Cancer Immunotherapies: Changing Lives and Science

Sometimes, trying to learn all the different cancer therapies out there can feel a bit like drowning in a sea of big, complicated names. There are seemingly infinite number of “-inib”s and “-umab”s used to treat cancer. My work in the division of cardiovascular medicine at Vanderbilt is focused on understanding the mechanisms of how cancer therapies cause heart and vascular disease. As I am knee-deep in experiments and projects, I find it important to step back and remember the awe I have for some of these cancer therapies. One project in the lab is assessing the immune-related adverse effects of cancer immunotherapies.

A paper published in the New England Journal of Medicine highlights an adverse cardiovascular effect of immune checkpoint-inhibitors that initiated a cascade of questions on the safety of these drugs. While we are still trying to profile the safety of immune checkpoint inhibitors, it is undeniable that these cancer immunotherapies are amazing from a scientific, medical, and patient perspective.

To marvel at the nature of immunotherapies, it helps to have a basic understanding of how they work. As an undergraduate student, I have developed a valuable skill at taking concepts that are very complicated and breaking them down by asking, “What is most important for me to know?” I apply this approach to understanding cancer immunotherapies as well. There are many visuals out there for understanding cancer immunotherapy and I refer you to search those for a more comprehensive, visual representation. One of the best ways I’ve heard it described, though, is “releasing the brakes on the immune system.”

While there are a few immune checkpoint inhibitors, and many more in clinical trials right now, I’m going to focus mostly on the PD-1/PD-L1 therapies. PD-1, or programmed death-1, is a receptor expressed on T cells. In valiant efforts to maintain immune homeostasis, dendritic cells or other antigen presenting cells express PD-L1, or programmed death ligand-1, on the surface of their cells. This ligand PD-L1 binds the receptor PD-1 expressed on the surface of T cells. This is a system that inhibits the T cells from attacking non-pathogenic cells that express the antigen shown to the T cell. Simply, these are the immune system “brakes.” In a healthy body, where the brakes function properly, PD-1 and PD-L1 are bound only in situations where immune response is not necessitated; in a utopian world, the dendritic cells would present pieces of tumor cell to the T cells, the T cells would recognize that antigen and initiate a response, and the immune system would carefully orchestrate a genocide of the tumor cells. The immune system would fulfil its role of patrolling the body for disturbances and executing the proper response. But in our real, non-utopian world, cancer cells are pesky, cunning molecular fiends.

Instead, the cancer cells have established mechanisms to overexpress PD-L1 (the brakes on the dendritic cells that inactivate T cells). In these cancers, the immune system doesn’t recognize the tumor cells because they are essentially invisible. Where the T cell normally recognizes the tumor cell and initiates a response, now the cancer cell has mimicked the dendritic cell to suppress the T cell-mediated immune response. This is where I began to marvel at the minds that thought to ask how we could utilize the body’s own defenses to destroy cancer. Since the cancer cells hide from the immune system by expressing ligands that bind and “activate the brakes”, how can we disturb this process and expose the cancer cells to the immune system? Enter the prognosis-altering, lifesaving development of immune checkpoint inhibitors.

Patients can now take immune checkpoint inhibitors against PD-1, PD-L1, CTLA-4, and others in clinical trials. These types of therapies have been used for a flurry of cancers, including melanoma and non-small cell lung cancer that typically have very poor prognoses. In June of this year, a paper was published in Science that where cancers with a genetic deficiency, regardless of cancer origin, were effectively treated with a PD-1 immune checkpoint inhibitor. This was the first time that a drug had been used, and FDA approved, for treating a subset of patients based only on a genetic mutation. Does this mean that in the future we will focus less on the cancer origin (such as distinguishing between breast cancer, colon cancer, melanoma, leukemia, etc.) and focus instead on the genetic fingerprint of the tumor? Maybe. If so, that would transform cancer treatment and further advance personalized medicine. I think immune checkpoint inhibitors are an incredible feat for science and medicine and have the potential to transform how we approach scientific questions, view cancer itself, and utilize the incredible machinery our bodies already have to fight off disease. To me, that is pretty amazing.

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Mary Barber

Mary Barber studies Chemistry and English Literature at Belmont University in Nashville, TN. An average day for her includes running from microbiology lecture to having discussions on the writings of Nabokov to designing experiments in the lab – she says it’s a little crazy but always fun. Her passions (currently) include studying cardiovascular disease caused by cancer therapies, writing, and monthly dates baking cupcakes with cancer patients. One day when she grow up Mary hopes to be a physician researcher, treat patients with heart problems, write books, and do yoga every day.