Why combine immunotherapy with targeted radiation therapy?

by Christian Hyde, MD

In the World War 2 movie, "Saving Private Ryan," a small town held by Allied foot soldiers is being over-run by Nazi tanks. At the crucial moment in the battle, when all hope seems lost, a friendly Allied airplane turns the tide by bombing an armored tank and rallying the exhausted defenders.

Similarly, with cancer, the main primary tumor and bulky metastases represent hard targets which have withstood immune destruction for months if not years. The tumor creates a ring of defense that make it difficult if not impossible for immune cells to infiltrate the enemy. Radiation therapy is the laser-guided smart-bomb that can be dropped on a tank hatch or down the chimney of a concrete bunker, forcing the tumor cells inside to surrender to the body’s re-invigorated immune soldiers.

It has been found in animals as well as humans, that once the tumor becomes too large and established, that immunotherapy simply becomes ineffective when confronted with overwhelming tumor bulk. What is needed then may be a combined effort using a force multiplier.

A “force multiplier” of 10 allows 5 soldiers to fight like 50. Air support is a force multiplier, technology is a force multiplier, good communication and good morale are all force multipliers. In cancer, radiation and immunotherapy are force multipliers for each other. These combined benefits can be “local,” meaning where the radiation is aimed, or “abscopal,” where the radiation “scope” has not been aimed.

This is a relatively new frontier, but early results offer room for encouragement and hope, even of cure. Some major uncertainties remain, but at least the following questions have some answers:

1. Is it safe to give immunotherapy after prior radiation?

Short answer: yes. We know from patients treated at UCLA with pembrolizumab (Keytruda) after chemo-radiation for non-small cell lung cancer, that giving immunotherapy later did not increase the risk of a lung side effect called pneumonitis, when compared to those who never received lung radiation. Perhaps surprisingly, patients who received prior radiation generally outlived those who did not, by double: living 10.7 months with prior radiation versus 5.3 months without radiation.(Shaverdian N, Lisberg AE, Bornazyan K, et al, Lancet Oncol, 2017)

We also know from the PACIFIC Trial, which gave durvalumab (Imfinzi) immunotherapy after chemo-radiation to stage IIIB non-small cell lung cancer patients, that safety is similar between those who did or did not receive radiation and immunotherapy. Notably, the median time to death or distant metastases was 59% longer with chemo-radiation plus immunotherapy (23.2 months) than with chemo-radiation alone (14.6 months). (Antonia SJ, Villegas A, Daniel D, et al; NEJM, 2017)

2. Is it safe to give radiation and immunotherapy at the same time?

Short answer: probably safe. We know from melanoma, where not just one but two immune checkpoint drugs are given together (ipilimumab+nivolumab) that adding radiation does not significantly increase local immune side effects. For example, radiating the abdomen does not necessarily increase the risk of autoimmune colitis or hepatitis. This comes from the work of Dr. Jonathan Schoenfeld, Dr. F. Stephen Hodi, and others in Boston who looked at side effects among patients who received PD-1 blockade, anti-CTLA-4, or both within 2 weeks of radiation therapy. The highest risk of any immune side effect was seen among those receiving both PD-1 and CTLA-4 inhibitors, which is well known from studies without radiation. (Bang A, Whilhite TJ, Pike LRG, et al; Int J Rad Oncol Biol Phys, 2017). 

The question of how to combine immunotherapy and radiation has also been evaluated in a prospective randomized trial at MD Anderson that gave high-dose radiation (radiosurgery) to lung or liver metastases during ipilimumab immunotherapy. This study was recently presented at the American Society for Radiation Oncology (ASTRO) meeting in 2017, by James Welsh, MD. His group showed combination ipilimumab plus radiosurgery to the liver or lung was safe and well tolerated with no severe (grade 4 or 5) toxicity. 

3. Is it effective to combine radiation and immunotherapy at the same time?

Short answer: Yes, but expect only local synergy for now. How does local synergy work? Like the military force multiplier: 10x5=50. An airplane alone against a bunker = damage that gets repaired later. Foot soldiers alone = siege but not victory. Air power plus soldiers = liberation. 

Focused radiation damages a tumor mass and lowers its barriers, making it easier for the immune system to recognize and infiltrate. Damaged cancer cells are smart though, and react to X-ray damage by showing a signal on their cell surface, like hoisting a friendly flag, that makes them safe from follow-up immune destruction. The “friendly flag” is a protein called PD-L1, but the current generation of checkpoint drugs help the patient’s immune system to ignore this friendly PD-L1 flag, like not seeing it or not trusting it. Damaged tumor cells hiding behind this false flag can then be permanently cleared by the enhanced immune system.

In the MD Anderson trial by Dr. Welsh and others, both local and maybe even distant synergy were seen in a patient with anaplastic thyroid cancer, a very serious type of cancer. The patient had a lung metastasis that was irradiated, and was controlled locally as expected, but there was also shrinkage in the primary tumor in the neck resulting in disease control for more than 13 months (ASTRO 2017 Meeting press release, www.astro.org). 

In conclusion, as new immune combinations become more effective, we can expect to see greater tumor control. However, auto-immune side effects, like friendly fire on the body’s own cells, are a limiting factor. Sometimes the immunotherapy needs reinforcement, too. By focusing the immune system on the targets that matter most, the tumors, and setting up those tumors for successful control, local radiation can help turn the tide in favor of the good guys: you.