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t m c » p u l s e | j u n e 2 0 1 5 17 "CTLA-4 interferes with the gas pedal of the T-cells and takes the gas off after a while," said Allison. His next insight was critical: could turning off those brakes on the immune system be a way to attack cancer? Allison and his team shifted focus to searching for ways to block CTLA-4, thus removing the brakes and allowing T-cells to respond freely. This type of treatment became known as immune checkpoint blockade. "That was the paradigm shift," said Sharma. "From trying to turn on T-cells, we're now trying to block inhibitory pathways. People kept say- ing, 'We need to harness the immune response.' Actually, we're not trying to harness or turn it on, we're just trying to unleash it. It's ready to go, it just has a lot of brakes around it." Allison developed an antibody to block CTLA-4, which turned into the drug ipilim- umab, used to fight metastatic melanoma. Ipilimumab, now known as Yervoy, showed unprecedented results. "In a study tracking 5,000 patients who received the drug," said Allison, "22 percent are alive 10 years after they stopped therapy." At the time the drug was developed, the median survival rate for late-stage melanoma was 11 months. In 2014, the FDA approved the drugs Keytruda and Opdivo, which inhibit another checkpoint molecule, PD-1, for the treatment of metastatic melanoma. In March 2015, Opdivo was also approved for lung cancer treatment. When taken together, anti-CTLA-4 and anti-PD-1 drugs have been shown to dramati- cally increase survival rates. "The combination of the anti-CTLA-4 and the anti-PD-1 in melanoma gives you 50 percent of patients responding," said Allison. "The whole goal now is to extend this to more types of cancer and find the right combinations where we can get the survival rate even higher." One key step MD Anderson took to enhance immunotherapy research for treating a variety of different cancer types was establishing it as a platform in the institution's Moon Shots Program, launched in 2012. "The Moon Shots are designed to decrease cancer mortality by having major ideas imple- mented, either through prevention, early detec- tion, or treatment," said MD Anderson President Ronald A. DePinho, M.D. "We call it research- driven patient care. We're not just focused on standard of care. We're not just focused on experimental modalities. We really bring the whole package together for patients." Allison is executive director and Sharma scientific director of the immunotherapy plat- form of the Moon Shots Program. "The Moon Shots programs are focused on particular tumor types—for example, women's cancer or prostate cancer—and immunotherapy plays a role in all of those," said Sharma. "Trying to integrate an immunotherapy treatment strategy for each tumor type is very important in helping the Moon Shots goals be accomplished, which is, of course, to eliminate and reduce mor- tality and morbidity of cancer." To that end, MD Anderson is engaged in 50 or more clinical trials related to immunother- apy at any given time, in addition to the hun- dreds of clinical trials MD Anderson manages overall. In fact, the institution's cancer clinical trial program is the largest in the country. The whole goal now is to extend this to more types of cancer and find the right combinations where we can get the survival rate even higher. — JAMES P. ALLISON, PH.D. Chair of the Immunology Department at The University of Texas MD Anderson Cancer Center