Jay Berzofsky in his home library, 2022.
Jay Berzofsky, M.D., Ph.D., who pioneered several major cancer immunology and immunotherapy treatment strategies, including vaccines that target neo-epitopes, is announcing his retirement after 50 years at NIH.
As an undergraduate at Harvard University, Berzofsky was drawn to organic chemistry, graduating with a bachelor’s degree in chemistry in 1967. He then enrolled in a dual M.D./Ph.D. program at the Albert Einstein College of Medicine, where his doctoral work focused on protein chemistry and biophysics, followed by an internship in internal medicine at Massachusetts General Hospital and a research associateship with Alan N. Schechter, M.D., at the National Institute of Diabetes and Digestive and Kidney Diseases in 1974. Here, he began exploring protein folding and branched into immunology in a collaboration with David H. Sachs, M.D., exploring immune-response genes, which determine how an organism will respond to a particular antigen.
Berzofsky joined NCI as an Investigator in 1976 and earned tenure to become a Senior Investigator in 1979. At the NCI, his work with T-cell epitopes sparked his interest in vaccine design, which led him to investigate HIV, malaria and, ultimately, cancer vaccines. Berzofsky became Chief of the Vaccine Branch in 2003. In 2005, he and his collaborators published the seminal results of a clinical trial using customized peptide vaccines containing point mutations found in advanced cancer patients’ own tumor biopsies. His lab continued to explore avenues for cancer treatments including cytokine and regulatory cell control of T-cell function and avidity, natural killer T cells and synergistic therapies using both immunotherapy and cancer vaccines.
“Jay is one of the most logical and critical thinkers I have ever worked with,” says Robert Yarchoan, M.D., Chief of the HIV and AIDS Malignancy Branch and longtime colleague of Berzofsky. “On a number of occasions, I have seen him pick out subtle patterns in complex data that ultimately led to a deep understanding of underlying immunologic processes.”
Berzofsky is a member of the Association of American Physicians and a Fellow of the American Association for the Advancement of Sciences (AAAS). He was elected president of the American Society for Clinical Investigation, served as chair of the Medical Sciences Section for AAAS, and named Distinguished Alumnus of the Year for 2007 by the Albert Einstein College of Medicine. He received the NIH Director’s Award and the NCI Merit Award in 2008, another NCI Director’s Merit Award in 2011, and a Career Award “for his important contribution to tumor immunotherapy” from the European Academy of Tumor Immunology in 2018.
What has been the most surprising thing about your scientific career, and what scientific achievements are you most proud of?
I’ve been at the NIH for 50 years and it's gone by very quickly. In my earliest days at NCI, we were interested in antigenic epitopes — the parts of an antigen that are recognized by an immune molecule, like an antibody or a T-cell receptor. I got into a collaboration looking at the 3D structure of antibody epitopes because this was a protein chemistry question. We showed that what a lot of antibodies recognized was not a linear sequence of amino acids, but rather non-contiguous parts of the 3D protein structure brought together in the context of the folded protein. We called these “assembled topographic sites.”
I started a collaboration with Charles DeLisi, Ph.D., and John Minna, M.D., on T-cell epitopes and we came up with an idea on a way to predict epitopes recognized by T cells. That led us into vaccines, because we said if we can predict T-cell epitopes, then maybe we can design synthetic vaccines specific to that epitope, instead of the whole protein.
The goal of a cancer vaccine is to induce an immune response that rejects the cancer without harming the body's normal cells. You want to target an antigen that's unique to or over-expressed in cancer cells. I started collaborating again with John Minna, and David Carbone, M.D., Ph.D., in his lab. We looked at mutations in the oncogene RAS and in the tumor suppressor protein p53 and showed that T cells could distinguish mutation-containing proteins from normal proteins.
This led to a clinical trial involving patients whose cancer cells contained mutant RAS or mutant p53 and were immunized with their own mutant epitopes. We published this study in the Journal of Clinical Oncology in 2005 and it demonstrated that the patients who responded to the vaccine and elicited a T-cell response had a median overall survival more than a year longer than the ones who did not respond immunologically. For advanced cancer patients, a year longer survival is significant. It was really the first example of a successful clinical trial using what are now called neo-epitopes.
Another milestone involves low- and high-avidity T cells. Martha Alexander-Miller, Ph.D., was a postdoc in our lab who studied the functional avidity of T cells, which is how much antigen it takes to activate a T cell. She discovered, in mice, that we could raise either low-avidity or high-avidity T cells specific for the same MHC-peptide complex, in which protein fragments from pathogens are bound and presented to T cells. This turned out to be important for adoptive T-cell therapy, or cellular immunotherapy, where a patient’s T cells are collected, grown up in the lab and then given back to the patient to fight their cancer. We also developed an epitope enhancement by modifying the sequence to get higher affinity binding to the MHC molecule to make a more potent vaccine.
We have also been interested in the idea that cancer vaccines may not have been successful in the past because the tumor microenvironment is so immunosuppressive that the T cells you induced were inhibited at the tumor. We hypothesized that there could be synergy between blocking immunosuppression and cancer vaccines if the immunosuppression was preventing cancer vaccines from working.
How did the intramural environment of CCR and NIH help your research?
We could not have done what we did without a lot of collaborations. There are people here with expertise in all fields of biomedicine, many of whom have made the milestones in my lab possible.
I didn't get my Ph.D. in immunology — I got it in protein chemistry and biophysics, and now I'm writing chapters in immunology textbooks. I learned immunology on the job from a number of very talented experts in the field, including David H. Sachs, M.D., Gene Shearer, Ph.D., Ron Schwartz, M.D., and Ron Germain, M.D., Ph.D.
What are you looking forward to most in your retirement?
The most important thing is spending more time with family — we have to travel to see our kids and grandkids, and so we don't see them nearly as often as we would like. I’m also looking forward to taking some extended trips. We have friends who take a month or two to vacation somewhere, and I've never been able to take off that much time. This frees us up to travel and see parts of the world that we haven't been to.
I’m trying to improve my piano playing too. I’m a big Beethoven fan and I wish I could play more of his piano sonatas, because a lot of them are too difficult, although I play some Chopin modestly well. I’ve been trying to learn French since I was in high school, and I’d like to become more fluent in French, and do some gardening.
Dr. Jay A. Berzofsky will retire from CCR on December 31, 2024.