In a new study entitled “Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer,” researchers investigated the potential of radiation therapy combined with two immunotherapies in melanoma treatment. The study was published in the journal Nature.
In this study, a research team at Penn’s Abramson Cancer Center devised a phase I clinical trial to test a previously suggested hypothesis that lacked experimental validation in which combining radiation therapy with an immunotherapy, anti–CTLA-4 antibody ipilimumab, boosts the immune response in melanoma patients. The team performed their study in 22 metastatic melanoma patients who received radiation therapy (specifically, stereotactic body radiation therapy) into a single tumor followed by anti-CTLA4 antibody ipilimumab treatment during four cycles.
The team observed that in unirradiated tumors, only 18 percent of patients exhibited a partial response, while 18 percent and 64 percent remained with stable and progressive disease, respectively. Although the team registered a level of response, most patients were unresponsive.
The same phenotype was observed with a mouse model of melanoma, with only 17 percent of mice responding to combined radiation and anti-CTLA4 antibody therapies. The results suggested a mechanism of resistance, observed in both patients and mice.
To understand the mechanisms behind this resistant phenotype, the team performed further studies in mice, observing that relapsed mouse tumors (after combined radiation and ipilimumab treatment) exhibited a “resistance gene signature” that was led by increased expression of PD-L1 – a known factor that dampens activation of immune T cells, leading to failed treatment.
When the authors introduced anti-PDL1 therapy, T-cells’ functionality was restored and mice exhibited an increased response to radiation therapy and anti-CTLA4, resulting in a 60 percent increased survival.
Observing human patients assessed in the clinical trial, the authors noted that, as in mice, patients with high-levels of PDL1 expressing tumors had no functional T cells and failed treatment, while patients with low-levels of tumor PDL1 thad survival rates of 50 percent.
The team concluded that PD-L1 expression in tumors is a devised strategy that allows tumors to escape anti-CTLA4-based therapy. In light of their findings, they suggest combining radiation therapy with anti-CTLA4 and anti-PD-L1 will allow overcoming tumor mechanisms to dampen the immune system, enhancing anti-tumor responses.
Andy J. Minn, MD, PhD, assistant professor of Radiation Oncology at the Perelman School of Medicine, University of Pennsylvania and study lead author commented in a press release, “Understanding resistance is very important. Although outcome can be improved when more therapies are combined, risk of side effects can increase. Precision medicine requires knowing when to give more and what to give.”
Robert Vonderheide, MD, DPhil, one of study’ co-authors added, “These results are extremely encouraging and will allow us to propel the work further, into bigger clinical studies investigating the triple threat. Once again, we are extending the reach of the immune system, and breaking the ceiling on what these drugs can do for our patients.”