By Joseph Longo
About half of all cancer patients will be treated with radiation therapy at some point during the course of their disease. Conventional radiation therapy involves the delivery of high doses of radiation to the tumour, usually in multiple smaller doses called fractions. When a cell is irradiated, its DNA becomes damaged. If this damage is left unrepaired, the cell dies. Unlike chemotherapy, which is usually delivered throughout the entire body, radiation therapy is delivered with high precision to a specific area. As a result, DNA damage only occurs in those cells within the radiation field. However, oncologists have noticed that, in a small number of patients with multiple tumours in different locations within the body, the delivery of radiation to one tumour can cause the other tumours outside of the radiation field to shrink in size.
How is this possible? The answer seems to lie within the immune system. When cancer cells die in response to radiation therapy, they release proteins and other molecules into the surrounding environment. These molecules act as “danger signals” that alert and recruit cells from the patient’s immune system. Immune cells known as T cells can recognize certain cancer-specific proteins as “foreign material”, which results in their activation. These activated T cells can then circulate the body and kill any cancer cell that displays that same foreign protein.
What does this mean for a patient receiving radiation therapy? Not only can radiation therapy directly kill cancer cells by causing DNA damage, but, in certain cases, it can also activate and exploit the patient’s immune system to kill cancer cells that may have survived the radiation treatment or spread to other parts of the body. This phenomenon is commonly referred to as the abscopal effect, and has been reported in several different cancer types, including lymphoma, melanoma and hepatocellular carcinoma [1].
In some cancers, the expression of certain proteins on the surface of the cancer cell can mask them from the immune system. Many of these proteins are now the targets for a class of cancer immunotherapy drugs called immune checkpoint inhibitors. The inhibitors work by blocking these cell surface proteins so that T cells can attack and kill the cancer cells. While these immune checkpoint inhibitors have resulted in some dramatic responses in a subset of cancer patients, the number of patients who benefit from immune checkpoint therapies is low [2]. Many clinical trials are now investigating the potential for radiation therapy to increase the number of patients who can benefit from immune checkpoint therapies in a number of different cancer types [3]. In a recent case report, a melanoma patient who progressed while on an immune checkpoint inhibitor, called ipilimumab, was subsequently prescribed palliative radiation therapy and an additional dose of ipilimumab. Remarkably, not only did the patient’s irradiated tumour shrink, but so did the tumours outside of the radiation field [4].
While promising, it should be noted that the abscopal effect of radiation therapy is a rare phenomenon, and more research is needed to fully understand the mechanism by which it occurs and how best to exploit it. In recent pre-clinical studies, it was identified that repeated low doses of radiation in combination with immune checkpoint inhibitors was more effective at activating tumour-specific T cells and inhibiting tumour growth compared to single, higher doses of radiation [5-6]. These studies have important clinical implications, as they suggest that certain radiation doses and fractionation schedules may be more effective at eliciting the abscopal effect than others. The results of on-going clinical trials and further basic research will inform us how best to use radiation therapy in combination with cancer immunotherapies going forward, and have the potential to greatly influence cancer patient care.
This article was written by Joseph Longo. Joseph is currently pursuing a PhD in the Department of Medical Biophysics at the University of Toronto. He studies how statins can be used to treat cancer. To learn more about Joseph and his research, check out our members page.
References
[1] Formenti & Demaria (2009). Systemic effects of local radiotherapy. Lancet Oncol 10:718-726.
[2] Sharma & Allison (2015). Immune checkpoint targeting in cancer therapy: Toward combination strategies with curative potential. Cell 161:205-214.
[3] Kang et al. (2016). Current clinical trials testing the combination of immunotherapy with radiotherapy. J Immunother Cancer doi: 10.1186/s40425-016-0156-7.
[4] Postow et al. (2012). Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med 366:925-931.
[5] Dewan et al. (2009). Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res 15:5379-5388.
[6] Vanpouille-Box et al. (2017). DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat Commun doi: 10.1038/ncomms15618.
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