Combining Immunotherapy and Radiation against Cancer

A cross-disciplinary team of scientists and physicians at the University of Pennsylvania is redefining the role of one of cancer medicine’s oldest tools and blazing a new trail in the treatment of patients. Their efforts, led by cancer immunologist and oncologist Bob Vonderheide and radiation oncologist Andy Minn, are demonstrating the promise of combining immune checkpoint inhibitors and radiation therapy.

Radiation therapy has been used to treat patients with cancer since the beginning of the 20th century. About half of all cancer patients receive some type of radiation therapy. It is typically used as a local therapy—that is, to treat the specific area of the body where a tumor is located. However, mounting evidence supports the idea that local radiation can also have effects throughout the body and that these effects are mediated by the immune system.

In fact, researchers are finding that as irradiated cancer cells die, they trigger an immune response much like vaccines do. Bob, Andy, and their colleagues—calling themselves the RadVax team (Rad for radiation and Vax for vaccine)—are testing the idea that the immune response triggered by radiation can be improved further by the addition of immune checkpoint inhibitors, a type of treatment that enhances the ability of the immune system to kill a tumor. If successful, the combination therapy will provide additional options for patients with metastatic cancer, including patients who do not respond to checkpoint inhibitors alone.

In 2015, the team reported results from the first clinical trial of radiation therapy combined with the immune checkpoint inhibitor ipilimumab (Yervoy®), which targets a protein called CTLA-4. In addition to testing the combination in patients with metastatic melanoma, they also studied it in mouse models of melanoma to gain further biological insights.

Although responses were observed in some of the patients, most did not benefit. However, studying both the mice and patient samples uncovered a resistance mechanism—a way in which the melanoma cells avoided being killed by the immune system—that likely explained the clinical findings. This led the team to their current strategy of deploying multiple checkpoint antibodies along with radiation. The triple combination, effective in mice, is currently being tested in patients in clinical trials.

Bob credits the NCI Cancer Center Support Grant (CCSG) to Abramson Cancer Center for the team’s success. Access to the infrastructure and personnel supported by the CCSG enabled the researchers to be nimble and get the studies off the ground quickly. This was a “CCSG in action,” said Bob.

The team that accomplished this study consisted of 25 researchers from a variety of scientific disciplines and included early-career and established investigators. Notably, the study’s first author Christina Twyman-Saint Victor was completing her research training at the time and is now an independent investigator with her own laboratory at Penn.

Additional clinical trials testing combinations of radiation therapy and immune checkpoint inhibitors are currently being conducted. Still, “there are many scientific questions that still need to be answered,” said Andy. With NCI’s support, the RadVax team aims to answer them. For example, more needs to be known about how these treatments interact at the cellular and molecular level to inform how best to combine them.

In 2017, NCI awarded Bob and Andy, along with Professor of Radiation Oncology Amit Maity, M.D., Ph.D., and Distinguished Professor of Microbiology E. John Wherry, Ph.D., a grant to continue this work in four cancer types. “Our team has one goal: to improve the health of patients,” said Bob. “We are using science to do that.”