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

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          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.

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          Most cited references 33

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          Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade.

           Y Iwai,  M. Ishida,  Y. Tanaka (2002)
          PD-1 is a receptor of the Ig superfamily that negatively regulates T cell antigen receptor signaling by interacting with the specific ligands (PD-L) and is suggested to play a role in the maintenance of self-tolerance. In the present study, we examined possible roles of the PD-1/PD-L system in tumor immunity. Transgenic expression of PD-L1, one of the PD-L, in P815 tumor cells rendered them less susceptible to the specific T cell antigen receptor-mediated lysis by cytotoxic T cells in vitro, and markedly enhanced their tumorigenesis and invasiveness in vivo in the syngeneic hosts as compared with the parental tumor cells that lacked endogenous PD-L. Both effects could be reversed by anti-PD-L1 Ab. Survey of murine tumor lines revealed that all of the myeloma cell lines examined naturally expressed PD-L1. Growth of the myeloma cells in normal syngeneic mice was inhibited significantly albeit transiently by the administration of anti-PD-L1 Ab in vivo and was suppressed completely in the syngeneic PD-1-deficient mice. These results suggest that the expression of PD-L1 can serve as a potent mechanism for potentially immunogenic tumors to escape from host immune responses and that blockade of interaction between PD-1 and PD-L may provide a promising strategy for specific tumor immunotherapy.
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            Expansion and Activation of CD103(+) Dendritic Cell Progenitors at the Tumor Site Enhances Tumor Responses to Therapeutic PD-L1 and BRAF Inhibition.

            Large numbers of melanoma lesions develop resistance to targeted inhibition of mutant BRAF or fail to respond to checkpoint blockade. We explored whether modulation of intratumoral antigen-presenting cells (APCs) could increase responses to these therapies. Using mouse melanoma models, we found that CD103(+) dendritic cells (DCs) were the only APCs transporting intact antigens to the lymph nodes and priming tumor-specific CD8(+) T cells. CD103(+) DCs were required to promote anti-tumoral effects upon blockade of the checkpoint ligand PD-L1; however, PD-L1 inhibition only led to partial responses. Systemic administration of the growth factor FLT3L followed by intratumoral poly I:C injections expanded and activated CD103(+) DC progenitors in the tumor, enhancing responses to BRAF and PD-L1 blockade and protecting mice from tumor rechallenge. Thus, the paucity of activated CD103(+) DCs in tumors limits checkpoint-blockade efficacy and combined FLT3L and poly I:C therapy can enhance tumor responses to checkpoint and BRAF blockade.
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              Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial.

              Preclinical studies have found radiotherapy enhances antitumour immune responses. We aimed to assess disease control and pulmonary toxicity in patients who previously received radiotherapy for non-small-cell lung cancer (NSCLC) before receiving pembrolizumab.

                Author and article information

                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                13 December 2018
                : 8
                1Department of Radiation Oncology, Emory University , Atlanta, GA, United States
                2Department of Microbiology and Immunology, Emory University , Atlanta, GA, United States
                3Department of Radiation Oncology, Henry Ford Health System , Detroit, MI, United States
                4Erlanger UT Radiation Oncology , Chattanooga, TN, United States
                5Mitchell Cancer Institute, University of Southern Alabama , Mobile, AL, United States
                6Georgia Cancer Center, Augusta University , Augusta, GA, United States
                Author notes

                Edited by: Udo S. Gaipl, Universitätsklinikum Erlangen, Germany

                Reviewed by: Rodabe N. Amaria, University of Texas MD Anderson Cancer Center, United States; Daniel Olive, Faculté de Médecine, Aix Marseille Université, France

                *Correspondence: Mohammad K. Khan drkhurram2000@ 123456gmail.com

                This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Oncology

                Copyright © 2018 Buchwald, Wynne, Nasti, Zhu, Mourad, Yan, Gupta, Khleif and Khan.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 3, Tables: 2, Equations: 0, References: 72, Pages: 10, Words: 8230

                Oncology & Radiotherapy

                radiation, immunotherapy, checkpoint blockade, abscopal effect, pd-1, pd-l1


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