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      Intra-hepatic Abscopal Effect Following Radioembolization of Hepatic Metastases

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          Abstract

          Purpose

          To search for abscopal effects (AE) distant to the site of radiation after sequential Yittrium-90 (Y-90) radioembolization (RE) of liver malignancies.

          Methods and Materials

          In this retrospective analysis, all patients treated by RE between 2007 and 2018 ( n = 907) were screened for the following setting/conditions: sequential RE of left and right liver lobe in two sessions, liver-specific MRI (MRI1) acquired max. 10 days before or after first RE (RE1), liver-specific MRI (MRI2) acquired with a minimum time interval of 20 days after MRI1, but before second RE (RE2). No systemic tumor therapies between MRI1 and MRI2. No patients with liver cirrhosis. Metastases > 5 mm in untreated liver lobes were compared in MRI1 and MRI2 and rated as follows: same size or larger in MRI2 = no abscopal effect (NAE); > 30% shrinkage without Y-90 contamination in SPECT/CT = abscopal effect (AE).

          Results

          Ninety six of 907 patients met aforementioned criteria. Median time-frame between RE1 and MRI2 was 34 (20–64) days. These 96 cases had 765 metastases which were evaluable (median 5(1–40) metastases per patient). Four patients could be identified with at least one shrinking metastasis of the untreated site: one patient with breast cancer (3 metastases: 0 NAE; 3 AE), one patient with prostate cancer (6 metastases: 3 NAE; 3 metastases > 30% shrinkage but possible Y-90 contamination) and two patients with shrinkage of one metastasis each but less than 30%.

          Conclusion

          Our retrospective study documents AE after RE of liver tumors in 1 out of 96 cases, 3 other cases remain unclear.

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          Most cited references34

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          Oncology meets immunology: the cancer-immunity cycle.

          The genetic and cellular alterations that define cancer provide the immune system with the means to generate T cell responses that recognize and eradicate cancer cells. However, elimination of cancer by T cells is only one step in the Cancer-Immunity Cycle, which manages the delicate balance between the recognition of nonself and the prevention of autoimmunity. Identification of cancer cell T cell inhibitory signals, including PD-L1, has prompted the development of a new class of cancer immunotherapy that specifically hinders immune effector inhibition, reinvigorating and potentially expanding preexisting anticancer immune responses. The presence of suppressive factors in the tumor microenvironment may explain the limited activity observed with previous immune-based therapies and why these therapies may be more effective in combination with agents that target other steps of the cycle. Emerging clinical data suggest that cancer immunotherapy is likely to become a key part of the clinical management of cancer. Copyright © 2013 Elsevier Inc. All rights reserved.
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            Immunogenic cell death in cancer and infectious disease

            Initiation of an adaptive immune response depends on the detection of both antigenic epitopes and adjuvant signals. Infectious pathogens and cancer cells often avoid immune detection by limiting the release of danger signals from dying cells. When is cell death immunogenic and what are the pathophysiological implications of this process?
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              Radiation and Dual Checkpoint Blockade Activates Non-Redundant Immune Mechanisms in Cancer

              Immune checkpoint inhibitors 1 result in impressive clinical responses 2–5 but optimal results will require combination with each other 6 and other therapies. This raises fundamental questions about mechanisms of non-redundancy and resistance. Here, we report major tumor regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation (RT) and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumors, resistance was common. Unbiased analyses of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T cell exhaustion. Accordingly, optimal response in melanoma and other cancer types requires RT, anti-CTLA4, and anti-PD-L1/PD-1. Anti-CTLA4 predominantly inhibits T regulatory cells (Tregs) to increase the CD8 T cell to Treg (CD8/Treg) ratio. RT enhances the diversity of the T cell receptor (TCR) repertoire of intratumoral T cells. Together, anti-CTLA4 promotes expansion of T cells, while RT shapes the TCR repertoire of the expanded peripheral clones. Addition of PD-L1 blockade reverses T cell exhaustion to mitigate depression in the CD8/Treg ratio and further encourages oligo-clonal T cell expansion. Similar to results from mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to RT + anti-CTLA4, demonstrated persistent T cell exhaustion, and rapidly progressed. Thus, PD-L1 on melanoma cells allows tumors to escape anti-CTLA4-based therapy, and the combination of RT, anti-CTLA4, and anti-PD-L1 promotes response and immunity through distinct mechanisms.
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                Author and article information

                Contributors
                maciej.powerski@med.ovgu.de
                ralph.drewes@med.ovgu.de
                jazan.omari@med.ovgu.de
                borna.relja@med.ovgu.de
                alexey.surov@med.ovgu.de
                maciej.pech@med.ovgu.de
                Journal
                Cardiovasc Intervent Radiol
                Cardiovasc Intervent Radiol
                Cardiovascular and Interventional Radiology
                Springer US (New York )
                0174-1551
                1432-086X
                17 August 2020
                17 August 2020
                2020
                : 43
                : 11
                : 1641-1649
                Affiliations
                [1 ]GRID grid.5807.a, ISNI 0000 0001 1018 4307, Department of Radiology and Nuclear Medicine, , Otto-Von-Guericke University, ; Leipziger Str. 44, 39120 Magdeburg, Germany
                [2 ]GRID grid.11451.30, ISNI 0000 0001 0531 3426, 2nd Department of Radiology, , Medical University of Gdansk, ; Mariana Smoluchowskiego 17, 80-214, Gdansk, Poland
                Author information
                http://orcid.org/0000-0001-6308-5695
                Article
                2612
                10.1007/s00270-020-02612-4
                7591411
                32808201
                6c9ca17f-ee94-4e35-99e2-caf89be02638
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 26 March 2020
                : 2 August 2020
                Categories
                Clinical Investigation
                Custom metadata
                © Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2020

                Cardiovascular Medicine
                abscopal effect,radioembolization,sirt
                Cardiovascular Medicine
                abscopal effect, radioembolization, sirt

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