Radiotherapy–Immunotherapy Combination: How Will We Bridge the Gap Between Pre-Clinical Promise and Effective Clinical Delivery?

SIMPLE SUMMARY: Radiotherapy is an important component of cancer treatment, given to around half of all cancer patients. Radiotherapy is known to be very effective at directly killing cancer but, until recently, the important effects that radiotherapy has on the surrounding immune cells were not widely appreciated. Over the last decade, immunotherapy approaches have made a major breakthrough in cancer treatment, and now play an important part of routine cancer care. Given that both radiotherapy and immunotherapy can stimulate anti-tumor immune response, it is logical to combine these approaches to try and improve anti-tumor immunity and cancer outcomes further. This review assesses the important clinical questions that need to be addressed to successfully combine radiotherapy and immunotherapy treatments by rethinking approaches to the delivery of radiotherapy, as well as the optimal type and scheduling of immunotherapy. ABSTRACT: Radiotherapy (RT) is highly effective at directly killing tumor cells and plays an important part in cancer treatments being delivered to around 50% of all cancer patients. The additional immunomodulatory properties of RT have been investigated, and if exploited effectively, have the potential to further improve the efficacy of RT and cancer outcomes. The initial results of combining RT with immunomodulatory agents have generated promising data in pre-clinical studies, which has in turn led to a large number of RT and immunotherapy clinical trials. The overarching aim of these combinations is to enhance anti-tumor immune responses and improve responses rates and patient outcomes. In order to maximize this undoubted opportunity, there remain a number of important questions that need to be addressed, including: (i) the optimal RT dose and fractionation schedule; (ii) the optimal RT target volume; (iii) the optimal immuno-oncology (IO) agent(s) to partner with RT; (iv) the optimal site(s)/route(s) of administration of IO agents; and finally, the optimal RT schedule. In this review, we will summarize progress to date and identify current gaps in knowledge that need to be addressed in order to facilitate effective clinical translation of RT and IO agent combinations.