Cancer researchers at OHSU have been awarded $1 million to test the idea that adjusting the diversity of bacteria inhabiting the intestines could make aggressive prostate cancers more responsive to treatment with immune therapy drugs called PD-1 inhibitors.
“There are some compelling hints that the gastrointestinal microbiome plays a big part in who responds and who doesn’t,” said co-principal investigator Julie Graff, M.D., an associate professor of hematology and medical oncology in the OHSU School of Medicine and section chief of hematology and oncology at the VA Portland Health Care System.
Graff and colleagues were the first to show clinical activity for a PD-1 inhibitor in men with aggressive, advanced-stage prostate cancer. But as is typical with these drugs, only a small subset of patients responded. Researchers have been unable to find a reliable way to predict which tumors will respond.
Gut microbes continuously interact with the immune system, and there is accumulating evidence that those interactions can alter cancer drug effectiveness. In one study of melanoma patients, bacterial diversity and abundance of two types of bacteria were strong predictors of positive response to a PD-1 inhibitor, while two other bacterial species were associated with non-response. In another study, coincidental use of antibiotics during the course of cancer therapy negatively correlated with patients’ response to treatment with a PD-1 inhibitor. In a mouse study, establishing one of the “good” bacteria species in antibiotic-treated mice restored the tumor-bearing animals’ response to immunotherapy.
If the study hypothesis is correct, the introduced bacteria will activate the immune system and increase sensitivity to pembrolizumab.
The $1 million award from the Prostate Cancer Foundation and the Movember Foundation will support a phase 2 clinical trial at the Portland VA. Graff’s team includes co-PIs Amy Moran, Ph.D., an assistant professor in the Department of Cell, Developmental and Cancer Biology in the OHSU School of Medicine, and Karen Sfanos, Ph.D., associate professor of pathology, oncology and urology at Johns Hopkins University. Co-investigators at the Portland VA include Nancy Ho, M.D., and Reid Thompson, M.D., Ph.D.
The clinical trial will enroll men with metastatic prostate cancer that is resistant to androgen deprivation therapy. Subjects will receive a fecal microbiota transplant from patients who previously responded to treatment with pembrolizumab, a monoclonal antibody that binds to the PD-1 receptor. Then the subjects will start therapy with pembrolizumab. If the study hypothesis is correct, the introduced bacteria will activate the immune system and increase sensitivity to pembrolizumab, improving immune responses against the tumor.
Periodic sampling of fecal bacteria will allow the researchers to find out how the diversity of species correlates with immune system function and tumor sensitivity to the immune therapy. Moran, an immunology and cancer biology expert, will lead efforts to understand how the subjects’ immune system activity reacts to the fecal transplant and immune therapy treatment.
Prior studies of men with metastatic prostate cancer showed no evidence of anti-tumor activity with immune therapies that work by blocking PD-1 signals. Being the first to show evidence of clinical activity for a PD-1 inhibitor in prostate cancer, Graff and colleagues at OHSU may have the only cohort of patients who can serve as donors for the fecal microbiota transplant.
“That means we are in a unique position to do this study,” Graff said.
Enrollment could begin as early as October, she said. Merck, maker of pembrolizumab, is also funding the clinical trial. Patients will be recruited at the VA Portland Health Care System, and by referral from VA medical centers in Seattle and Los Angeles.
Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer by Julie N. Graff, Joshi J. Alumkal, Charles G. Drake, George V. Thomas, William L. Redmond, Mohammad Farhad, Jeremy Cetnar, Frederick S. Ey, Raymond C. Bergan, Rachel Slottke and Tomasz M. Beer, Oncotarget (2016)
Precision medicine using microbiota by Christian Jobin, Science (Jan. 5, 2018)
Image: Xenograft model of prostate cancer (NCI Visuals Online)