Immunotherapy – “checkpoint inhibitor” drugs that help the immune system recognize and fight off cancer – works much better in kidney cancer and melanoma than in prostate cancer. Why?
Scientist Emmanuel S. Antonarakis, M.D., professor of oncology and urology, believes these drugs may be targeting the wrong immune mechanisms in prostate cancer. “Checkpoint inhibitors unlock specific molecules, such as PD-1 and CTLA-4, that act as handcuffs on the body’s powerful T cells, which normally fight off enemy invaders.” With the restraints lifted, T cells seem to wake up, notice that something is very wrong, and attack cancer cells.
Building on the work of former Brady urologist Ashley Ross, M.D., Ph.D., Antonarakis and cancer immunologist Eugene Shenderov, M.D., D.Phil., are investigating a promising new target: a molecule called B7-H3. “B7-H3 is not only highly expressed on prostate cancer cells,” says Antonarakis, “but it appears to be associated with more rapid progression of prostate cancer following local treatment with surgery or radiation.”
The team designed a clinical trial to study the anti-tumor, immunological and clinical effects of targeting B7-H3 in high-risk men with localized prostate cancer who are about to undergo prostatectomy. Prostatectomy patients present an ideal opportunity for pathologists to study “before and after” tumor tissue – the biopsy samples taken at diagnosis, and then the removed prostate specimen. “In our trial, 32 patients were treated with Enoblituzumab, a humanized monoclonal antibody against B7-H3, before surgery.” Then, after surgery, expert prostate cancer pathologist, Angelo De Marzo, M.D., Ph.D., examined the tissue, looking for evidence of an antitumor immune response.
Prelimary results are promising: “Enoblituzumab was well tolerated,” Shenderov says, “and did not seem to produce as many side effects as other immunotherapy drugs.” Also, “prostatectomy samples from men who received Enoblituzumab showed an altered tumor microenvironment in a fashion that indicates enhanced immune infiltration – a hallmark of responsiveness to immunotherapy.”
Even more exciting: “A significant proportion of patients had a drop in their PSA level as well as a decrease in their Gleason scores after receiving Enoblituzumab,” adds Antonarakis. “Despite enrolling patients who had a high risk of prostate cancer recurrence, the majority of these men remain cancer-free for 12 months or more after prostatectomy.”
These results are so promising that Antonarakis and Shenderov are designing new studies to target B7-H3 in men with metastatic prostate cancer – the first studies of their kind.