Focused Radiation May Help Turn on the Immune System

Focused Radiation May Help Turn on the Immune System

by Christian Hyde, MD

Radiation given in combination with immunotherapy can potentially kick-start an exhausted immune system. This has been most famously observed in a melanoma patient on Ipilimumab, published by Dr. Michael Postow and others in the New England Journal of Medicine. At first, the ipilimumab worked, and her tumors shrank. Then the tumors developed resistance and regrew. By radiating one of her tumors near the spine, with 3 large doses of radiation, her immunity was restored, and all her tumors shrank, not just the irradiated tumor. The combination increased tumor specific T-cells and antibodies.

The result has a scientific nickname: the abscopal effect, derived from a combination (aptly enough) of two words—ab, for “away,” and scopus, for “target.” The effect, first reported about 50 years ago, is currently rare, seen in a small number of patients who undergo radiation therapy for metastatic disease.

Radiation doses of 8 to 10 Gray appear to be ideal to wake up the immune system and cause the tumor to become inflamed such that it is fertile ground for immune activity. Recent work by Dr. Silvia Formenti and others has shown that these high doses of radiation makes cancer cells look and act like virus-infected cells. The radiated cancer cells produce interferon and display more surface antigens, helping to target themselves for immune destruction, using many of the same pathways as a virus-infected cell. 

The abscopal effect is rare because radiation also simultaneously increases the production of inhibitory blomolecules and regulatory T-cells, which stop killer T-cells from overdoing their job. The same processes that activate the immune system thus control how far it can spread, shutting down the immune response before it causes too much collateral damage in the body, keeping radiation responses local.

At least three key pathways have been shown to limit the spread of anti-tumor immunity after radiation:

1. Regulatory T-cells increase in response to radiation. These “Tregs” can be recruited by tumors to help protect tumor cells from immune destruction.
2. Programmed Death-Ligand 1, or PD-L1. Tumor cells increase this protein on their cell membrane in response to radiation, a change that can be detected on circulating tumor cells during a course of radiation therapy. This makes them resistant to CD-8 T-cell killing.
3. IDO-1 is an enzyme that is upregulated in tumor surroundings in response to radiation, which paralyzes killer T-cells crossing into the area, like soldiers getting stuck in a moat.

All three of these mechanisms were shown to be at work by Dr. Elena Muraro and others following 3 daily doses of 10 Gray each in breast cancer patients with up to 6 metastases irradiated. In theory, if a patient takes immunotherapy drugs like ipilimumab, nivolumab, and epacadostat during radiation, it may help deplete the Tregs, overcome PD-L1, and block IDO, respectively, allowing a local immune response to broaden to other metastases. 

Chemotherapy has taught us that multiple drugs, usually 4 or more with independent mechanisms, are needed before cure rates exceed 90%, such as ABVD for Hodgkin’s lymphoma. Blocking one resistance pathway is seldom enough, just like blocking one road into a city won’t stop all traffic; traffic simply increases on all the other roads. There are many available routes of immunity to regulate, including checkpoints, cytokines, antibodies, and cells. It’s probably not until we get multi-drug combinations, added to radiation, that the distant abscopal effect becomes a regular thing. In the meantime, the “adscopal”, or local synergist effects of radiation plus PD-1 inhibitors, are also showing promise.

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.

Get to Know Sentinel Author: Christian Hyde, MD

Name: Christian Hyde, MD

Title: Radiation Oncologist, Diplomate of the American Board of Radiology

Employer: Cancer Treatment Centers of America, in the Southeastern Region

When and why did you become a SITC member?

I joined SITC a few years ago due to a long-standing interest in immunity. One of my earliest experiences with my immune system was at age 12 during a Boy Scout project in Utah clearing trails through the woods. I was exposed to poison oak, causing a mild rash on my legs and arms. When we went back a few weeks later, I volunteered to take care of all the poison oak bushes, thinking my prior exposure had inoculated me against it. I was dead wrong. A few days later I was in the doctor’s office with my face swollen up like a balloon and weepy sores all over my body. I had to take a cortisol injection to turn down my T-cell immune response which was attacking the poison oak antigens on my skin and even attacking areas where I wasn’t directly exposed. Needless to say, I learned a lot that day about the power of the immune system and how little I understood it, and that not all exposures are protective – in fact they can rev up the immune response. We see that with cancer immunotherapy.