Yale Cancer Center (YCC) scientist Lieping Chen, MD, PhD, who pioneered cancer immunotherapy studies targeting the PD-1/PD-L1 pathway, is suggesting a dramatically different paradigm for research in the field.
Drugs that unleash the immune system against tumors have delivered the most striking advances in cancer treatment in this decade. Among these immunotherapy drugs, those that target the PD-1/PD-L1 biological pathway with monoclonal antibodies, have achieved by far the greatest impact, gathering U.S. Food and Drug Administration approvals to treat more than a dozen types of cancer.
The “immune enhancement” approach that is traditional in cancer immunotherapy, such as cytokines, cancer vaccine and anti-CTLA-4, seeks to pump up the immune system throughout the body. Chen’s alternate concept, which he calls “immune normalization”, focuses instead on restoring normal immune response in the tumor microenvironment—the area directly around the tumor.
“You have to look at the defect in the immune response in the microenvironment, rather than just generally promoting immune response,” said Chen, United Technologies Corporation Professor in Cancer Research and Professor of Immunobiology, of Dermatology and of Medical Oncology, and co-director of the Cancer Immunology Program at YCC.
In a perspective in the journal Cell, Chen and first author Miguel Sanmamed, M.D., Ph.D., formerly in the Chen lab and now an assistant professor at the University of Navarra in Pamplona, Spain, describe the evidence for immune normalization as a better concept for developing effective caner immunotherapy drugs.
Back in 1999, Chen and his colleagues reported the discovery of PD-L1, a protein often expressed on the surface of tumor cells and nearby supporting cells, which can bind to the PD-1 protein on the surface of T cells and stop those cells from attacking the tumor.
After studying PD-1/PD-L1 immune mechanisms for more than 20 years, and reviewing the clinical history of anti-PD drugs, Chen says he realized that this pathway doesn’t work the same way as traditional immunotherapies.
Rather than pumping up production of immune response throughout the body, “the PD pathway is highly selective, working only in the tumor site, which is a more promising approach,” he said. The promise has been demonstrated by today’s anti-PD antibody drugs, which are the first FDA-approved immunotherapies to show higher rates of tumor responses than severe side effects among cancer patients.
“The traditional approach to immunotherapy says that the tumor grows because we just don’t give it enough immunity, so let’s just push immunity to the maximum amount our body can tolerate,” Chen said. This traditional strategy is very similar to the game plan often used for treatment with chemotherapies.
But this well-established strategy doesn’t address one long-standing puzzle in clinic: Many, perhaps most, people with advanced cancers retain relatively healthy immune systems. So why don’t their immune cells charge into the tumor and wipe it out?
“The tumor microenvironment is a very powerful suppressor, and it basically prevents the immune cells from getting into the tumor, or shuts them down if they do get in,” Chen explained.
Immune normalization tries to fix that problem. “Immune normalization says, let’s not just blindly enhance all the immune response,” Chen said. “Rather than doing that, we should go into the patient, identify the problem, and then selectively fix the problem. Once you fix the problem such as too much PD-L1, the immune system could get back to work normally, and it can get rid of the tumor by itself.”
Anti-PD therapy first requires a careful study of the patient’s tumor microenvironment to identify whether the PD-1/PD-L1 immune pathway is active. If not, the therapy is unlikely to work.
“In the clinic right now, these drugs are helping about 30% of patients,” he added. “That leaves 70% of patients, so what’s wrong in those cases? That is what we are working on now — trying to identify what other mechanisms cancer is using to escape from immune response.”
Around the globe, researchers also are studying how and when anti-PD-pathway drugs can best be combined with other cancer treatments. Many hundreds of clinical trials of such combinations are underway.
“Unfortunately, the majority of these combination studies are not based on good science,” Chen commented. One frequent problem is that combining two agents that both boost immune response throughout the body, as an immune enhancement strategy mandates, can also rapidly increase toxicities, he pointed out. A strategy of seeking immune normalization, in contrast, may help to find effective combinations that patients can tolerate much better.
“In our field, we need to turn around conceptually and find a different way to think about these questions,” Chen summed up. “Otherwise we will continue to do the same things again, and that will waste a lot of time.”
About Yale Cancer Center(YCC) is one of only 49 National Cancer Institute (NCI-designated comprehensive cancer) centers in the nation and the only such center in Connecticut. Comprehensive cancer centers play a vital role in the advancement of the NCI’s goal of reducing morbidity and mortality from cancer through scientific research, cancer prevention, and innovative cancer treatment.