A recent article from Prostate Cancer News Today (April 4th) stated that Yervoy (ipilimumab) showed little benefit when administered to 16 patients awaiting surgery with locally advanced prostate cancer at the University of Texas M.D. Anderson Cancer Center. The study was published in Nature Medicine.
Ipilimumab (also known as MDX-101 and MDX-010 and marketed as Yervoy) is a human monoclonal antibody developed by Bristol-Myers-Squibb and approved for the treatment of melanoma. It is currently undergoing clinical trials in metastatic, hormone-refractory prostate cancer among other cancers. It works by activating a patient’s own immune system by causing cytotoxic T-lymphocytes to potentially combat tumor cells. Specifically, it targets cytotoxic T-lymphocyte antigen-4 (CTLA-4), preventing the antigen from interacting with its ligands and thereby activating the patient’s own immune system by causing these T-cells to potentially combat tumor cells. More simply, Yervoy blocks a switch that turns off an anti-tumor cellular response. Therefore, Yervoy is an agent that “blocks a blocker” thereby aiding the immune system to fight the tumor. The bad news however is that prostate cancer responds to Yervoy by increasing the expression of two other immune checkpoint molecules, PD-L1 and VISTA. And both send a “don’t-eat-me signal” to immune cells. That reaction is why Yervoy, by itself, offers little patient benefit.
Yervoy increased the numbers of T-cells in tumors, as well as another kind of immune cell, macrophages. But researchers also discovered that the tumor cell tissue had two proteins on their surfaces, PD-L1 and VISTA, that were not there before treatment. These proteins are called immune checkpoints because they can stop the chain of events that lead to an immune reaction. Basically they signal the shutdown of T-cells in the tumor environment. These results are prime examples of the dynamic state of the immune system; when a change is made in one specific area, it may manifest itself in other areas simultaneously. It is like trying to alter one card while not changing other cards comprising a house of cards.
“Observing immune response at one point in time doesn’t reflect what’s going on because the immune system is so dynamic,” said Dr. Padmanee Sharma, a professor of genitourinary medical oncology and immunology at the University of Texas MD Anderson Cancer Center. You can change the immune response with Yervoy, but what else changes becomes incredibly important.