Radiation, Immune Checkpoint Blockade and the Abscopal Effect: A Critical Review on Timing, Dose and Fractionation

Abstract

The combination of radiation and immunotherapy is currently an exciting avenue of pre-clinical and clinical investigation. The synergy between these two treatment modalities has the potential to expand the role of radiation from a purely local therapy, to a role in advanced and metastatic disease. Tumor regression outside of the irradiated field, known as the abscopal effect, is a recognized phenomenon mediated by lymphocytes and enhanced by checkpoint blockade. In this review, we summarize the known mechanistic data behind the immunostimulatory effects of radiation and how this is enhanced by immunotherapy. We also provide pre-clinical data supporting specific radiation timing and optimal dose/fractionation for induction of a robust anti-tumor immune response with or without checkpoint blockade. Importantly, these data are placed in a larger context of understanding T-cell exhaustion and the impact of immunotherapy on this phenotype. We also include relevant pre-clinical studies done in non-tumor systems. We discuss the published clinical trials and briefly summarize salient case reports evaluating the abscopal effect. Much of the data discussed here remains at the preliminary stage, and a number of interesting avenues of research remain under investigation.

Monitoring CD8a+ T Cell Responses to Radiotherapy and CTLA-4 Blockade Using [64Cu]NOTA-CD8a PET Imaging

“…Increased CD8 + numbers in the spleen of mice have previously been demonstrated on day 8 following a fractionated 3 × 9.18 Gy dose in combination with anti-PD-1 [30]. The exact T cell infiltration kinetics indeed depend on murine tumor model and XRT dose schedule [31] and it is plausible that our dosing regimen or the timing of PET imaging was not optimal to detect systemic changes in CD8a + numbers. This notion is supported by the flow cytometric ex vivo analysis, which did not show differences in splenic CD45 + CD8a + numbers among treatment groups on day 8 following therapy initiation (Fig.…”

Adrenergic stress constrains the development of anti-tumor immunity and abscopal responses following local radiation

“…Other questions arise from these data. For example, what is the impact of adrenergic stress on the efficacy of different radiation schedules (e.g., fractionated vs. hypofractionated) and on antitumor immunity 61 ? Here, we used single fraction doses that are known to be suboptimal in controlling tumor growth within the field of irradiation and do not result in abscopal effects.…”

Impact of Sequencing Radiation Therapy and Immune Checkpoint Inhibitors in the Treatment of Melanoma Brain Metastases

“…In line with our observations, RT induces various mechanisms that may enhance response to subsequent therapy with ICI, including enhanced antigen-presenting cells, induction of immune stimulatory cytokines and chemokines, enhanced T cell infiltration, induction of immune stimulatory cytokine production by T cells, maintenance of T cell effector function, and partial reversal of T cell dysfunction. [15][16][17] Of note, an important consideration when interpreting the RNA-seq data from this study is the timing of tumor resection and RT/ICI. The majority of evaluated specimens (11 of 17) were resected before adjuvant RT, suggesting that the differential gene expression may be more representative of intrinsic tumor biology than effects of prescribed therapies.…”