AUTHOR=Buchwald Zachary S. , Wynne Jacob , Nasti Tahseen H. , Zhu Simeng , Mourad Waleed F. , Yan Weisi , Gupta Seema , Khleif Samir N. , Khan Mohammad K. TITLE=Radiation, Immune Checkpoint Blockade and the Abscopal Effect: A Critical Review on Timing, Dose and Fractionation JOURNAL=Frontiers in Oncology VOLUME=8 YEAR=2018 URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2018.00612 DOI=10.3389/fonc.2018.00612 ISSN=2234-943X 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.