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      Review of cancer treatment with immune checkpoint inhibitors : Current concepts, expectations, limitations and pitfalls

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          Summary

          Immunotherapy by checkpoint inhibition is about to profoundly change cancer therapy. The number of indications are growing at an unprecedented speed. Clinical studies have demonstrated efficacy in a variety of solid tumors and in hematologic malignancies, although some clinical trials have produced negative results. Thus, it is fair to assume that there are obvious limitations and pitfalls in immunotherapy. Future concepts for combination treatment of immune checkpoint inhibitors have to be developed, but there is also urgent need for better and standardized biomarkers to identify those cancer patients who will benefit from treatment by checkpoint inhibition. The current overview summarizes current knowledge on immune checkpoint inhibitor treatment in malignancies, its outlook and limitations, diagnostic means and, finally, side effect management.

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          Most cited references40

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          Radiotherapy and immunotherapy: a beneficial liaison?

          The interaction between radiotherapy and the host immune system has uncovered new mechanisms that can be exploited to improve the efficacy of radiotherapy. In this article, the authors highlight data providing new explanations for the success or failure of radiotherapy, and postulate, using radiation-induced tumour equilibrium (RITE) as an example, how the combination of immune-modulation and radiation could tip the balance of the host immune response to promote cure.
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            Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients.

            CD4+CD25+ regulatory T cells are involved in the prevention of autoimmune diseases and in tumor-induced tolerance. We previously demonstrated in tumor-bearing rodents that one injection of cyclophosphamide could significantly decrease both numbers and suppressive functions of regulatory T cells, facilitating vaccine-induced tumor rejection. In humans, iterative low dosing of cyclophosphamide, referred to as "metronomic" therapy, has recently been used in patients with advanced chemotherapy resistant cancers with the aim of reducing tumor angiogenesis. Here we show that oral administration of metronomic cyclophosphamide in advanced cancer patients induces a profound and selective reduction of circulating regulatory T cells, associated with a suppression of their inhibitory functions on conventional T cells and NK cells leading to a restoration of peripheral T cell proliferation and innate killing activities. Therefore, metronomic regimen of cyclophosphamide does not only affect tumor angiogenesis but also strongly curtails immunosuppressive regulatory T cells, favoring a better control of tumor progression. Altogether these data support cyclophosphamide regimen as a valuable treatment for reducing tumor-induced immune tolerance before setting to work anticancer immunotherapy.
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              Clinical development of CAR T cells—challenges and opportunities in translating innovative treatment concepts

              Abstract Chimeric antigen receptor (CAR) T cell therapy, together with checkpoint inhibition, has been celebrated as a breakthrough technology due to the substantial benefit observed in clinical trials with patients suffering from relapsed or refractory B‐cell malignancies. In this review, we provide a comprehensive overview of the clinical trials performed so far worldwide and analyze parameters such as targeted antigen and indication, CAR molecular design, CAR T cell manufacturing, anti‐tumor activities, and related toxicities. More than 200 CAR T cell clinical trials have been initiated so far, most of which aim to treat lymphoma or leukemia patients using CD19‐specific CARs. An increasing number of studies address solid tumors as well. Notably, not all clinical trials conducted so far have shown promising results. Indeed, in a few patients CAR T cell therapy resulted in severe adverse events with fatal outcome. Of note, less than 10% of the ongoing CAR T cell clinical trials are performed in Europe. Taking lead from our analysis, we discuss the problems and general hurdles preventing efficient clinical development of CAR T cells as well as opportunities, with a special focus on the European stage.
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                Author and article information

                Contributors
                christiane.thallinger@meduniwien.ac.at
                Journal
                Wien Klin Wochenschr
                Wien. Klin. Wochenschr
                Wiener Klinische Wochenschrift
                Springer Vienna (Vienna )
                0043-5325
                1613-7671
                2 November 2017
                2 November 2017
                2018
                : 130
                : 3
                : 85-91
                Affiliations
                [1 ]ISNI 0000 0004 0520 9719, GRID grid.411904.9, Clinical Division of Oncology, Department of Medicine I, , General Hospital, ; Währinger Gürtel 18–20, 1090 Vienna, Austria
                [2 ]GRID grid.488232.7, Central European Cooperative Oncology Group, ; Vienna, Austria
                [3 ]ISNI 0000 0000 9259 8492, GRID grid.22937.3d, Comprehensive Cancer Center, General Hospital, , Medical University Vienna, ; Vienna, Austria
                [4 ]ISNI 0000 0000 9259 8492, GRID grid.22937.3d, Department of Pathology, General Hospital, , Medical University Vienna, ; Vienna, Austria
                [5 ]ISNI 0000 0000 9259 8492, GRID grid.22937.3d, Department of Dermatology, General Hospital, , Medical University Vienna, ; Vienna, Austria
                [6 ]ISNI 0000 0000 9259 8492, GRID grid.22937.3d, Department of Radiology, General Hospital, , Medical University Vienna, ; Vienna, Austria
                [7 ]European Cancer Patient Coalition (ECPC), Brussels, Belgium
                [8 ]ISNI 0000 0000 9259 8492, GRID grid.22937.3d, Institute for Cancer Research, Department of Medicine I, , Medical University Vienna, ; Vienna, Austria
                [9 ]ISNI 0000 0000 9259 8492, GRID grid.22937.3d, Clinical Division of Hematology, Department of Medicine I, , Medical University Vienna, ; Vienna, Austria
                Author information
                http://orcid.org/0000-0003-2714-535X
                Article
                1285
                10.1007/s00508-017-1285-9
                5816095
                29098404
                a216a5ae-430c-43ec-898a-5a3248d2da9b
                © The Author(s) 2017

                Open Access This 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.

                History
                : 22 August 2017
                : 10 October 2017
                Funding
                Funded by: Medical University of Vienna
                Categories
                Review Article
                Custom metadata
                © Springer-Verlag GmbH Austria, part of Springer Nature 2018

                Medicine
                cancer,immunotherapy,pd-1,experts,review
                Medicine
                cancer, immunotherapy, pd-1, experts, review

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