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December 21, 2017

Meet the Scientist Who Helped Discover a Class of Potent Cancer Drugs

Unexpected Research Results Change Immunology Paradigms

Meet the Scientist Who Helped Discover a Class of Potent Cancer Drugs

Dr. Bluestone encouraged co-workers at the Parker Institute for Cancer Immunotherapy to participate in the 2017 March for Science. Featured here are Dr. Bluestone, his wife, and several co-workers in matching T-shirts and holding signs for the march.

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    Dr. Bluestone speaks at the Parker Institute for Cancer Immunotherapy.

    The time was the early 1990s, and scientists were racing to discover how T cells become activated. They knew the structure of the T cell receptor and that binding with the cell surface protein CD28 switched T cells on. But they were missing a piece—they didn’t know yet that T cells could be switched off, or blocked from ever turning on. Once uncovered, that key detail would introduce a new class of potent cancer drugs called immune checkpoint inhibitors, which harness the immune system to combat cancer.

    One scientist who played a pivotal role in this discovery was Jeffrey Bluestone, Ph.D., who is president and CEO of the Parker Institute for Cancer Immunotherapy in California and A.W. and Mary Margaret Clausen Distinguished Professor of Metabolism and Endocrinology at the University of California, San Francisco. He has become renowned for his contributions to the field of immunomodulation, and was shortlisted for the Nobel Prize in 2016 and again in 2017

  • Getting His Start

    “I was interested in science from a pretty young age, you know, with the rock collections, blowing things up in the basement. That kind of stuff,” says Jeffrey Bluestone, PhD, chuckling softly. “But I really started getting pretty excited about science when I was a senior in college.”

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    Dr. Jeffrey Bluestone

    During the 1970s, he attended Cook College, a part of Rutgers University in New Jersey, and majored in biology, graduating with high honors. During his senior year, he worked with a faculty member on what he thought was a small project at the time. The project turned out to be much more significant, as the molecule of interest was a calcium-binding protein that was later known as calmodulin.

    At that time, he says he didn’t think he had what it took to be a scientist. “Bob Cousins, who was my mentor then, was great at being able to instill in me a sense of confidence that I could actually make it in some field of science. I was young, impressionable—and so, that has lasted with me for decades.”

    He went on to complete a master’s program in microbiology at Rutgers and earn his Ph.D. in medical sciences in 1980 at Cornell University (Sloan Kettering Division) in New York City. For his post-doctoral work, he went to the National Cancer Institute campus at the National Institutes of Health (NIH) in Bethesda, Maryland. It was there that he started working on organ transplantation. He spent those early days growing individual T-cell clones, attempting to understand the basis for their recognition of foreign tissue and how that could inform the production of a tolerogenic drug.

    Dr. Bluestone says it was during his time at the NIH that he became “totally convinced” that for all immunological diseases, whether it be cancer, autoimmunity, or transplantation, the T cell was going to be the cell that dictated an appropriate immune response. His work on T cells has since touched a breadth of areas, from diabetes to organ transplantation to cancer.

    “When I left the NIH in ‘87 to go to the University of Chicago, my goal then really was to try to understand what were the core signals that decided whether a T cell got turned on or turned off during an immune response,” he says.

  • CTLA-4: A New Paradigm

    Once at the University of Chicago, Dr. Bluestone and several others were working to understand T-cell activation. At the time, CD28 was the paradigm for how the T cell became activated and was the focus of much attention.

    “People were looking for other molecules that could substitute for, or amplify, the CD28 effect,” he says. His lab, like others, were making antibodies against cell surface molecules that might play a role in T-cell activation, and among the antibodies his lab made were those targeting CTLA-4, a protein receptor that decorates the surface of T cells.

    At the time, researchers knew that the structure of CTLA-4 was similar to that of CD28 and bound the same molecules on antigen-presenting cells. The evidence suggested CTLA-4 was a sister molecule of CD28 and that it switched T cells on.

    But when Theresa Walunas, a graduate student in Dr. Bluestone’s lab, created and tested the CTLA-4 antibody, the T cells unexpectedly became activated, implying CTLA-4 was a negative regulator.

    “That was so outside of the dogma,” Dr. Bluestone says about the finding. “Everything led people, including myself and others, to think CTLA-4 must be another costimulatory molecule, so this result was just wacky.”

    Now it became clear that when CTLA-4 bound its ligand, the T cell turned off and the immune response halted. When CTLA-4 was unbound, the immune response ramped up and boosted immunity.

    When Dr. Bluestone revealed this finding, the field initially resisted. It didn’t fit the current model of understanding.

    “It was very controversial for what I thought was a pretty important observation. We had a hard time getting it published, and I don’t think it was because the data were bad. I think the data were actually good,” says Dr. Bluestone. “I think it was because the community just didn’t buy it, partly because there were some other papers that had different results, but mostly because the dogma in the field was not consistent with our observations.”

    The paper was eventually accepted and published in 1994 in the journal Immunity.

    Long-time colleague and fellow immunologist Fred Ramsdell, Ph.D., vice president of research at the Parker Institute for Cancer Immunotherapy, recalls the reaction to the discovery that CTLA-4 is a negative regulator of T-cell activation.

    “It really was a new paradigm,” Dr. Ramsdell noted. He says the concept of inhibitory receptors on the T cell, like CTLA-4, was challenging for people to understand at the time because it wasn’t a common concept.

    “Jeff was at the forefront, along with others, [of] identifying this as a negative regulator of T-cell responses,” echoed another long-time colleague, Laurence Turka, M.D., who is co-director of the Center for Transplantation Sciences at Massachusetts General Hospital.

    One of the other key scientists in the field was James Allison, Ph.D., who was at the University of California, Berkeley at that time. In 1996, Dr. Allison published a paper that showed blocking CTLA-4 inhibited tumor growth in mice. Now, he is recognized as being a part of the discovery that CTLA-4 negatively regulates T-cell activation. Another scientist was Craig Thompson, M.D., who, at the time, was a colleague of Dr. Bluestone at the University of Chicago. Dr. Thompson was also working to understand T-cell activation, but he was focused on studying the role of CD28.

    “Overall, that whole field was really new,” says Roli Khattri, Ph.D., who was a post-doctoral student in Dr. Bluestone’s lab at the time and recalls the contributions from Drs. Allison and Thompson. Dr. Khattri is now director of pharmacology at Celgene. “A lot of the cutting-edge work happened out of Jeff’s lab, so it was very exciting to me.”

    “I don’t think I would have expected going into this field that the T cells would have been such a complex control system for activation,” says Dr. Bluestone. “Since then, it’s been spectacular what’s happened for patients.”

    The first immune checkpoint inhibition therapy that came from this work was a CTLA-4 inhibitor called Yervoy® (ipilimumab). The FDA approved ipilimumab in 2011 for melanoma, and for a portion of metastatic melanoma patients, this immunotherapy has extended the survival rate from months to years. Since then, other big-name immune checkpoint inhibitors, namely Keytruda® (pembrolizumab) and Opdivo® (nivolumab), have been approved for use in patients for certain types of cancer. 

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