Doorways to Discovery
November 11, 2014

At Johns Hopkins, questions that arise in the clinic become targets for research, and findings from research circle back into potential treatments for new patients. That’s exactly how neurosurgeon Michael Lim’s latest clinical trial got started.

While caring for patients with melanoma that metastasized to the brain, Lim noticed that a subset of brain tumors that were irradiated developed a robust inflammation in this area.

At the time, he was also studying a family of cancer drugs known as checkpoint inhibitors. This class of immunotherapies targets molecules on the surfaces of cancer cells that effectively shut off the body’s immune response, allowing these cells to evade death and proliferate unchecked. Two particular checkpoint inhibitors, antibodies against the proteins PD-1 and CTLA-4, have shown promise in helping extend survival for several different types of cancers. However, neither of them alone has proven to be a cure.

Because the inflammation Lim saw in the clinic indicated an immune response, he wondered whether combining radiation with one of the checkpoint inhibitors might deliver a one-two punch to patients’ cancers, providing a more effective therapy than either modality on its own.

To test his idea, he looked at a mouse model of glioblastoma. Exposing the mice to radiation and to PD-1 produced a significant number of long-term survivors—mice whose cancer never reappeared. More remarkable, when Lim and his colleagues reinjected the treated animals with tumor cells, they remained cancer-free. “It showed us that their immune system was now trained to kill cancer,” he says.

Since antibodies against CTLA-4 are FDA-approved to treat melanoma but antibodies against PD-1 aren’t yet, Lim and his colleagues repeated the experiment using CTLA-4 in a mouse model of metastatic melanoma. These results were similarly exciting—so promising that Lim and his colleagues recently opened a clinical trial to test the effects of this combination in patients with metastatic melanoma. 

In a separate clinical trial this one involving patients with advanced melanoma that has metastasized, Michael Lim is also taking a one-two punch approach. This time he’s using a drug called ipilimumab—which targets the immune system—and is teaming it with stereotactic radiosurgery, a precise type of radiation therapy. The experimental treatment, delivered over the course of two months, builds on research that has shown that radiation therapy may prime tumors to respond to subsequent immunotherapy.