At this year’s annual oncology meetings, attended by thousands of the world’s leading cancer doctors, there was one clear stand-out star: a molecule called PD-1. Short for programmed cell death-1, PD-1 is an immune checkpoint protein, found on T cells, that acts to dampen immune responses. Drugs known as checkpoint inhibitors target and block this checkpoint, effectively “taking the brakes off” T cells, and in the process enabling a more powerful immune response against cancer. As shown in recent clinical trials, such drugs are an astonishingly effective way to treat an increasing number of cancers, including melanoma, lung, bladder, and kidney cancer.
For their collective contributions to the discovery of the PD-1 pathway, four individuals will share the 2014 William B. Coley Award for Distinguished Research in Tumor Immunology:
- Tasuku Honjo, M.D., Ph.D., of Kyoto University School of Medicine
- Lieping Chen, M.D., Ph.D., of Yale University School of Medicine
- Arlene Sharpe, M.D., Ph.D., of Harvard Medical School
- Gordon Freeman, Ph.D., of Harvard Medical School and the Dana-Farber Cancer Institute
In honoring these individuals with its top scientific award in tumor immunology, the Cancer Research Institute recognizes the immense benefit to patients, and to science, that the discovery of PD-1 as a new immune checkpoint represents.
“The discovery of PD-1 as a new immune checkpoint that can be exploited in cancer immunotherapy was a triumph of scientific collaboration, made possible by a continuum of research spanning more than a decade,” said Jill O’Donnell-Tormey, Ph.D., CEO and director of scientific affairs at CRI. “With PD-1 checkpoint inhibitors added to the therapeutic arsenal of combination therapies, we hope to see even bigger responses in more patients.”
The Road to PD-1
Back in the early 1990s, Tasuku Honjo (right) and his colleagues were looking to identify genes involved in programmed cell death, a natural process that is part of normal cellular housekeeping. Through a kind of genetic process of elimination, they identified a gene in cell culture lines that was required for normal programmed cell death. They named this gene, fittingly, programmed cell death-1 (PD-1). (For review, see Okazaki and Honjo, 2007.)
Despite the context of its discovery and its “death” moniker, the exact function of PD-1 remained elusive for several years. Clues to it biological function came in 1999 from genetic knock-out experiments in mice, where Honjo and colleagues disrupted the PD-1 gene and waited to see what would happen. Interestingly, about half of these mice developed a lupus-like syndrome, suggesting that PD-1 was somehow involved in negatively regulating immune function. Lupus is an auto-immune disorder caused by an over-reactive immune system that attacks normal cells.
Further clues to its function came from discovering the natural ligands for the PD-1 receptor, called PD-L1 and PD-L2—work that was accomplished by Arlene Sharpe and Gordon Freeman (pictured left) at Harvard, in collaboration with the Honjo lab, in 2000 and 2001. By identifying the signals needed to engage the PD-1 pathway, this work provided crucial tools with which to study the pathway and prove its role in negatively regulating T cell function. “Gordon and Arlene closed the loop,” said Jim Allison, who chaired the team of CRI scientists and former Coley Award winners who chose this year’s recipients.
In addition to confirming the immunosuppressive role of the PD-1 pathway, Sharpe and Freeman further noted that their newly identified ligands were found on some cancer cell lines, and suggested that the PD-1 pathway might play a role in tumor evasion of the immune system. “It is worth noting that PD-L1 and PD-L2 mRNA expression are up-regulated in a variety of tumor cell lines,” they noted in a 2001 Nature Immunology article. “These findings give impetus to the investigation of whether PD-L expression on tumors attenuates anti-tumor responses.”
Around the same time that Sharpe and Freeman were identifying the ligands for PD-1, Lieping Chen (pictured right), then of the Mayo Clinic and now of Yale University, was independently discovering PD-L1, which he called B7-H1 (Dong, 1999). Chen went on to make a strong link between B7-H1/PD-L1 and cancer. In 2002, he showed that multiple tumor types express B7-H1/PD-L1, and that PD-L1 on tumors can cause apoptosis (programmed cell death) of tumor-specific T cells. He further showed that antibodies directed against PD-L1 could lead to tumor rejection. “These findings have implications for the design of T cell–based cancer immunotherapy,” Chen and his colleagues wrote, with significant understatement, in a 2002 Nature Medicine article.
A New Drug
Researchers now know that many types of tumors express PD-L1. By activating the PD-1 pathway, tumor cells can effectively disarm the very T cells that might have gone on to kill them. In this way, cancer evades the immune system. From this basic understanding of how PD-1 functions in cancer, it was but a short intellectual leap to blocking this interaction with a drug.
The drug development work on the first anti-PD-1 molecule was accomplished principally by scientists at Medarex, a biotech company in California. Clinical trials of this molecule, an antibody called nivolumab, began in 2007 at several academic centers in the U.S. Medarex was acquired in 2009 by Bristol-Myers Squibb.
Numerous checkpoint inhibitors targeting PD-1 and PD-L1, from multiple companies, are now being tested in clinical trials, including pembrolizumab (Merck), MPDL3280A (Genentech), and MEDI4736 (MedImmune/AstraZeneca).
The concept of using immune checkpoint inhibitors in cancer therapy is not itself new. Jim Allison, Ph.D., director CRI’s Scientific Advisory Council, established the concept back in the mid-1990s, with his work on CTLA-4, the first recognized immune checkpoint, which led to the FDA approval of Yervoy® in 2011. What is new with PD-1 is the idea that cancer cells can “hijack” immune checkpoints as a means to ward off an impending immune attack.
Because PD-1 is activated mostly at sites of tumor or other areas of active immune attack, the side effects of anti-PD-1 therapy tend to be less severe than with anti-CTLA-4 antibodies, which potentially affect all circulating T cells in the body, and can therefore cause significant, though manageable, auto-immune side effects.
Anti-PD-1 therapy is being explored as monotherapy for a number of cancers, including melanoma, kidney, and lung, and the results so far have been impressive. Even more promising are clinical studies that combine checkpoint inhibitor antibodies. CRI’s clinical director, Jedd Wolchok, M.D., Ph.D., is a principal investigator of one such study, combining ipilumumab (anti-CTLA-4) and nivolumab (anti-PD-1) in patients with advanced melanoma. As reported at this year’s ASCO meeting, the 2-year overall survival rate for patients receiving the optimal dose combination of ipilimumab and nivolumab on this trial was 88%. “It doesn’t get better than that in metastatic melanoma,” said Jeffrey S. Weber, M.D., Ph.D., of Moffitt Cancer Center in his discussion of the results.
For their groundbreaking work that is revolutionizing cancer therapy today, CRI congratulates this year’s Coley Award winners. They join a prestigious group of scientific leaders in cancer immunology who have been previously recognized with the honor. CRI will bestow the awards at its annual gala taking place in October in New York City.
Taku Okazaki and Tasuku Honjo (2007) PD-1 and PD-1 ligands: from discovery to clinical application. International Immunology. 19(7):813-824.
Haidong Dong, Gefeng Zhu, Koji Tamada & Lieping Chen (1999) B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nature Medicine. 5(12) 1365-1369.
Gordon J. Freeman, Andrew J. Long, Yoshiko Iwaic, et al., (2000) Engagement of the Pd-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation. JEM. 192(7):1027-1034.
Yvette Latchman, Clive R.Wood, Tatyana Chernova, et al., (2001) PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nature Immunology. 2(3):261-268.
Haidong Dong, Scott E. Strome, Diva R. Salomao et al., (2002) Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion. Nature Medicine. 8(8):793-799.