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.

Keywords: administration sequencing; administration site/route; fractionation schedule; immuno-oncology agents; immunotherapy; radiotherapy; radiotherapy dose; treatment field; tumor volume.

Figure 1

Immunomodulatory effects of radiotherapy. Local radiation to the tumor can elicit immunogenic cell death, leading to the release of cytokines and DAMPs that in turn trigger innate signaling pathways. These signals favor the recruitment of APCs such as DCs, promote uptake of dying tumor cells, and enhance the processing of TAAs and cross-presentation of antigenic-peptides, via MHC I, to CD8⁺ T cells. Cross-presentation of tumor-antigens can lead to the priming of tumor-specific T lymphocytes, which can then traffic back to the tumor site, infiltrate into the tumor, and potentially exert cytolytic effector activity. Radiation can also induce the release of type-I IFN from both cancer and immune cells, as well as trigger complement activation, which can reinforce both DC and T cell activation. RT can also cause upregulation of MHC I, the adhesion molecule, ICAM, and the membrane protein NKG2D type II (ligand), that ultimately enhance tumor recognition and killing by T cells and NK cells, respectively. Abbreviations. DAMPs: damage associated molecular patterns; APCs: antigen presenting cells; DCs: dendritic cells; TAAs: tumor-associated antigens; MHC I: major histocompatibility complex class I; IFN: interferon; NKG2D: natural killer group 2D; NKs: natural killer cells. Figure created with the aid of biorender.com and https://smart.servier.com/.

Figure 2

The potential effects of radiation field and volume on immune responses and tumor. The size of the treatment field and the volume of the tumor irradiated can influence both local and systemic anti-cancer immune responses. (A) Including the DLNs (right side) in the radiation field could affect the balance of cytokines and chemokines which, together with the release and processing of tumor antigens, leads to trafficking and migration of immune cells (i.e., CD8⁺ T cells and DCs) to the tumor. Cancer cell eradication will be mediated by activated (green halo) CD8⁺ T cells. However, RT directed towards DLNs may also have cytotoxic effects on lymphocytes, hence impeding an effective anti-tumor immune response. (B) The irradiation of oligometastases, in addition to the primary tumor, might favor the expression or release of greater amounts and/or new tumor antigens, in a way that is proportional to the tumor burden. Multi-site RT may therefore lead to the priming and subsequent infiltration of immune cells into the different lesions (sensitization of the tumors to immune infiltration). (C) Partial tumor irradiation might be a way to indirectly control the whole tumor, by generating immune activation starting from the hemi-irradiated part. For example, activated CD T cells (shown in green) may migrate from the field of RT into the remainder of the tumor, whereby they may display anti-cancer activity in the non-irradiated part. Abbreviations. DCs: dendritic cells; TAAs: tumor-associated antigens. Figure created with the aid of biorender.com and https://smart.servier.com/.