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      Current clinical trials testing the combination of immunotherapy with radiotherapy

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          Abstract

          Increasing evidence demonstrates that radiation acts as an immune stimulus, recruiting immune mediators that enable anti-tumor responses within and outside the radiation field. There has been a rapid expansion in the number of clinical trials harnessing radiation to enhance antitumor immunity. If positive, results of these trials will lead to a paradigm shift in the use of radiotherapy. In this review, we discuss the rationale for trials combining radiation with various immunotherapies, provide an update of recent clinical trial results and highlight trials currently in progress. We also address issues pertaining to the optimal incorporation of immunotherapy with radiation, including sequencing of treatment, radiation dosing and evaluation of clinical trial endpoints.

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          Models, mechanisms and clinical evidence for cancer dormancy.

          Julio Aguirre-Ghiso (2007)
          Patients with cancer can develop recurrent metastatic disease with latency periods that range from years even to decades. This pause can be explained by cancer dormancy, a stage in cancer progression in which residual disease is present but remains asymptomatic. Cancer dormancy is poorly understood, resulting in major shortcomings in our understanding of the full complexity of the disease. Here, I review experimental and clinical evidence that supports the existence of various mechanisms of cancer dormancy including angiogenic dormancy, cellular dormancy (G0-G1 arrest) and immunosurveillance. The advances in this field provide an emerging picture of how cancer dormancy can ensue and how it could be therapeutically targeted.
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            Decisions about dendritic cells: past, present, and future.

            Ralph M. Steinman (2012)
            A properly functioning adaptive immune system signifies the best features of life. It is diverse beyond compare, tolerant without fail, and capable of behaving appropriately with a myriad of infections and other challenges. Dendritic cells are required to explain how this remarkable system is energized and directed. I frame this article in terms of the major decisions that my colleagues and I have made in dendritic cell science and some of the guiding themes at the time the decisions were made. As a result of progress worldwide, there is now evidence of a central role for dendritic cells in initiating antigen-specific immunity and tolerance. The in vivo distribution and development of a previously unrecognized white cell lineage is better understood, as is the importance of dendritic cell maturation to link innate and adaptive immunity in response to many stimuli. Our current focus is on antigen uptake receptors on dendritic cells. These receptors enable experiments involving selective targeting of antigens in situ and new approaches to vaccine design in preclinical and clinical systems.
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              Combining radiotherapy and cancer immunotherapy: a paradigm shift.

              Silvia Formenti, Sandra Demaria (2013)
              The therapeutic application of ionizing radiation has been largely based on its cytocidal power combined with the ability to selectively target tumors. Radiotherapy effects on survival of cancer patients are generally interpreted as the consequence of improved local control of the tumor, directly decreasing systemic spread. Experimental data from multiple cancer models have provided sufficient evidence to propose a paradigm shift, whereby some of the effects of ionizing radiation are recognized as contributing to systemic antitumor immunity. Recent examples of objective responses achieved by adding radiotherapy to immunotherapy in metastatic cancer patients support this view. Therefore, the traditional palliative role of radiotherapy in metastatic disease is evolving into that of a powerful adjuvant for immunotherapy. This combination strategy adds to the current anticancer arsenal and offers opportunities to harness the immune system to extend survival, even among metastatic and heavily pretreated cancer patients. We briefly summarize key evidence supporting the role of radiotherapy as an immune adjuvant. A critical appraisal of the current status of knowledge must include potential immunosuppressive effects of radiation that can hamper its capacity to convert the irradiated tumor into an in situ, individualized vaccine. Moreover, we discuss some of the current challenges to translate this knowledge to the clinic as more trials testing radiation with different immunotherapies are proposed.
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                Author and article information

                Contributors
                Josephine Kang: jok9106@med.cornell.edu
                Sandra Demaria: szd3005@med.cornell.edu
                Silvia Formenti: 212-746-3600 , formenti@med.cornell.edu
                Journal
                Journal ID (nlm-ta): J Immunother Cancer
                Journal ID (iso-abbrev): J Immunother Cancer
                Title: Journal for Immunotherapy of Cancer
                Publisher: BioMed Central (London )
                ISSN (Electronic): 2051-1426
                Publication date (Electronic): 20 September 2016
                Publication date PMC-release: 20 September 2016
                Publication date Collection: 2016
                Volume: 4
                Electronic Location Identifier: 51
                Affiliations
                [1 ]Department of Radiation Oncology, Weill Cornell Medicine, 525 East 68th Street, New York, NY 10065 USA
                [2 ]Department of Radiation Oncology, Stich Radiation Center, 525 East 68th Street, New York, NY 10065 USA
                Article
                Publisher ID: 156
                DOI: 10.1186/s40425-016-0156-7
                PMC ID: 5028964
                PubMed ID: 27660705
                SO-VID: 51e88405-f04d-4165-a9b1-550f6f1fa033
                Copyright © © The Author(s). 2016
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 10 June 2016
                Date accepted : 2 August 2016
                Categories
                Subject: Clinical Trials Monitor
                Custom metadata
                issue-copyright-statement © The Author(s) 2016

                Keywords: antitumor immunity,immunotherapy,radiotherapy,stereotactic body radiation therapy,abscopal effect,ctla-4,pd-1,pd-l1,tgfβ
                Data availability:
                Keywords: antitumor immunity, immunotherapy, radiotherapy, stereotactic body radiation therapy, abscopal effect, ctla-4, pd-1, pd-l1, tgfβ

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