An Important Research Goal: Make Immunotherapy Reliably Effective for More Patients Who Have Cancer

WE’VE KNOWN FOR OVER a century about rare patients who experience spontaneous regressions of cancer. We don’t have absolute proof, but, presumably, this occurs because their immune systems are able to rally and fight the disease.

Even before we had immunotherapies like checkpoint inhibitors, we saw signals of the immune system’s activity against cancer. Some patients with melanoma developed antibodies against the disease that also fought their own skin pigment so that they developed vitiligo (white skin patches); some developed inflammation of the thyroid gland due to their immune response.

Across our population, it’s very likely that our immune systems protect us from the earliest microscopic stages of cancer by eradicating the disease before we ever realize it is there. Another hint about our natural immunity resides in the knowledge that people who have suppressed immune systems are more likely to develop certain cancers. These clues offer reminders that one of our first lines of defense against cancer is our own immune system. Now researchers are developing a host of drugs to help it succeed when cancer has already developed.

Checkpoint inhibitors are immunotherapy drugs that take the brakes off the immune system so that it can better fight cancer, and they represent a big step forward — not just because they improve outcomes for many patients but also because they have allowed us to understand one mechanism by which cancer cells escape immunity. But with a minority of eligible patients responding to these drugs, few long-term responses and some cancer types still without such treatments, much more must be accomplished.

An idea that makes more and more sense as we look at these gaps is that various types of immunotherapies will have to be combined to create effective treatments for a broader swath of patients. Plenty of immunotherapy strategies that could be part of those equations are being explored — and with promising results.

Advances in the science of cancer immunology include the identification of many “levers” of the immune system that can be pulled by newer drugs. Experimental checkpoint inhibitors target different proteins than do the checkpoint drugs already approved by the Food and Drug Administration, and there are also entirely new methods for disabling checkpoints. Another strategy involves activating co-stimulatory molecules that sit on the surface of cancer cells so that they will stimulate T cells to fight the disease. Oncolytic viruses, meanwhile, have been deactivated so that they can be used as delivery systems for immune-boosting drugs. Then, too, there are STING agonists, which target a protein called “stimulator of interferon genes,” part of the normal human immune system. By activating STING, these agonists spur the production of interferons and cytokines, proteins that can pump up the immune system with extra T cells so it can better fight cancer.

We are making stepwise improvements, both big and small, in the development of immunotherapies, and we must continue on this vital path. Only with focused and in-depth study over the course of many years, as well as the participation of more patients in clinical trials, will we amass the tools needed to effectively and reliably fight cancer with immunotherapy.

DEBU TRIPATHY, M.D.Editor-in-ChiefProfessor of MedicineChair, Department of Breast Medical OncologyThe University of Texas MD Anderson Cancer Center