Future Is Promising for Cancer Immunotherapy

Immunotherapy may be the key to transforming cancer from a death sentence to a chronic condition. Some progress has already been made; checkpoint blockade has changed the prognosis for 10 usually lethal tumor types, including stage IV melanoma.

Laurie H. Glimcher, MD

Laurie H. Glimcher, MD

“If we can combine data in the patient medical record, immunoprofile with tumor genomics, pathology, and imaging, we should be able to predict the optimal treatment for all of our cancer patients and treat them successfully,” said Laurie H. Glimcher, MD, President and CEO of the Dana-Farber Cancer Institute in Boston. “I think we can get there in 3 to 5 years”

Dr. Glimcher drew a guarded but hopeful picture during the Thomas B. Ferguson Lecture, Cancer Immunotherapy: The End of the Beginning. The immune system has long been a backwater in oncology research. That changed when immunotherapy produced a Nobel prize in 2018 for James P. Allison, PhD, of MD Anderson Cancer Center in Houston, and Tasuku Honjo, MD, PhD, of Kyoto University in Japan.

Their discoveries led to checkpoint inhibitors, blocking receptors that prevent T cells from attacking tumor cells. Checkpoint blockade is the most successful immunotherapy, but is successful in only 20% of patients. The next step is to expand both the robustness and duration of response as well as the types of cancers amenable to immunotherapy.

Adaptive T cell therapy, or CAR-T, inserts a chimeric antigen receptor (CAR) into T cells that have been removed from the patient. The CAR is primed to attack specific surface antigens in the patient’s own cancer. The activated T cells are expanded and reinfused into the patient. CAR-T can be very successful. It also can be highly toxic and is enormously expensive. The next steps are to develop off-the-shelf allogenic products and find other mechanisms to bind T cells to the tumor.

Bi-specific antibodies, which bind to both a T cell and a tumor cell at the same time, show good early results, Dr. Glimcher said.

Therapeutic cancer vaccines have largely failed, but work continues. Researchers at Dana-Farber and in Germany have shown positive results with a therapeutic melanoma vaccine in early clinical trials.

The tumor microenvironment (TME) is the least advanced immunotherapy. Tumors alter immune and other cell types in their immediate environment to create a protective immunosuppressive moat.

The most advanced TME research focuses on the IRE-1/XBP1 signaling pathway, the endoplasmic reticulum stress response. Disrupting the pathway drains the immunosuppressive moat, allowing the immune system to attack tumor while suppressing tumor growth.