Raising the tail of the survival curve, which is our slogan for getting durable responses and perhaps cures in the largest fraction of our patients, is possible. It’s a huge challenge, but I’m confident it is within reach.
—James P. Allison, PhD
The concept of using activation of the innate immune system and an inflammatory response against a bacterial component to instigate an antitumor response was studied in the 1960s, which led to the development of intravesical bacillus Calmette-Guérin, now used in the treatment of superficial bladder cancer. Over the following decades, the promise of immunotherapy ebbed and flowed until a couple of decades ago, when researchers saw promise in T-cell activation, paving the way for a revival of immunotherapy. Today, one of the most exciting areas in immunotherapy is checkpoint blockade.
The ASCO Post recently spoke with James P. Allison, PhD, who received the 2015 Lasker-DeBakey Clinical Medical Research Award for his pioneering work in enabling T cells to attack cancer cells by removing “checkpoints” that normally inhibit T-cell activity.
A Career-Changing Period
Please tell the readers a bit about your career and your current position.
I came from a small town in south Texas and received both my bachelor degree and PhD at the University of Texas in Austin. I then did postdoctoral training at the Scripps Clinic in La Jolla, California. I returned to Texas and took my first faculty position at the University of Texas Science Park, which was part of MD Anderson Cancer Center. I stayed there about 8 years. I was actually trained in biochemistry but became interested in immunology—specifically T cells and the complex activation processes—and switched fields.
In 1984, I moved to the University of California, Berkeley, where I became Head of the Immunology Program and Director of the Cancer Research Lab. I continued my work in T cells, and during that work, I began wondering whether T cells could be manipulated in a way to fight cancer cells. It turned out to be a career-changing period.
Although Berkeley was a fantastic place, it didn’t have a clinic, so in 2004, I moved to Sloan Kettering Cancer Center in New York and was there for almost 10 years. About 3 years ago, I returned to MD Anderson Cancer Center, where I am now Chair of the Immunology Program and Director of the Immunotherapy Platform.
The concept of immunosurveillance was proposed back in the 1950s. What did we learn from this approach that helped move the field forward?
From its inception, the idea of immunosurveillance was quite controversial. It regained favor in the 1960s and then lost support for awhile. The theory suggested that tumors are constantly developing, but they are detected by immune system cells, which can eradicate them; the cancer only recurs when this immune surveillance fails. And now we’ve reached a point where we recognize that the immune system can detect tumors, and we are using this knowledge to further the field.
Please discuss the initial investigations on T-cell activation and how they paved the way for the renewed interest in immunotherapy.
During my first faculty job, I became very interested in T cells, which could cruise around your body with about 100 million different specific receptors. When a T cell encounters a foreign antigen, it results in T-cell activation, rapid proliferation, and development of the functional capacity to directly kill or make cytokines to help kill the offending cell.
Moreover, we thought that immunotherapy using T cells could cure the problem without killing you in the process. That said, cell communication is a very complicated process, and my first accomplishment was defining the structure of the T-cell antigen receptor at the protein level. It became clear very quickly in work from many labs that the antigen receptor signal by itself was not sufficient to “turn on” a naive T cell. It’s necessary but not sufficient.
Several labs demonstrated that costimulatory factors could only be provided by dendritic cell signals, which were unique in providing that second signal. The question remained: What is that signal? We showed that the receptor on the T cell was a molecule called CD-28. Turning it on required both the T-cell antigen-receptor signal and CD-28 costimulatory signal, at pretty much the same time. Subsequently, other researchers showed that a molecule called B7 was the CD-28 ligand on antigen-presenting cells. Given this finding, it seemed that one of the reasons that tumor cells are virtually invisible is because solid tumors do not provide the costimulatory signal.
There was also a molecule called CTLA-4 with a DNA sequence very homologous to CD-28, but nobody knew what it did, except that it only expressed itself after activation. There was a vigorous race to figure it out. The group that got there first showed that it bound to the same molecule that CD-28 bound to.
The first studies demonstrated that CTLA-4 could not costimulate on itself; however, it could synergize with CD-28 and sustain costimulation to keep the T cells activated. My lab and that of Jeff Bluestone came to the conclusion that the prevailing notion, which was already in textbooks, was backward. Actually the CTLA-4 antibodies were removing the negative signal, resulting in an increase in activity, not providing another positive signal. This finding kicked up some heated negative and positive debates at conferences. It was a lot of fun.
When we got the results, I started thinking about it in the context of tumors, which was a change of focus for me, because I didn’t originally get into this work in cancer therapies; I wanted to know how T cells worked. So, we then knew that tumors didn’t have the second costimulatory ligand, making them essentially invisible to the immune system. So the tumors just kept growing. But by then, we realized that when a T cell gets a costimulatory signal, it initiates its natural propensity to kill things. However, at the same time, the costimulatory signal turns on the CTLA-4 gene, which basically initiates an off switch (or inhibitory program), which will eventually stop the T-cell response and let the tumor continue to grow unmolested by the immune system.
After a lot of thinking on this, I realized that since the tumor has had a head start, maybe the CTLA-4–driven program stops the T cell before it can respond effectively with the tumor. Therefore, setting up a blockade of the CTLA-4 expression, or checkpoint, enhances antitumor T-cell responses and the tumor-rejection process.
Creation of Immune Checkpoint Therapy
How did this concept of checkpoint blockade relate to cancer therapy?
Actually it did so in two ways. First, using a monoclonal antibody therapy doesn’t target the tumor cell specifically but engages a target on the patient’s immune system, giving it the opportunity to have benefit in a wide variety of tumors.
Second, this action of not targeting a specific tumor unleashes the immune system by removing the inhibitory pathways. And clinical trials with anti–CTLA-4 showed tumor regression in patients with a host of different tumors, and based largely on this work, the field of immune checkpoint therapy was created.
Raising the Tail of the Survival Curve
Do you have any last thoughts on this exciting line of research?
In melanoma, 22% of patients given ipilimumab (Yervoy) are still alive after 10 years, but what about the other 78% of melanoma patients? And what about patients with other tumors? These are the challenges we are wrestling with daily in the lab. Raising the tail of the survival curve, which is our slogan for getting durable responses and perhaps cures in the largest fraction of our patients, is possible. It’s a huge challenge, but I’m confident it is within reach. ■
Disclosure: Dr. Allison is a licensor of intellectual property and receives royalties from Bristol Myers-Squibb; is founder, a licensor of intellectual property, and scientific advisory board member of Jounce Therapeutics; is a licensor of intellectual property and receives royalties from Merck; is a founder and scientific advisory board member of Neon Therapeutics; and a scentific advisory board member of Kite Pharmaceuticals.