Adding to his already quite impressive list of honors and awards, the Lasker Foundation announced today that James P. Allison, Ph.D., director of CRI’s Scientific Advisory Council, is the 2015 winner of the prestigious Lasker-DeBakey Clinical Medical Research Award.
Named after the advertising executive and philanthropist Albert Lasker, husband of the fierce cancer advocate Mary Lasker, as well as medical pioneer Michael DeBakey, the Lasker-DeBakey Award recognizes scientists whose basic discoveries have improved the clinical treatment of patients. Dr. Allison is being recognized specifically for his contributions to the development of a powerful new form of cancer therapy known as immune checkpoint blockade. Often likened to “taking the brakes off” the immune system, checkpoint blockade is a way to enhance the natural power of the immune system to fight cancer.
“Jim Allison’s work on checkpoint blockade created a whole new approach for cancer immunotherapy, one that is radically improving—and in many cases saving—the lives of people with cancer.”
— Jill O'Donnell-Tormey, Ph.D.
Dr. Allison, a professor and chair of the department of immunology at The University of Texas MD Anderson Cancer Center, is effectively the father of this new approach. He was the first to show that blocking the activity of a molecule called CTLA-4, found on T cells, could cause tumor rejection in mice. The paper, published in 1996 in the journal Science, confirmed that CTLA-4 is a negative regulator of T cell function—operating as an immune system “brake,” or checkpoint—and showed that checkpoint blockade could be an effective form of cancer treatment.
This work led to the creation of the first checkpoint inhibitor, ipilimumab (Yervoy®), which was the first drug ever to show a survival advantage in patients with advanced melanoma, and was approved by the FDA in 2011. Since then, several other checkpoint inhibitors have come into use including nivolumab (Opdivo®) and pembrolizumab (Keytruda®), which target other immune checkpoints. Collectively, these drugs have produced some of the most dramatic clinical responses ever seen, in a range of different cancers, and are widely credited with having launched a new era in cancer immunology. Fittingly, in 2013, Science magazine named cancer immunotherapy the “breakthrough of the year,” citing Allison’s work in particular.
“It is no exaggeration to say that the recent field of cancer immunology can be divided two eras: before CTLA-4 and after,” said Jill O’Donnell-Tormey, CEO and director of scientific affairs at CRI. “Jim Allison’s work on checkpoint blockade created a whole new approach for cancer immunotherapy, one that is radically improving—and in many cases saving—the lives of people with cancer.”
From Gas Pedals to Brakes
The road to checkpoint blockade therapy was neither direct nor easy. CTLA-4 was first identified in the late 1980s. At that time, it was clear that T cells required two signals to properly activate them: one signal, from the T cell receptor, functions like an ignition switch, turning the T cell on; a second signal, from a molecule called CD28, functions like a gas pedal, telling it to “go.” Based on genetic similarity (homology) to CD28, many people believed CTLA-4 to be a second “costimulatory signal”—another gas pedal. But Allison had a different idea. Experiments that he and a grad student, Matthew Krummel, Ph.D. (CRI Investigator, 2004-2008), were conducting at UC-Berkeley in the early 1990s suggested that CTLA-4 operated in an opposing fashion to CD28—as a brake, not a gas pedal. And by releasing this brake, Allison hypothesized, perhaps the immune system could be unleashed to fight cancer.
The idea was widely dismissed at time. “The hunt was on for proteins that turned on the immune system,” said Phil D. Greenberg, M.D., head of immunology at Fred Hutchinson Cancer Center and member of CRI’s Scientific Advisory Council. “People weren’t thinking about signals that inhibited it.” Even after showing that his hypothesis was correct, Allison had a hard time interesting companies in the molecule. But eventually the idea took hold. A small company called Medarex (later purchased by Bristol-Myers Squibb) was the first to get in on the action. Now companies can’t wait to jump on the immunotherapy bandwagon, and analysts predict that immunotherapy will be the backbone of cancer treatment for the majority of cancers in the coming years.
In addition to its direct clinical relevance, Allison’s work also helps to make sense of some of the past failures of cancer immunotherapies to realize their full potential. In particular, it shows why therapeutic cancer vaccines focused on stimulating an immune response to cancer do not usually provide robust clinical benefit to patients. The immune system has natural brakes that keep these immune responses in check. To fully take advantage of immunotherapies, it’s necessary to release the immune system’s brakes.
Former Coley Award Winner and CRI Grantee
Dr. Allison has deep and lasting connections with the Cancer Research Institute. He became director of CRI’s Scientific Advisory Council in 2011, succeeding longtime director Lloyd J. Old, M.D. Dr. Allison received CRI’s top scientific honor, the William B. Coley Award for Distinguished Research in Basic and Tumor Immunology, in 2005, for his work on CTLA-4. Dr. Allison joins the list of other past Coley Award recipients who have since gone on to receive major scientific awards, underscoring the Coley Award selection committee’s foresight and the award’s significance as a predictor of future recognition by others outside the fields of immunology or tumor immunology.
CRI began funding research in Dr. Allison’s lab in 1992. The first grant was awarded to Dr. Fiona Harding, a postdoctoral fellow, to study the role of CD28 in T cell activation. He has since mentored six CRI postdoctoral fellows, on topics like CTLA-4, PD-1, and new checkpoint proteins B7-H3 and B7x. His most recent support from CRI is the CRI-SU2C Cancer Immunology Translational Research Dream Team award, a $10 million grant to study immune checkpoint inhibitors and adoptive T cell transfer in numerous cancers.
Dr. Allison is the recipient of many previous awards and honors for his work, including the 2014 Canada Gairdner Award, the inaugural AACR-CRI Lloyd J. Old Award in Cancer Immunology in 2013, the 2013 Innovations Award for Bioscience from The Economist magazine, the 2014 Breakthrough Prize in Life Sciences, and the 2014 Szent-Györgyi Prize. The Lasker is particularly exciting because it is widely considered a stepping stone to a Nobel Prize. Eighty-six Lasker awardees have received the Nobel Prize, including 44 in the last three decades. For that reason, the Lasker is often thought of as the “American Nobel.”
We congratulate Dr. Allison on his superlative achievement!
You can read an interview with Dr. Allison, “The Texas T Cell Mechanic,” on the Cancer Research Institute website.