The study, published online March 9 in Nature, used both a clinical trial and mouse study to better understand how to improve immune inhibitors and how cancer becomes resistant to therapy.
The immune system uses T cells, which are immune cells, to fight cancer and other pathogen-infected cells. Cancer stops this activity by using inhibitory receptors called immune checkpoint receptors. Recently, researchers have used antibodies against these inhibitory receptors on T cells, called immune checkpoint inhibitors, to re-activate T cells. While this has resulted in promising clinical responses across a variety of cancers, most patients have cancer that does not respond.
This study, led by Andy Minn, M.D., Ph.D., assistant professor of radiation oncology at the Abramson Family Cancer Research Institute, and a team of researchers at the University of Pennsylvania Perelman School of Medicine, working with Ishwaran, examined ways to improve the efficacy of checkpoint inhibitors and understand how cancer cells become resistant to this therapy, by using a clinical trial and laboratory study on metastatic melanoma.
To improve upon immune checkpoint blockade, the researchers combined an immune checkpoint inhibitor (anti-CTLA4) with radiation therapy to the metastatic tumors in a Phase I clinical trial. They found that the combination of radiation and ipilimumab, the anti-CTLA4 antibody used, did not lead to unexpected toxicities and the overall survival was encouraging. The same combination of radiation and ipilimumab studied in the laboratory demonstrated that radiation does enhance anti-CTLA4. However, in both patients and mice, failure was common.
To better understand how the melanoma became resistant to the therapy, the researchers studied the tumors in the mice. They found that resistance in mice results from melanoma turning up its expression of PD-L1, a protein that can turn on a second immune checkpoint pathway that, like CTLA4, disables T cells. High levels of PD-L1 on melanoma were also associated with patients who failed in the clinical trial. In the mice, treatment resistance was reversed and survival was dramatically improved by adding an antibody to PD-L1 to radiation and anti-CTLA4. “These mouse studies suggest that improved response in patients could also occur with the same triple threat of radiation, anti-CTLA4, and anti-PD-L1,” said Minn. Researchers expect to test this triple threat in clinical trials.
It is believed that adding radiation results in a synergistic attack, turning the destroyed tumor cells into a vaccine against the cancer. Irradiated tumor cells are believed to release antigens that help train the immune system to fight other tumors in the body. The treatment has earned the name “RadVax” because of its vaccine-like qualities.
Ishwaran, who is also Director of Statistical Methodology in the Division of Biostatistics, developed powerful computational and statistical methods to uncover how radiation improves immune checkpoint blockade and how resistance can occur by statistical analysis of changes occurring in melanoma and the immune system. Minn describes Ishwaran’s work as “invaluable for these studies,” and the two have collaborated on similar research involving breast cancer published in Cell.
Minn said, “Hemant’s work is helping us decipher and make sense of “big data” generated in the laboratory to understand how cancer can become resistant to both immunotherapies and more standard therapies such as radiation and chemotherapy.”
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