Yale Radiation Oncologist Searches for the Elusive "Abscopal" Effect

Allison Campbell, MD, PhD

Findings from early clinical trials have demonstrated intriguing potential for the combination of immune checkpoint inhibitors and radiation therapy to produce systemic responses in patients with cancer, but much larger studies are needed to establish the population most likely to benefit from this approach, according to Allison Campbell, MD, PhD.

Campbell, a radiation oncologist at Yale School of Medicine in New Haven, Connecticut, has authored several reviews on the subject of combined radiation therapy and immunotherapy. She is the lead author of a phase II study of stereotactic body radiotherapy (SBRT) in patients with non—small cell lung cancer whose disease had progressed on the PD-1 inhibitor pembrolizumab (Keytruda). Findings presented at the 2019 American Society for Radiation Oncology Annual Meeting showed that SBRT resulted in a systemic response rate of nearly 10% and a disease control rate of 57% in 21 patients who completed treatment.

In an interview with OncologyLive^®, Campbell discussed the synergy between the 2 treatment modalities and the challenges facing ongoing clinical development.

OncLive: Could you briefly describe what is behind the synergy between immunotherapy and radiation therapy?

Campbell: Immunotherapy is a general term that can refer to any treatment that activates the immune system to fight cancer. Two things are needed for an effective immune response: (1) an activating signal that tells the immune system to attack and (2) a target. Immunotherapy provides the activating signal. Radiation can help provide a target because when cancer cells are killed with radiation, those dead tumor cells attract the attention of the immune system.

Does this synergy apply to all types of immunotherapy?

This synergy applies to all checkpoint inhibitors, which is what people usually think of when they think of immunotherapy. Checkpoint inhibitors block inhibitory pathways in T cells, a special type of immune cell that can kill cancer cells. When you inhibit an inhibitory pathway, it results in activation. A good metaphor to think of is lifting your foot off the brake in a car.

In your opinion, what are the most exciting clinical trial results to date with this combination?

The most exciting clinical trials are those in which an abscopal effect has been observed. The word abscopal means “away [ab] from the target [scopus].” It refers to a special type of synergy between radiation and immunotherapy. In a small number of patients with metastatic cancer who are on immunotherapy, radiation to just 1 site of disease has been shown to result in tumor regression throughout the whole body.

What are the major barriers to incorporating this combination into routine clinical care?

At this point, we are still learning about how to best deliver the radiation and how best to time it relative to immunotherapy. Trials are being performed now that look at these questions. For any therapy to become the standard of care, what is ultimately needed is a phase III randomized trial showing a benefit in a large population of patients.

What are the most urgent unanswered questions about combining immunotherapy and radiation therapy?

There have been promising results from early trials showing synergy between immunotherapy and radiation, but these abscopal responses are usually seen in a small number of patients. We need to learn all we can about the [patients] who respond well to the combination of immunotherapy and radiation so we can predict who will benefit most and how we might improve the proportion of patients who have a good response.

Campbell AM, Cai WL, Burkhardt D, et al. Final results of a phase II prospective trial evaluating the combination of stereotactic body radiotherapy (SBRT) with concurrent pembrolizumab in patients with metastatic non—small cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys. 2019;105(1):S36-S37. doi: 10.1016/j.ijrobp.2019.06.453.