James Larner, MD
In non–small cell lung cancer (NSCLC), determining whether radiation can truly potentiate response to immunotherapy requires a better understanding of underlying permutations and pathways, explained James Larner, MD.
Following findings of the phase III PACIFIC trial, which showed an improvement in overall survival for durvalumab (Imfinzi) as consolidation therapy after definitive chemoradiotherapy in patients with unresectable stage III NSCLC, other studies are looking at how to use radiation to trigger the immune system.
“An optimist would say that the glass is three-quarters full,” said Larner, professor and chair of Radiation Oncology, University of Virginia Health System. “We’ve made huge inroads. Radiation is a potent stimulator of the immune system and most, if not all, patients should get radiation to potentiate immune checkpoint blockade.”
In an interview during the 2018 OncLive
State of the Science SummitTM
on Advanced Non–Small Cell Lung Cancer, Larner discussed the process by which radiation interacts with the immune system and how physicians are working to improve treatment responses for patients with NSCLC.
OncLive: What is the role of radiation therapy in combination with immune-oncology agents?
: Immunotherapy has had a tremendous impact on lung cancer and other solid tumors. The real question in my mind is, “Why do patients become resistant to immunotherapy?” If we can figure out the mechanisms of resistance, we have the potential to manipulate the system, invert resistance, and increase response rates. Historically, radiation has been thought of as a DNA-damaging agent.
Over the past decade or so, there has been interest in the use of radiation therapy to stimulate the immune system. Radiation has tremendous potential in that regard. Radiation increases antigen presentation. It increases dendritic cell activity through the damage-associated molecular pattern with the release of ATP and calreticulin, high mobility group proteins, and so forth. This results in the so-called abscopal effect, whereby if you radiate a lung cancer or a metastatic deposit in the left lung, you can see regression in the right lung or the liver. It's potentiating immune checkpoint blockade.
There are a lot of unknowns in terms of how to integrate radiation with immune checkpoint blockade. Do you give radiation first, or do you give immunotherapy first? What dose of radiation is optimal? Recently, there have been several molecular pathways that have been identified. These include the cGAS-STING pathway where damaged DNA goes into the cytosol and turns on an interferon response that leads to dendritic cell stimulation. If you give too high or too low of a dose you may not get that response.