Developments in Combining Targeted Radionuclide Therapies and Immunotherapies for Cancer Treatment

Abstract

Targeted radionuclide therapy (TRT) and immunotherapy are rapidly growing classes of cancer treatments. Basic, translational, and clinical research are now investigating therapeutic combinations of these agents. In comparison to external beam radiation therapy (EBRT), TRT has the unique advantage of treating all disease sites following intravenous injection and selective tumor uptake and retention-a particularly beneficial property in metastatic disease settings. The therapeutic value of combining radiation therapy with immune checkpoint blockade to treat metastases has been demonstrated in preclinical studies, whereas results of clinical studies have been mixed. Several clinical trials combining TRT and immune checkpoint blockade have been initiated based on preclinical studies combining these with EBRT and/or TRT. Despite the interest in translation of TRT and immunotherapy combinations, many questions remain surrounding the mechanisms of interaction and the optimal approach to clinical implementation of these combinations. This review highlights the mechanisms of interaction between anti-tumor immunity and radiation therapy and the status of basic and translational research and clinical trials investigating combinations of TRT and immunotherapies.

Keywords: anti-tumor immunity; external beam radiation therapy (EBRT); targeted radionuclide therapy (TRT); tumor microenvironment (TME).

Figure 1

Tumor microenvironment irradiation by alpha-emitters versus beta-emitters. Physical property differences of alpha particles and beta particles lead to different tumor irradiation patterns. Alpha particles (high linear energy transfer (LET), short tissue range) traverse 1–2 cell diameters with a high density of ionization events along their track. Beta particles (low LET, long tissue range) travel millimeters in tissue with sparse ionization events, and have the potential to irradiate many structures in addition to the cell of targeted radionuclide therapy (TRT) uptake. Created with BioRender.com.

Figure 2

Schematic of immune activation mechanisms by targeted radionuclide therapy (TRT). Initially, tumor cells treated by TRT undergo immunogenic cell death (ICD), releasing tumor specific antigens in the process, while other surviving cells undergo phenotypic changes. These include increased PD-L1, MHC-I, and Fas expression, as well as IFNβ production through activation of the cGAS/STING pathway. Additionally, innate immune cell populations increase in the tumor microenvironment (TME), including dendritic cells (DCs), natural killer (NK) cells, macrophages, and other innate myeloid cells. Finally, a robust adaptive immune response is generated, characterized by increased CTLA-4⁺ CD8⁺ and PD-1⁺ CD8⁺ T cell populations, as well as effector memory T cell populations, and both increases and decreases in regulatory T cell populations. Created with BioRender.com.