Study Finds Radiation Plus Immunotherapy Combination May Elicit Optimal Response in Metastatic Melanoma Patients

Radiation therapy in combination with two immunotherapies could elicit an optimal response in more patients with metastatic melanoma, according to a new study.

A team of researchers from Penn’s Abramson Cancer Center found that treating metastatic melanoma with a triple threat, including radiation therapy and two immunotherapies that target the CTLA4 and PD-1 pathways, could elicit a response that will boost the immune system’s attack on the disease.

The study, led by senior authors Andy J. Minn, MD, PhD, assistant professor of Radiation Oncology, Robert Vonderheide, MD, DPhil, the Hanna Wise Professor in Cancer Research, Amit Maity, MD, PhD, professor of Radiation Oncology, and E. John Wherry, PhD, professor of Microbiology and director of the Institute for Immunology at the Perelman School of Medicine at the University of Pennsylvania, was published in Nature. The study reports for the first time on the response and resistance to radiation combined with ipilimuman, an antibody against CTLA4, in both patients and mice.

In the early-stage clinical study RadVax, the team found that combining ipilimumab with radiation was safe and effective in shrinking tumors in a subset of 22 metastatic melanoma patients (18 percent). The concurrent mouse study provided some clarity on a mechanism of resistance, known as the PD-L1 pathway, found in many patients whose cancers have progressed, suggesting that an antibody against PD-L1 or its partner PD-1 is an ideal third treatment to improve response and immunity.

“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,” Minn said. “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.”

Ipilimumab is approved by the US Food and Drug Administration (FDA), and is an anti-CTLA4 antibody that serves to lift a break on the immune system, allowing T cells to attack tumor cells. Antibodies that block the PD-L1 pathway, which is used by cancer cells to hide from the immune system, include pembrolizumab or nivolumab, anti-PD-1 immunotherapies approved by the FDA recently. It is believed that adding radiation results in a synergistic attack, turning the destroyed tumor cells as a vaccine against the cancer. Irradiated tumor cells are believed to release antigens that help the immune system fight other tumors in the body. The treatment is named RadVax, due to its vaccine-like qualities.

The research team recruited 22 previously treated and untreated stage IV melanoma patients for a Phase I clinical trial that investigated the use of both modalities. The group received sterotactic body radiation therapy (SBRT) to a single tumor followed three to five days later with ipilimumab every three weeks for four cycles. The researchers found that 18 percent of patients had partial response in unirradiated tumors, 18 percent had stable disease and 64 percent 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 for 18.4 months and 21.3 months, respectively. The group’s overall survival rate was 35 percent, which is an improvement over a past Phase III study that showed an overall survival rate of 20 percent in patients on ipilimumab alone.

“This approach is changing the way we view radiation – from strictly a local form of therapy to one that may augment a systemic response when given an immunotherapy,” said Maity.

The response in mice was similar, with 17 percent responding to the combination of radiation therapy and an anti-CTLA4 antibody.

To better understand the mechanism of resistance observed in several patients, the researchers turned to mice. Mouse tumors that relapsed following radiation an anti-CTLA4 revealed that PD-L1, known to inhibit the activation of T cells, was among the top unregulated genes that made up a resistance gene signature. Mice with tumors showing high PD-L1 had disabled T cells and all failed treatment. In mice, PD-L1 inhibition restored both T cell function and tumor response to radiation therapy and anti-CTLA4, increasing survival to 60 percent. The authors conclude that PD-L1 on tumor cells can be a dominant resistance mechanism to radiation therapy and ipilimumab.

“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, said Minn.

Source: Penn Medicine

Last updated: 3/10/15; 3:55pm EST


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