Discovery
January 22, 2016

The body's own immune system can pack an amazing punch. When the body decides to recognize something as an enemy and the full power of its militia kicks in, the effect can be powerful — too powerful in the case of an autoimmune disease, and not powerful enough in cancer.

Although the idea of cancer-targeted immunotherapy has been around for decades, only recently has it begun to show some stunning successes in melanoma, lung cancer, kidney cancer, and bladder cancer. In prostate cancer, however, success has come more slowly. Brady scientist Charles Drake, M.D., Ph.D., an immuno-oncologist and one of the thought leaders in the field, is taking a new tack. "Results of immunotherapy in prostate cancer have been less impressive than in other diseases, with immune checkpoint blockade showing little evidence of response in several clinical trials," Drake says. "But based on our published data, we hypothesized that combining immunotherapy with hormonal therapy — earlier in the course of disease — before the cancer stops responding to hormonal therapy — could lead to better outcomes."

Using an animal model that "reliably responds to castration," or androgen ablation, the medical shutoff of testosterone, "but later develops castration- resistant disease, we tested the relative timing of hormonal therapy and immunotherapy," Drake explains. "Immunotherapy alone, either early or late in the disease's course, was ineffective. But when we gave immunotherapy just before hormonal therapy, the results were striking. A significant proportion of animals never developed castration-resistant disease."

There are different types of immune checkpoint inhibitors. Drake and colleagues tried PD-1 blockade, and found that it was "unimpressive." Then they tried CTLA-4 blockade, which was more promising, and a new compound was better still. A CTLA-4 antibody that targets and depletes regulatory T cells (which suppress the immune system) "was the most efficacious immunotherapy we found," Drake says. "Taken together, we hope that these promising results will drive a translational clinical trial, in which anti-CTLA-4 is administered in combination with a short course of hormonal therapy in men with high-risk disease whose PSA has returned and is on the rise." Drake and colleagues presented these results at the American Association for Cancer Research's annual meeting in 2015.