Treating metastatic melanoma with a triple threat that includes radiation therapy and two immunotherapies that target the CTLA4 and PD-1 pathways could elicit an optimal response in more patients. The response will boost the immune system’s attack on the disease, suggests a new study published in Nature (2015; doi:10.1038/nature14292).

The study, conducted by a multidisciplinary team of researchers from the University of Pennsylvania’s Abramson Cancer Center in Philadelphia, reports for the first time on the response and resistance to radiation combined with ipilimumab (an antibody against CTLA4) in both patients and mice.

“These new immunotherapies are potent treatment options that have generated a lot of excitement in the past few years, but we know that many patients fail to respond, underscoring the need to further improve the drugs’ abilities,” said senior author Andy J. Minn, MD, PhD, assistant professor of Radiation Oncology. “Anecdotally, we know that combining radiation with immunotherapy can be powerful, so we were very motivated to move forward with both a clinical trial to demonstrate that this combination is a promising route to pursue and with laboratory studies to understand why response happens and why it does not.”

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Ipilimumab is an FDA-approved, anti-CTLA4 antibody that serves to lift a brake on the immune system, allowing T cells to infiltrate and attack tumor cells. Antibodies that block the PD-L1 pathway, which cancer cells use to hide from the immune system, include pembrolizumab or nivolumab, anti-PD-1 immunotherapies recently approved by the FDA.

Adding radiation is believed to result 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.

The impetus for the Penn phase I clinical study was a metastatic melanoma patient in his early 50s who was treated with an anti-CTLA4 antibody at Penn Medicine by co-author Lynn M. Schuchter, MD, chief of Hematology/Oncology at Penn’s Abramson Cancer Center. While on an anti-CTLA4 antibody, the patient’s condition worsened, and he required palliative radiation therapy. Over the course of many months after both modalities and no further treatment, however, his metastatic cancer started to resolve, and he was eventually deemed nearly cancer free.

Attempting to mirror his treatment experience, the researchers recruited 22 patients with previously treated and untreated stage IV melanoma for a phase I clinical trial that investigated the use of both modalities. The group received stereotactic body radiation therapy (SBRT) to a single tumor followed 3 to 5 days later with ipilimumab every 3 weeks for four cycles.

The team found that 18% of patients had partial response in unirradiated tumors, 18% had stable disease and 64% had progressive disease. The median progression free survival and overall survival for patients was 3.8 months and 10.7 months with a median follow up of 18.4 and 21.3 months, respectively. The group’s overall survival rate was 35%. A past, phase III study showed an overall survival rate of 20% in patients taking ipilimumab alone.

The researchers explained that this approach is changing their perspective on radiation, from a strictly local form of therapy to one that might augment a systemic response when given with immunotherapy.