Researcher Shares Personal Account of Immunotherapy Advances

About 30 years ago, cancer researcher Drew Pardoll had a revelation. He was treating bone marrow transplant patients who were at risk of developing graft-versus-host disease, a complication in which the T cells from the donor’s graft recognize the patient’s tissues as foreign and attack them.

Pardoll, director of cancer immunology at the Johns Hopkins Kimmel Cancer Center in Baltimore, said patients were often hospitalized for one to two months, but if they survived their GVHD, he was able to tell them their cancer may not recur because the T cells that caused GVHD also were attacking the patient’s tumor.“You could just see in front of your eyes what the immune system could do, and how powerful the immune system was, both for bad and for good,” he said, adding that he first believed then that the immune system could be used to treat cancer.Pardoll shared his personal account of advances in immunotherapy—a treatment that harnesses the body’s immune system to fight cancer—with participants in the Scientist↔Survivor Program at the American Association for Cancer Research (AACR) Annual Meeting 2015 on April 20 in Philadelphia. Early in his career, Pardoll sought to understand the immune system’s potential in killing cancer by studying basic immunology in a laboratory at the National Institute of Allergy and Infectious Diseases (NIAID). After becoming a faculty member at Johns Hopkins, he began to incorporate what he learned at NIAID into his cancer research.

 In the 1990s, he began to genetically engineer tumor cells in mice to produce immunologic factors that would attract dendritic cells, a type of immune cell that can activate T cells. He said that work had led him to develop the cancer vaccine GVAX, an immunotherapy that’s currently being tested in clinical trials for patients with pancreatic cancer, colorectal cancer and acute myeloid leukemia. At the time, he said, a frustrating and disappointing finding emerged from the GVAX trials he and his colleagues conducted.“We could see that we were activating T cells, immune responses by the vaccine against antigens in the tumor, but that was rarely translating to a clinical benefit in tumor regression,” he said.Pardoll said they began to understand that tumors create suppressive signals within their environments that turn off the activated T cells. These signals normally prevent the immune system from attacking the body, but tumors co-opt the body’s natural systems to protect themselves.“As we began to look at tumors with all the tools that molecular biology and genomics gave us, we began to find lots of these inhibitory pathways,” he said. “It was actually kind of scary. How can you get through this gauntlet if you’re a lonely T cell and you’re trying to get in and kill that tumor?”

In 2002, Pardoll and his colleagues became interested in one of the inhibitory pathways, or checkpoints, called PD-1 (programmed cell death-1). The team began working with a small biotech company to develop antibodies that work against PD-1. In 2006, clinical trials began at Johns Hopkins to test these antibodies on patients with melanoma, kidney, lung, colon and prostate cancer. Clinical trial results were dramatic and sustained for some patients, although not all, with melanoma, kidney cancer and lung cancer.Six companies have developed antibodies against PD-1 and its partner, PD-L1. Pardoll said PD-1 targeted drugs likely will be effective against 10 different cancer types.Just five years ago, he said, “Immunotherapy had been left for dead.” Today, it stands as a promising breakthrough in cancer treatment. Pardoll said he has trouble getting used to the mounting enthusiasm surrounding immunotherapy.

Above all, he says, he will always be amazed when a patient undergoing immunotherapy returns to the clinic and their tumor has shrunk.