Insights from Dr. James Allison, Discoverer of CTLA-4
Earlier this month, Vanderbilt University hosted the founder of immune checkpoint inhibition and fellow Checkpoints band member Dr. Jim Allison. Dr. Allison is a highly regarded immunologist at MD Anderson, revered for his discovery of CTLA-4 and the development of ipilimumab, the first FDA-approved immune checkpoint inhibitor for the treatment of metastatic cancer. In today’s tumor immunology craze, many people overlook his significant contributions to basic immunology (sequencing the gamma delta T cell receptor, as well as understanding T cell co-stimulation).
Several MSTP students had the opportunity to have breakfast or lunch with the Lasker Award winning scientist. In these sessions, Dr. Allison shared his philosophical approach to having a successful career in science. He stated, “Do the best foundational science you can, and then think about the applications…it wasn’t about screening a bunch of tumors. It was just about trying to understand T cells.” In fact, Dr. Allison has always focused on following the basic science question, inspired by simple observations, which ultimately lead to him following the basic science all the way to drug development and clinical trials. He recounted stories as a grad student in which he re-challenged cured mice with their original tumors, and to his amazement, these tumors never grew back. These fundamental experiments drove his stubbornness to pursue tumor immunology in the face of harsh critics and famous clinical failures. Dr. Allison also told us not to be dismayed if we can’t answer our most vexing scientific questions because eventually technology will improve to help you do so. To help graduate students, Dr. Allison advised us all to “Do the experiment that will prove your hypothesis wrong,” emphasizing the importance of rigorous experimental design.
Dr. Allison also emphasized the necessity for science advocacy. He feels strongly that prominent scientists need to communicate the negative impact of decreased funding opportunities in today’s research environment. Dr. Allison also described how he needed to advocate for his own science and ensure that clinical trials were designed in accordance with his basic science insights. He described experiences in which some clinicians tried to evaluate ipilimumab the same way cancer therapeutics have traditionally been evaluated using progression-free survival without the insight from murine studies that tumors always progressed in size before shrinking in response to treatment. Dr. Allison fought long and hard to get clinicians to run trials informed by his experiments. In the end, Dr. Allison persevered and the trials of these drugs succeeded. In fact, one of the first patients with metastatic melanoma treated with ipilimumab was hospice-bound after receiving numerous treatments including high-dose IL-2. She received a single course of ipilimumab and was disease-free four months later. She is still disease-free 17 years later. As Dr. Allison emphasized, we have a lot more to understand before every cancer patient can be treated successfully with immune checkpoint inhibitors. However, Dr. Allison’s journey from basic structural biology to a revolutionary, life-saving clinical application is an inspiration to all of us as future physician-scientists.