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:
- Regulatory T-cells increase in response to radiation. These “Tregs” can be recruited by tumors to help protect tumor cells from immune destruction.
- 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.
- 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.
Excellent points to be noted on the dose of radiation delivery to tumor sites as well as distant tumor sites and highlight on the three key pathways mentioned on this blog written by Dr. Christian Hyde.
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