Drug Found To Stimulate Immune System In Patients With Prostate Cancer

Darryl Pape was one of 19 participants in the Oregon Health & Science University Cancer Institute trial.

"I was in such bad shape. I couldn't even sit on a plane for more than two hours without a lot of pain. I was praying for some clinical trial that would help," said Pape, 54, of Portland, Ore.

Pape was running out of options for his prostate cancer. He was diagnosed almost seven years ago and had tried different cancer drugs, but each only for a while. Last year his cancer count, or prostate specific antigen (PSA), was at a high level -- an indicator that his cancer was growing and spreading and it was not responding to any drugs.

A prostate-specific antigen test measures the amount of prostate-specific antigen in the blood. PSA is released into a man's blood by his prostate gland. Healthy men have low amounts of PSA in the blood. PSA may increase as a result of prostate cancer.

Pape, a very religious man, was looking for a miracle. He found one when he was eligible for a clinical trial testing the effectiveness of Ipilimumab, at the OHSU Cancer Institute. After the first infusion of the drug, Pape said he could feel it working. After the second infusion, he said his symptoms went away.

"I felt great at that point," he said.

Not everyone has the same response, and Pape did suffer some side effects. But one year later, Pape is in complete remission.

"I got my life back," he said.

Tomasz Beer, M.D., a member of the OHSU Cancer Institute, will be giving the oral presentation on this research Monday, June 2, at 11:30 a.m. during the annual American Society of Clinical Oncology in Chicago.

"From what we have seen, this shows that the immune system can be useful to treat prostate cancer. Results show that in some patients, the immune system can be successfully harnessed to cause cancer regressions, and that is both exciting and encouraging," said Beer, the Grover C. Bagby Endowed Chair for Cancer Research, director of the Prostate Cancer Research Program at the OHSU Cancer Institute, associate professor of medicine (hematology/medical oncology), OHSU School of Medicine.

It was confirmed that seven or 21 percent, of the 33 study participants had PSA declines of 50 percent.

The secret to how the drug works lies in a complex set of interactions in the immune system. The immune system is designed to attack foreign invaders such as viruses and bacteria, sending out a barrage of T-cells to destroy it through inflammation or direct killing. The immune system is also thought to play a role in surveillance for the detection and elimination of altered cells of the body, such as cancer cells. Whether a cancer progresses or not depends, in part, on the ability of the cancer to evade the immune response. One way in which cancer cells can evade the immune system is to take advantage of natural controls of the immune response that act to dial down, or down regulate, the strength of the response and allow the tumor to grow.

Scientists have discovered that an important mechanism for down regulation is mediated by a molecule called CTLA-4. The T cells are initially activated by other immune cells, called dendritic cells, that display the foreign, or cancerous, antigens to the T cells and instruct them to be active. After this initial activation, CTLA-4 appears on the surface of the T cells, and when CTLA-4 interacts with the dendritic cells, the next set of signals are to turn the response down, or even off. CTLA-4 is part of a regulatory mechanism that normally protects the body from immune overreactions, but when it is expressed in the presence of mutant cancer cells the result is tumor evasion of the immune response. Ipilimumab is an antibody that blocks CTLA-4, releasing this safety brake, and allowing the immune response to have a stronger anti-tumor effect.

The clinical trial is being conducted at six sites through the Prostate Cancer Clinical Trials Consortium. The consortium is funded by a grant from the U.S. Department of Defense and brings together 10 of the top prostate cancer research programs in the country. The OHSU Cancer Institute is a founding member of the consortium. Memorial Sloan-Kettering Cancer Center serves at the coordinating center for this trial. Centers in the consortium involved in this study include the OHSU Cancer Institute, University of Washington and Memorial Sloan-Kettering Cancer Center.

Researchers are investigating to find out the safety and efficacy of Ipilimumab in prostate cancer, and are also working to better understand the value of adding radiation as a means to further stimulate the immune response to the tumor.

Other researchers involved in this study include: Susan Slovin, Memorial Sloan-Kettering Cancer Center; C.S. Higano, University of Washington; Sheela Tejwani, Henry Ford Health System; Tanya Dorff, The Angeles Clinic and Research Institute; Howard Scher, Memorial Sloan-Kettering Cancer Center; Elizabeth Stankevich, Israel Lowy, M.D., Ph.D., both Medarex.