Melanoma Immunotherapy and the Microbiome

The ongoing evolution of our understanding of the importance of the human microbiome to a myriad of physiological and disease processes may very well reshape much of medical science. Indeed, its influence and manipulation has already taken root and produced promising results in many disciplines - for example, gastroenterology in the treatment of clostridium difficile infections and inflammatory bowel disease.

The microbiome's role in cancer development and therapy modulation is in its infancy, but already there are signs and preliminary research that the flora and fauna - the vast multitudes of microbes that inhabit the human body - may play a role in not only the development of certain malignancies but also how an individual reacts to various therapeutic regimens. The makeup of one's microbiome may factor quite significantly in whether a person responds, or fails to respond, to treatment. Modulating or changing the microbiome of an individual may one day allow previously failed therapies to be successful in more patients.

The successes over the last three to five years with immune checkpoint inhibitors (e.g., anti CTLA-4 and anti-PD-1 and PD-L1 agents) in metastatic melanoma have produced curative efficacy in the range of 30 to 40 percent. However, this still leaves a full 60 percent of patients in the nonresponder category. With the yearly incidence of new melanoma cases in the United States approaching 76,000, approximately 9,000 of which are advanced or metastatic cases, converting even a small percentage of advanced case nonresponders to these immunotherapies would benefit a significant number of patients. A patient's microbiome composition may be the key to unlocking the efficacy of immunotherapy agents for some of the patients who currently do not respond to the therapy.

A New Clinical Trial

The role of the microbiome in advanced melanoma treatment with immunotherapy agents is being pursued by Diwakar Davar, MD, medical oncologist, and Hassane Zarour, MD, cancer immunologist and co-leader of the Melanoma Program at UPMC Hillman Cancer Center, in a new clinical trial set to begin recruiting patients in 2018. Drs. Davar and Zarour are both part of the Melanoma Program at UPMC, and are co-investigators on the new investigator-initiated trial seeking to understand whether a change to an individual's microbiome may trigger a response to immunotherapy in a percentage of cases of metastatic melanoma who do not initially respond to the treatment.

Drs. Davar and Zarour will enroll 20 patients with advanced metastatic melanoma who have undergone treatment with pembrolizumab (Keytruda) and have failed or become nonresponsive to the therapy during their treatment regimen. These individuals will receive a fecal micro.biota transplant (FMT) obtained from patients who have proven to be long-term responders to pembrolizumab. The FMT will be administered via colonoscopy with an initial single dose, after which this group of patients will again receive pembrolizumab therapy with their responsiveness to treatment monitored. Responding patients who subsequently progress may be offered a second FMT.

"Our first goal is to understand exactly what proportion of the 60 percent of immunotherapy nonresponders are not responding to treatment with pembrolizumab, because of an altered intestinal microflora," says Dr. Davar.  "FMT is safe, and such a strategy truly has the potential to significantly improve the clinical outcome of advanced melanoma patients who have failed PD1 therapy and who have no other good therapeutic option," says Dr. Zarour.

This research conducted by Drs. Zarour and Davar will identify whether responses to therapy (if seen) are dependent on a single microbe or a group of networked microbes. It will also investigate the mechanisms used by the gut microbiome to stimulate potent anti-tumor immune responses in melanoma patients.

References

^1. Fecal Microbiota Transplant (FMT) in Melanoma Patients. ClinicalTrials.gov Identifier: NCT03341143.