James P. Allison, PhD, reflects on his research in immunology, the impact it has had on patients with cancer, and where the field is headed.
James Allison, PhD
The immense impact of immunotherapy is well known to those in the oncology space. Over the last few years, it has become a therapeutic option that more and more patients request, as they have seen the life-changing outcomes it has had on those battling malignancies, such as melanoma and non—small cell lung cancer.
On October 1, 2018, the Nobel Assembly at Karolinska Institutet announced that James P. Allison, PhD, had won the 2018 Nobel Prize in Physiology or Medicine along with Tasuku Honjo, MD, PhD, for their work that led to the use of checkpoint inhibitors in the treatment of patients with cancer.
Allison, who is the chair of Immunology and executive director of the Immunotherapy Platform at The University of Texas MD Anderson Cancer Center, is well known for spearheading the research that led to the first FDA-approved immune checkpoint inhibitor, ipilimumab (Yervoy). In 2014, Allison was recognized with a Giants of Cancer Care® award in the category of Scientific Advances.
In an interview with OncLive following the announcement of his Nobel Prize, Allison reflected on his research in immunology, the impact it has had on patients with cancer, and where the field is headed.Allison: Firstly, just having enough funding to concentrate on fundamental science puts pressure on everyone to actually do translational stuff from the start. The truth is, you are not going to get any major discoveries that way—you have to do the fundamental science and understand the mechanisms. That is where CTLA-4 blockade came from. [We were] not trying to cure cancer, it came from trying to understand the mechanisms of T-cell activation. Once we understood that, I [thought], "This gives me an idea about a new way to treat cancer." I would submit that no one who was just trying to figure out how to use the immune system would have ever found CTLA-4. That is the first thing: to provide more funding for fundamental science, and mechanisms that are potentially important for treating [patients with] cancer. Then, be aware of new discoveries and things that will take you along the way. Both need to be done.
For a few years, I had a hard time finding anyone who would take a chance on what we were trying to do because they did not understand the mechanisms. I think the answer is more science—more hardcore science. When I started, I was interested in a subset of immunology, which was T cells. There was nothing known about them except that they cruised all around your body, looked for problems, and fixed them. The mechanisms just fascinated me. How do they do that? How do they recognize it? How do they get turned on and get turned off, and decide what to do?
We still, in my opinion, are only scratching the surface on understanding the complexities of those mechanisms. It used to be that people thought there were these discrete pathways that T cells differentiate along and are stimulated by. Now, we are beginning to see that it is more fluid than that—it is a dynamic process.
If we are going to really use T cells and immunotherapy, we need to understand those sorts of things. We need to understand the impact of epigenetics and the development of different signaling pathways in some detail. Particularly if we are going to start putting these things in combination with genomically-targeted kinase inhibitors, that is a very powerful way to go. We don't know enough about what those things do to the immune system to make any movement there.
It has become clear in the last 3 years or so that immunotherapy is the fourth pillar of cancer therapy. Surgery, radiation, and chemotherapy are pretty much “siloed,” and immunotherapy is unique, as it can work with those other things. What we need to do now is work on a universal way of combining all of these and hope for synergy. If you come in with a checkpoint blockade, you will get T cells that [the patient] will have for the rest of their life—the chemotherapy will be gone in hours.
We need to learn what controls these things, the steps in which T cells differentiate, and what effect epigenetic drugs have on those. We need to find ways of reversing epigenetic signals that may freeze a T cell at a particular point, rather than letting it go on and be reactivated. With ipilimumab, we were not treating the cancer, we were treating the immune system—the cancer had nothing to do with it. The question was, "How can you treat cancer if you ignore the cancer cells?" That put a lot of people off. With respect to side effects, we never saw any in mice in our preclinical studies; even in the toxicities studies that Medarex went through in monkeys, there were really high levels of sustained treatment. Yet, they popped up in people, but people are not mice. [Humans] have had thousands of viral infections, probably many of which you never know about. Your immune system is very experienced. However, when these side effects appeared, they were not what you would get with certain chemotherapies.
Physicians developed algorithms to ask how to mediate the problems with these adverse events. The people that I am around at The University of Texas MD Anderson Cancer Center have so much experience that there are no daunting side effects. By and large, patients can be easily managed with proper care, a lot of attention, early detection, and intervention. The physicians have done an amazing job mitigating those.As a scientist, much of my work is done with mice, and they don't thank you for caring for them. Then again, maybe they shouldn't because we gave them the cancer in the first place.
For several years after the clinical trials started with ipilimumab, I was kind of distant from it and only saw it as numbers. [There was a lot of cancer that occurred in my own family], so I knew what it meant, but it was not until I met the first patient that really struck me. This was a 22-year-old woman who was diagnosed with metastatic melanoma, who had just finished college, and was engaged to be married. She had lung and cutaneous metastases, and had failed everything. She went on one of the early trials of ipilimumab and I met her when she was first declared tumor-free. The doctor said, "The guy who invented this drug is here. Do you want to meet him?" So, I went over, and it was one of the most emotional experiences I have had. A few years later, she sent me a photo of her first baby. She is 14 years out now, and she has a family who is doing fine, and that to me illustrates that not only is the person saved, but the whole lineage is saved. For a basic scientist, that is about as good as it gets.
One of the things that I have always admired oncologists for is that in certain cancer types, they are going to fail. I don't understand, emotionally, how they can deal with it when you are just trying to extend life for a few months, or palliative medicine. It takes such courage to do that. I feel very good about the fact that these new therapies, that I have had a part in developing, actually give hope to both patients and their doctors. People have told me that in their clinics now, they don't feel like everyone is going to die. A certain fraction of them will be given years of quality life, if not cure—which is a dangerous word to use.