How a Rebellious Scientist Helped Launch the Modern Age of Immunotherapy

OncologyLive, July 2015, Volume 16, Issue 7

James P. Allison, PhD, was honored in the Scientific Advances category with a 2014 Giants of Cancer Care® award, a program that the Intellisphere® Oncology Specialty Group launched to honor leaders in the field.

James P. Allison, PhD

James P. Allison, PhD, has never hesitated to buck the system. As a teenager, the pioneering oncology researcher refused to take biology at his small-town Texas high school because the theory of evolution had been omitted from lessons for religious reasons. Instead, Allison took a university correspondence course, working alone in an empty classroom.

“I’d already decided that I wanted to be either a doctor or a scientist, and I knew that Darwin is to biology as Newton is to physics, so I refused to take the course. It got me into trouble with some of the teachers,” said Allison, who went on to earn a doctorate in biological science and launch a nearly 40-year career dedicated to stimulating the human immune system to fight cancer. In November 2012, he left several leadership positions at Memorial Sloan Kettering Cancer Center in New York to step into the chairmanship of the Department of Immunology at The University of Texas MD Anderson Cancer Center.

Allison’s readiness to challenge the status quo has never left him. It certainly showed itself as he made discoveries about the workings of T cells, which help protect the body from pathogens. Spurred also by personal and familial experience with cancer, Allison was willing to probe his theories even amid skepticism in the scientific community.

A case in point emerged when Allison began to suspect that the molecule CTLA-4 (cytotoxic T-lymphocyte- associated antigen 4) inhibited antibody response. He weighed that idea in the face of theories to the contrary: in textbooks, CTLA-4 had been categorized as a molecule that stimulated immune response.

Allison pursued his idea anyway. The result was ipilimumab (Yervoy), which was approved by the FDA on March 25, 2011, as a treatment for unresectable or metastatic melanoma.

Allison’s years of work on that project reaffirmed his guiding philosophy.

“Let your mind lead,” advised Allison, a member of the National Academy of Sciences and the Institute of Medicine who in his free time enjoys playing blues harmonica and sailing. “Don’t pay attention to conventional wisdom if you’ve got data that show otherwise.

Sometimes it’s hard to go against the system, but you have to do it if something needs to be accepted.” Over the years, Allison’s discoveries have led not only to ipilimumab, but also to a growing interest within the scientific community in creating other immune checkpoint modulators for antitumor therapy.

Another research group has developed nivolumab (Opdivo), which works by blocking an inhibitory molecule known as programmed death-1 (PD-1).

The FDA approved nivolumab as a treatment for patients with unresectable or metastatic melanoma in December 2014 and then expanded its indication into metastatic squamous non—small cell lung cancer less than 3 months later. And researchers reported in June that combining ipilimumab and nivolumab more than tripled median progression-free survival compared with ipilimumab alone (11.5 mo vs 2.9 mo) in a phase III trial among patients with stage III/IV melanoma.

For developing ipilimumab and sparking the burgeoning field of modulating immune checkpoints for antitumor therapy, Allison has been chosen by OncLive to receive one of its Giants of Cancer Care® awards for 2014, in the area of Scientific Advances.

“Winning the Giants of Cancer Care award meant a lot to me,” Allison said. “For a basic scientist to be acknowledged by an award for cancer care is really fulfilling and amazing to me. For a while, I was considered an ivory-tower, pointy-headed intellectual pursuing these arcane ideas about immunology. I think this gives basic scientists credibility in the cancer-care community.”

The Approval of Ipilimumab

The drug that started it all, ipilimumab, is an antibody that targets CTLA-4, a molecule on the immune system’s T cells that impedes their ability to fight cancer. Once stimulated, T cells can protect the body from disease by attacking alien proteins, or antigens, such as tumor cells. Normally, after a time, that attack is halted by CTLA-4, even though dangerous cells may remain. Ipilimumab is designed to eliminate CTLA-4’s “stop” message, so that T cells can continue to fight indefinitely.

Administered intravenously, ipilimumab, also known as CTLA-4 blockade, works best if an anticancer therapy—such as radiation, chemotherapy, freezing, or targeted therapy—is first used to stimulate T cells to go on the attack, Allison said. Once that has been accomplished, the scientist said, the drug could be widely useful.

“You’re treating the immune system, not the cancer, so it can be used, potentially, against every kind of cancer,” he explained.

Exploring New Applications for Ipilimumab Now that ipilimumab is a standard of care for melanoma, it is being explored for the treatment of additional stages of the disease—such as completely resected stage III melanoma—and in other cancers, including metastatic renal cell carcinoma, breast cancer, and metastatic castration-resistant prostate cancer. Allison looks forward to the drug being tested in diseases such as glioblastoma and pancreatic cancer, which have been “resistant to traditional treatments,” he said.

Numerous studies also are being conducted to test combinations of ipilimumab and other agents—although that process should be made easier, Allison said, through the removal of some of the economic and political barriers involved in including two drugs made by different companies in a single clinical trial.

While Allison told OncologyLive in 2011 that many scientists were still resistant to the idea that immunotherapy could work in cancer, the concept has been gaining speed ever since. That same year, in fact, the National Institutes of Health created its Cancer Immunotherapy Trials Network, a collaboration between academia, industry, and philanthropic organizations that is helping 27 research sites across North America to develop immunotherapeutic anticancer agents that have been discovered but not yet approved for use in patients.

Cancer Has Taken a Personal Toll

For Allison, all of that progress is meaningful on more than a professional level. Like the patients he’s dedicated to helping, the scientist and family man has lost much to cancer.

When Allison was 10, his mother died of lymphoma. Two of her brothers also succumbed to cancers, one to melanoma and the other to lung cancer. Then, 6 years ago, Allison’s brother died of prostate cancer, around the same time that Allison underwent a prostatectomy as he fought the disease himself.

The scientist was in graduate school at The University of Texas at Austin when he vowed to investigate treatments for cancer.

“I just thought, ‘This is a terrible thing, and there’s got to be a better way than chemotherapy and radiation,’ which my mother and one of my uncles had,” Allison said. “I saw all the negative effects.”

In 1982, Allison was working at The University of Texas System Cancer Center when his research sparked a discovery that has been at the heart of his work ever since: he became the first scientist to figure out how T cells recognize alien proteins within the body.

“We [identified] the antigen receptor on T cells,” Allison said. “That was important because it’s like the ignition switch on T cells, the thing that recognizes peptide or bacterial protein or tumor antigens.”

Six years later, at the University of California, Berkeley, Allison was working among researchers who realized that T cells needed to do more than recognize invading pathogens to start their attack. They needed a costimulatory signal, another molecule, to act as a gas pedal and make them go. Allison’s group determined that the costimulatory molecule was CD28.

The final piece of the puzzle fell into place in 1996, when Allison and his fellow researchers noticed a gene that was structurally similar to CD28—CTLA-4— and started experimenting to see what it did.

“We found that if you delete CTLA-4, the T cells keep dividing. It’s like you take the brakes off going downhill and can’t stop,” Allison said. “So I thought, ‘Maybe this molecule shuts down T cells and keeps you from getting a strong enough immune response to deal with a tumor, and maybe if we block that molecule we can get the immune system to kill cancer cells and not cause side effects in mice.’ And that’s exactly what we found. With many tumors, injecting this one molecule was enough to get a tumor rejected.”

Coming Full Circle

By moving recently to his posts at MD Anderson, Allison was, in a way, returning to his roots. A native of Alice, Texas, where his father was a country doctor, Allison earned his bachelor’s degree in microbiology and his doctorate in biological sciences from The University of Texas at Austin. After his postdoctoral fellowship at Scripps Clinic and Research Foundation in California, Allison’s first faculty appointment was at MD Anderson’s Science Park—Research Division in Smithville, Texas, for 8 years.

Allison next moved to the University of California, Berkeley, where he was a professor in the Division of Immunology and director of the Cancer Research Laboratory. Then, in 2004, he moved again—this time to Memorial Sloan Kettering Cancer Center, where he took on roles as the David H. Koch Chair in Immunologic Studies, director of the Ludwig Center for Cancer Immunotherapy, and attending immunologist in the Department of Medicine.

v MSK was among the 150 sites where clinical trials of ipilimumab were being conducted. There, Allison was able to analyze the immune responses of study participants to help predict which categories of patients would most likely benefit from ipilimumab, and under what circumstances.

That work also helped Allison hatch ideas for second-generation drugs.

“As I saw my drug developing, I wanted to be a part of it,” he said. “I wanted to learn more about what went on in the clinic and to offer advice, because this was a totally new concept. You can’t approach it the same way you would if you were giving a drug that will go into a tumor cell and kill it.”

Three years ago, Allison landed at MD Anderson with the help of a $10 million scientific recruitment grant for established investigators given by the Cancer Prevention and Research Institute of Texas.

He plays an instrumental role in MD Anderson’s relatively new Moon Shots Program, aimed at dramatically accelerating the pace of the conversion of scientific discoveries into clinical advances that reduce cancer deaths. The program is designed to attract philanthropic funding to expedite efforts already under way to develop new treatments to improve patient survival, reduce complications, and enhance survivorship and quality of life, according to the institution’s website.

“The main reason for coming to MD Anderson is the opportunity offered by a clinical community that’s open to using immunological approaches to treat cancer combined with other therapies,” Allison said when his role there was announced.

“We plan to build a large platform where basic scientists interested in mouse models of cancer work side by side with physician-scientists who treat patients to analyze tissues from those patients and truly understand the mechanisms involved,” Allison said.

“We can accelerate the transition of new combinations of drugs into the clinic beyond phase I clinical trials and broaden our focus beyond melanoma and prostate cancer to other types of cancer.”

“We all know that no single drug will cure cancer,” he added. “I think this is where we’ll start getting cures, or at least long-term survival of patients. There’s lots of enthusiasm for this approach at MD Anderson, and I’m really excited about it.”

A particular goal for Allison in the years ahead is to further increase the percentage of patients who are able to gain long-term survival from immune checkpoint drugs.

“In the past, we’ve focused on moving median survival over a few months, and that’s been sufficient to get drugs approved,” he said. “What we know from immunological studies is that you can do that, but you also get a tail of the curve: After a certain point, a fraction of patients with melanoma—20%—have durable responses that can last a decade. So the median looks like a few months, but that 20% could be considered cured.

“By combining these [types of medications], you can move that [group of patients who have durable responses] to 40% or 50%, so my goal is to raise the tail of the survival curves to as close to 100% as we can get them, and to extend these therapies to as many different types of cancer as we can, because there’s no reason immunotherapy won’t work against many different types of cancer, if not all,” said Allison.

Along with that should come a new paradigm for measuring the efficacy of drugs and registering them that would move more quickly than the typical 5 years it takes to track overall survival in clinical trials, Allison added.

Also ahead is a potential opportunity for Allison to help shape the scientific talent of the future.

In December 2013, Allison’s work earned him the Breakthrough Prize in Life Sciences—given by a group of American entrepreneurs including Facebook CEO Mark Zuckerberg—which came with a $3 million award.

As a potential use for part of that award, Allison was considering launching a program for high school students and college undergraduates designed to foster their interest in biomedicine, MD Anderson said in a press release at the time.

If that happens, those students might someday know the rush Allison experiences whenever he makes a discovery—the thrill that drew him to science in the first place.

“I enjoy the feeling,” he said, “of being the first one on the planet to figure something out.”

“A Lasting Legacy of Accomplishment”

Howard L. Kaufman, MD, FACS Associate Director for Clinical Sciences

Rutgers Cancer Institute of New Jersey

New Brunswick, NJ

“James Allison’s groundbreaking work on the regulation of T-cell activation, and his elucidation of how T-cell checkpoints can be used as therapeutic targets, has revolutionized our understanding of T-cell biology and ushered in the modern era in tumor immunotherapy.

“His work has led to a major paradigm shift in the treatment of cancer with the potential to impact millions of patients. In addition to his research, Dr Allison has been a generous contributor to the development of the next generation of immunology investigators. His mentorship and leadership in the field have been exemplary and he will leave a lasting legacy of accomplishment for his students, colleagues, patients, and humanity.”

Antoni Ribas, MD, PhD

Professor, Department of Medicine, Hematology/Oncology

UCLA/Jonsson Comprehensive Cancer Center Los Angeles, CA

“Dr James Allison is responsible for one of the key advances in the fight against cancer, the use of immune checkpoint inhibitors that are resulting in unprecedented rates of durable tumor responses in patients with different cancers. The field of immunotherapy for cancer had not made significant progress for over 100 years after initial—mostly anecdotal—observations that some cancers may respond to an immune-activating treatment. Dr Allison, by studying the mechanisms of how T cells recognize cancer and what is required for their adequate activation, had the paradigm-shifting idea that what was needed was to release the checkpoints that were limiting an immune response to cancer, as opposed to the prior attempts to turn on an immune response.

“His studies testing this approach in preclinical models led to the clinical development of the first treatment that improved survival in patients with metastatic melanoma, the cytotoxic T-lymphocyte associated antigen-4 (CTLA-4)-blocking antibody ipilimumab, and the subsequent development of a series of blocking antibodies to other checkpoints, most notably the ones blocking the programmed death receptor-1 (PD-1). These antibodies unleash an effective immune response to metastatic cancers and lead to long-term remissions. With ipilimumab, patients with metastatic melanoma continue to respond for more than a decade after receiving the antibody and are probably cured of an otherwise deadly cancer.

“Dr Allison’s work continues to be at the forefront of the field by studying how to combine checkpoint inhibitors and other cancer therapies, and how T cells recognize and kill cancers. He is also a recognized leader in policies and programs advancing immunotherapy for cancer and has mentored a long list of successful investigators.”

Dr. Allison's Selected Papers

  • Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell. 2015;161(2):205-214.
  • Veenstra RG, Flynn R, Kreymborg K, et al. B7-H3 expression in donor T cells and host cells negatively regulates acute graft-versus-host disease lethality [published online March 26, 2015]. Blood. 2015;125(21):3335-3346.
  • Gubin MM, Zhang X, Schuster H, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature. 2014;515(7528):577-581.
  • Tang C, Wang X, Soh H, et al. Combining radiation and immunotherapy: a new systemic therapy for solid tumors? Cancer Immunol Res. 2014;2(9):831-838.
  • Holmgaard RB, Zamarin D, Munn DH, et al. Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4 [published online June 10, 2013]. J Exp Med. 2013;210(7):1389-1402.
  • Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366(10):925-931.
  • Balachandran VP, Cavnar MJ, Zeng S, et al. Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nat Med. 2011;17(9):1094-1000.
  • Callahan MK, Wolchok JD, Allison JP. Anti-CTLA-4 antibody therapy: immune monitoring during clinical development of a novel immunotherapy. Semin Oncol. 2010;37(5):473-484.
  • Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors [published online February 16, 2010]. Proc Natl Acad Sci U S A. 2010;107(9):4275-4280.
  • Cheever MA, Allison JP, Ferris AS, et al. The prioritization of cancer antigens: a National Cancer Institute pilot project for the acceleration of translational research. Clin Cancer Res. 2009;15(17):5323-5237.
  • Peggs KS, Quezada SA, Allison JP. Cancer immunotherapy: co-stimulatory agonists and co-inhibitory antagonists [published online February 18, 2009]. Clin Exp Immunol. 2009;157(1):9-19.
  • Segal NH, Parsons DW, Peggs KS, et al. Epitope landscape in breast and colorectal cancer. Cancer Res. 2008;68(3): 889-892.