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

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.

Safety of PD-1/PD-L1 Inhibitors Combined With Palliative Radiotherapy and Anti-Angiogenic Therapy in Advanced Hepatocellular Carcinoma

“…These signals favor the recruitment of antigen-presenting cells (APCs) and enhance their phagocytic activity, processing of tumor-associated antigens (TAAs), and cross-presentation of antigenic peptides on major histocompatibility complex class I (MHC I). Cross-presentation of tumor antigens can lead to subsequent priming and trafficking of tumor-specific T lymphocytes into the tumor microenvironment ( 11 ). The initial results of combining radiotherapy with immunomodulatory agents have generated promising data in pre-clinical studies ( 12 , 13 ), which has, in turn, led to a large number of radiotherapy and immunotherapy clinical trials ( 14 , 15 ).…”

Atypical Response Patterns in Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors—Navigating the Radiologic Potpourri

“…We acknowledge that clinical trials are in development and have yet to show definitive benefit with the addition of SBRT [8,21]. However, much remains to be discovered about the optimal timing and dosing of SBRT [20][21][22]. If we did indeed show isolated lesions responding to an abscopal effect of SBRT, perhaps this out-of-field effect could be made more global by irradiating a greater total volume or number of sites of tumors [23,24].…”

“…In our series, most of the patients had lesions that were shown to be stable or progressing on at least two prior scans, yet we know that late responses and late pseudoprogressions are possible. We acknowledge that clinical trials are in development and have yet to show definitive benefit with the addition of SBRT [8,21]. However, much remains to be discovered about the optimal timing and dosing of SBRT [20][21][22].…”

Treatment of Cancer with Radio-Immunotherapy: What We Currently Know and What the Future May Hold

“…In addition to focusing on patient populations most likely to benefit from radio-immunotherapy, future studies should also investigate novel means of widening the therapeutic ratio of radio-immunotherapy. A number of ongoing studies aim to characterize combinations of immunomodulatory agents that may be able to enhance and/or improve upon the efficacy of radio-immunotherapy regimens that utilize ICB [54]. Recent evidence also suggests that the microbiome affects anti-tumor immune responses induced by both ICB [55] and radiotherapy [56,57], and therefore this could be a point of further investigation going forward.…”