Medscape: There has been a lot of interest over the past few years in exploring the benefits of different types of immune-based therapies. What have we learned from those experiences and where are we likely to go from here?
Dr. Slovin: One of the primary areas of research involves CTLA4, which acts as a checkpoint for T cells and helps the T cells discriminate between self and nonself antigens, therefore protecting against the development of autoimmunity. The theory was that in the development of cancer, CTLA4 holds back the T cells from fighting off cancerous cells, allowing them to multiply unchecked. In prostate cancer, ipilimumab, or MDX010, a fully human anti-CTLA4 monoclonal antibody, has been tested in combination with vaccines[7] and is now being tested as a single agent and in a combination approach using radiotherapy to promote tumor antigen release.[8]
In combination with vaccines, ipilimumab seems to cause very significant antitumor effects, including PSA reductions and radiographic improvements. It was thought that it was the combination of the drug with the vaccine that produced the response, but because the drug went straight into phase 1/2 combination therapy, there was a desire to find out what ipilimumab contributed as an independent agent.
Phase 1 trial data so far with ipilimumab as a single agent show that the drug is relatively safe, and there is a suggestion that it has an antitumor effect.[8] Specifically, there has been 1 complete response and several partial responses. Also, in some of the patients who have responded, there is a suggestion that the response is tightly linked to the development of autoimmunity, including significant although manageable diarrhea and severe fatigue. These effects clearly indicate that the drug is, as anticipated, interfering with the activity of CTLA4 within the body. The addition of radiotherapy as a primer has shown some very dramatic responses but additional toxicity as well. This effort is continuing with a much more extended cohort to better understand the role of ipilimumab in CRPC.
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