Allison Shares His Path to Groundbreaking Achievements in Immuno-Oncology

Partner | Cancer Centers | <b>MD Anderson</b>

James P. Allison, PhD, permanently etched his legacy into immuno-oncology with the development of ipilimumab, work that helped him win a Giants of Cancer Care® award for Scientific Advances in 2014.

James P. Allison, PhD, permanently etched his legacy into immuno-oncology with the development of ipilimumab (Yervoy), work that helped him win a Giants of Cancer Care® award for Scientific Advances in 2014. Four years later, the Nobel assembly at Karolinska Institute honored Allison and Tasuku Honjo, MD, PhD, with the Nobel Prize in Physiology or Medicine for their work that led to the use of checkpoint inhibitors and cancer treatment.

Today, Allison is Regental Professor and chair of the department of immunology, the Olga Keith Wiess Distinguished University Chair for Cancer Research, director of the Parker Institute for Cancer Research, and the Executive Director of the Immunotherapy Platform at The University of Texas MD Anderson Cancer Center. In an interview with OncLive®, he discussed his early career at MD Anderson, which provided him with the opportunity to work on his groundbreaking research with ipilimumab for patients with cancer; shared his proudest achievements and discussed plans for future research.

OncLive®: Since winning the 2018 Nobel Prize in Physiology or Medicine, what has been the focus of your research? What plans do you have for future studies?

Allison: I was beginning to realize [around] the time of [receiving] the Nobel Prize that for the first time, checkpoint blockade and other immunotherapies were truly curative therapies, but the fraction of patients responding to them is relatively small at this point. What we know in melanoma, for example, is that with ipilimumab [Yervoy] monotherapy approximately 20% of patients are alive 10 years after a single round of treatment. This is pretty good, but why not 100%?

When PD-1–targeted [therapies] came along and were added to [the treatment paradigm], [survival benefit] went up to approximately 50%. That randomized trial has been out long enough now [that] there is 5 years of follow-up, and it is still at 50%. Considering that when we started this work, the median survival with melanoma was 7 months, fewer than 3% of patients were alive at 5 years, and there was no drug approved, greater than 50% is good. But, again, why not 100%? In bladder [cancer], it is 30% to 40%, but why not higher?

That is what I have been doing with my scientific partner and my partner in life, my wife, Padmanee Sharma, MD, PhD. We formed a program at MD Anderson called the Immunotherapy Platform. I have been a basic scientist all my life and just dabbled in immunotherapy a little bit. Then I became a translation guy, but now we are really doing reverse translation. It is clinical trial–based work, where we get specimens from patients on trials, then take them back to the laboratory and look at mechanism to try to gain insight into [possible] new combinations. We know what a good signal looks like, and we know the components of it. It is not just T cells, it is myeloid cells, and we are beginning to realize that fibroblasts can play a role and it is more complicated than we thought.

We are trying to dissect the critical stuff back in the laboratory, go to mouse experiments to test hypotheses, then go back with an iteration of change, and it has been quite successful. I have made a lot of progress, particularly in genitourinary cancers, and we are beginning to start looking at things like glioblastoma and pancreatic cancer. They’ve have been [somewhat] recalcitrant so far, but it is [about] trying to make these therapies work better.

You were also the first recipient to win the Nobel Prize from the University of Texas MD Anderson Cancer Center. What did it mean to you to bring this back to the institution where you have spent so much of your career?

It means a lot because, over the years, MD Anderson has done so much for me. I had my very first faculty appointment at MD Anderson. I had been interested in immunology and T cells, which were first being recognized in the late 1960s when I was an undergraduate. [I realized] that that was what I want to do as a biochemist. I wanted to work on them, but I did not have a chance until I got that faculty job. I did my postdoctoral research at an immunology lab, where I had to do protein purification, because they want to take advantage of my skills. When I came to MD Anderson, I had a project that I was hired to do, but on the side [I was able to] indulge my curiosity and worked out the structure of the T-cell antigen receptor for the first time in 1981.

This propelled me to other stuff, but that early work was all done at MD Andersen because I had the freedom and support to just do what I wanted to. I was lucky. Then, after 20 years at University of California, Berkeley, and 10 years at Memorial Sloan Kettering Cancer Center, I am back [at MD Anderson]. One of the things I will never forget is when I came back from Stockholm and did a walkthrough [of the facility] with Peter WT Pisters, MD, the president of the MD Anderson Cancer Center. [When I walked] through the hospital there were hundreds of people, patients, staff, just cheering, and there was just such an outpouring of love. I was happy to have been able to bring something back that meant so much to everyone.

Was there ever a point during the development of ipilimumab that you thought it may not work? What were the challenges that you faced to get to the finish line?

The biggest challenge at the time was the bias against immunotherapy. I considered myself a basic scientist, and I was working on mechanisms and regulation of T-cell responses. Every now and then, when I [discovered] something that I thought might be useful in cancer, I would jump into that [research] for a while and try and learn something, and then jump back. [Eventually,] I was able to put together that if we blocked checkpoints, we could unleash the immune system’s T cells.

I knew people were going to be skeptical, so we did the work in many strains of mice and many different tumors, so that it worked in essentially [every different way], either as a monotherapy, radical chemotherapy, radiation, or vaccine. They were all transplantable lines, so we never found a cure. I was at Berkeley at the time and trying to take it to clinic was [difficult because] there were no patients and there was no hospital. This was in 1995, when the biotech revolution was starting and there were not a lot of outlets for it.

I went to Big Pharma and to several biotech companies, and they all said it was interesting, but that immunotherapy doesn’t work. I said, ‘But it does work, you moron.’ If somebody wanted to challenge my data and give an alternative explanation, [that would have been fine], but nobody did that. People did not challenge the data; they just challenged the whole notion of immunotherapy. I thought, how can you say that if you do not try it? This is mechanism based. I never thought it would not work, I just thought there was a significant chance I would not be able to convince anybody to take a chance on it.

It took 3 years going around from company to company. Finally, a friend of mine had a mouse model where they replaced the mouse genes with human immunoglobulin genes, and they could immediately make a human antibody ready to go to the clinic. They did not have any application, so it was perfect that we came together.

After that, it all happened quickly. We made an antibody in no time and went to the clinic. In 1 of the phase 1/2 trials, out of 14 patients, 3 had objective responses, and 1 of them is still alive 20 years later. Again, I never doubted that it would work. To the best of our ability, I was convinced it would work. I was worried there may be adverse effects, and a lot of other stuff, but I thought the principle was sound because it was based on mechanism. The thing that depressed me after a while was just that nobody would listen.

Aside from ipilimumab, what clinical changes or impacts have manifested as a result of your findings?

One of the things that happened was the demonstration that PD-1 is a checkpoint. Before it was thought to be a molecule that played a role in negative selection of T cells in the thymus. As our phase 1 data was coming out, the question then was, why just 20% in melanoma? There are some mechanistic explanations, but the more interesting scientific explanation was that maybe there were other checkpoints, because CTLA-4 was the first. Sure enough, [I and others worked to show that] PD-1 was [a checkpoint] too. The term is used loosely now, but it has really put immuno-oncology on the map. [We now realize that] immunotherapy is not voodoo. It is the 4th pillar of cancer therapy now and needs to be recognized that way.

It can be curative. We need to work harder to understand how to combine all the riches that we have, [including] the new molecules and combinations with more conventional therapies. I have been amazed at the magnitude of immuno-oncology these days. If we do it right, and pay attention to science, hopefully we are going to be curing a lot more patients with cancer.

MD Anderson's Moon Shots program launched in 2012 and brought you back to the institution. What are the significant changes that you have seen with this program in the past 10 years?

That was started by Ronald DePinho, MD, and the idea was to build teams to capture the low hanging fruit and make rapid advances as a way of showing that we could do something about cancer. It has been reasonably successful here and they have widened it now. There is a glioblastoma Moon Shot and a pancreatic Moon Shot, so it has expanded, and they have provided money for building teams. It is still quite a force here [in terms of] getting people together to approach the cancers as a unit rather than just individuals.

How did the perspective of not only being a cancer survivor, but having lost family members to cancer affect your research? Was there a heightened sense of urgency?

There was a lot of urgency in the early days of ipilimumab when we finally got the antibody made and were in the clinic. I was trying to hurry it along because my brother had metastatic castration-resistant prostate cancer and I was hoping that we might be able to treat him. I learned that there is only so fast you can go, and we did not get there early enough. It certainly made me appreciate doing [my] work efficiently, trying not to waste time doing silly things, and trying to make everything as science-based and mechanism-based as we can. Speed is important, but not as important as getting it right.

You have also been named a Giants of Cancer Care® award winner. What does it mean to you to be recognized as a pioneer in the field of oncology by your colleagues?

It was pretty amazing. I was quite honored and surprised because I consider myself like a basic immunologist. I have always had cancer in the back of my mind but did not wake up every day thinking about curing cancer. Now I do, but back then [I did not]. I appreciate the award. The Giants of Cancer Care® [is a big deal], and something [huge] for basic scientists.

What has been your proudest personal moment and your proudest professional moment?

My proudest professional moment perhaps was being at ASCO when the first registration trial for ipilimumab was presented. That may be both personal and professional because I realized [everything had] been worth it. This is here now, and is treating people, and it is going to help a lot of patients. I did not know what it was going to mean, but just seeing the presentation and everybody just going nuts [was special]. I was told, and I do not know if it was true or not, that it was the biggest session at ASCO ever. This was a curative therapy, and it was going to change everything. I was in the middle of it, both in awe and so happy.

I had started going to ASCO a few years before, and immunologists would meet in small rooms. Now it is the opposite. At AACR one year I spoke to 12,000 people, and it was amazing. It was a big change from 5 years earlier, where it would be 50 or 75 [people].