The story behind the development of immune checkpoint inhibitors, fulfilling the promise of cancer immunotherapy
Work described in this story was made possible in part by federal funding supported by taxpayers. At Harvard Medical School, the future of efforts like this — done in service to humanity — now hangs in the balance due to the government’s decision to terminate large numbers of federally funded grants and contracts across Harvard University.
In the 1990s, a series of discoveries paved the way for a new type of cancer treatment — one that harnesses the body’s own immune system to fight cancer.
Cancer immunotherapies have transformed cancer care and extended the lives of millions of patients. Immune checkpoint inhibitors — a form of cancer immunotherapy that is now FDA-approved for the treatment of more than 25 cancer types — began with science conducted in labs at Harvard Medical School and Dana-Farber Cancer Institute.
Married for 47 years, and scientific collaborators for about as long, Arlene Sharpe, chair of the HMS Department of Immunology and Kolokotrones University Professor, and Gordon Freeman, HMS professor of medicine at Dana-Farber, have dedicated their careers to unraveling the mysteries of the immune system and fulfilling the long-elusive promise of cancer immunotherapy. In the early 2000s, Sharpe and Freeman, along with their colleagues, achieved a breakthrough: They discovered that some cancers could evade detection and destruction by the body’s immune defenses by subverting an immune pathway called PD-1/PD-L1. The researchers found that by blocking or genetically deleting either of the two molecules, PD-1 or PD-L1, and the interaction between them, they could enhance T-cell immune activity. This could restore the body’s ability to find and vanquish tumors in animal models.
But questions remained. Could the panoply of new insights about the PD-1/PD-L1 pathway help researchers develop safe and effective new therapies for cancer patients? Scientists at multiple biopharmaceutical companies built on these critical insights in search for answers.
One of those scientists was Ira Mellman, then vice president of cancer immunology at Genentech. He led a group charged with the design of anti-PD-1 and anti-PD-L1 therapies for cancer that restore the immune system’s ability to spot and destroy tumors. Mellman’s team developed Genentech’s anti-PD-L1 antibody, preparing it for clinical trials and, ultimately, helping to bring the drug, now known as Tecentriq, to FDA approval in the United States.
“Almost right out of the gate, in phase 1a trials, we saw results,” Mellman recalled. “I know now, having done drug discovery for 17 years, you hardly ever see that. And, when you do see that, you go for it.”
Today, immune checkpoint inhibitors have dramatically expanded the options for cancer patients. For people with melanoma, these medicines have radically changed outcomes. Before these therapies, few people survived metastatic melanoma for more than two years. But in a recent long-term follow-up of clinical trials, about half of patients with advanced melanoma who were treated with a combination of checkpoint inhibitors were still alive after 10 years.
In this video, Sharpe, Freeman, and Mellman share the story behind these basic science discoveries that became a new class of therapies, transformed cancer treatment, and infused newfound energy and excitement into the field of cancer immunotherapy.