hwu, M.D., of Melanoma Medical Oncology; Padmanee Sharma, M.D., Ph.D., of Genitourinary Medical Oncology and Immunology; and Jim Allison, Ph.D., of Immunology.