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      Implementing liquid biopsies into clinical decision making for cancer immunotherapy

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          Abstract

          During the last decade, novel immunotherapeutic strategies, in particular antibodies directed against immune checkpoint inhibitors, have revolutionized the treatment of different malignancies leading to an improved survival of patients. Identification of immune-related biomarkers for diagnosis, prognosis, monitoring of immune responses and selection of patients for specific cancer immunotherapies is urgently required and therefore areas of intensive research. Easily accessible samples in particular liquid biopsies (body fluids), such as blood, saliva or urine, are preferred for serial tumor biopsies.

          Although monitoring of immune and tumor responses prior, during and post immunotherapy has led to significant advances of patients’ outcome, valid and stable prognostic biomarkers are still missing. This might be due to the limited capacity of the technologies employed, reproducibility of results as well as assay stability and validation of results. Therefore solid approaches to assess immune regulation and modulation as well as to follow up the nature of the tumor in liquid biopsies are urgently required to discover valuable and relevant biomarkers including sample preparation, timing of the collection and the type of liquid samples. This article summarizes our knowledge of the well-known liquid material in a new context as liquid biopsy and focuses on collection and assay requirements for the analysis and the technical developments that allow the implementation of different high-throughput assays to detect alterations at the genetic and immunologic level, which could be used for monitoring treatment efficiency, acquired therapy resistance mechanisms and the prognostic value of the liquid biopsies.

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          Most cited references63

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          CANCER IMMUNOLOGY. The "cancer immunogram".

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            The Next Hurdle in Cancer Immunotherapy: Overcoming the Non-T-Cell-Inflamed Tumor Microenvironment.

            A growing body of evidence suggests that a major subset of patients with advanced solid tumors shows evidence for a T-cell-inflamed tumor microenvironment. This phenotype has positive prognostic value for several types of early stage cancer, suggesting that the attempt by the host to generate an anti-tumor immune response reflects a biologic process associated with improved patient outcomes. In metastatic disease, the presence of this phenotype appears to be associated with clinical response to several immunotherapies, including cancer vaccines, checkpoint blockade, and adoptive T-cell transfer. With the high rate of clinical response to several of these therapies, along with early data indicating that combination immunotherapies may be even more potent, it seems likely that effective immune-based therapies will become a reality for patients with a range of different cancers that physiologically support the T-cell-inflamed tumor microenvironment in a subset of individuals. Therefore, one of the next significant hurdles will be to develop new therapeutic interventions that will enable these immunotherapies to be effective in patients with the non-T-cell-inflamed phenotype. Rational development of such interventions will benefit from a detailed molecular understanding of the mechanisms that explain the presence or absence of the T-cell-inflamed tumor microenvironment, which in turn will benefit from focused interrogation of patient samples. This iterative "reverse-translational" research strategy has already identified new candidate therapeutic targets and approaches. It is envisioned that the end result of these investigations will be an expanded array of interventions that will broaden the fraction of patients benefitting from immunotherapies in the clinic.
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              Liquid Biopsies, What We Do Not Know (Yet).

              The inherent molecular heterogeneity of metastatic tumors and the ability of cancer genomes to dynamically evolve are not properly captured by tissue specimens. Analysis of cell-free DNA and circulating tumor cells has the potential to change clinical practice by exploiting blood rather than tissue as a source of information. Liquid biopsies are already used to monitor disease response and track the emergence of drug resistance. The suitability of blood-based molecular profiles for early detection and monitoring minimal residual disease is being evaluated. In this review, we address open questions in this fast-evolving field of research.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                18 July 2017
                24 April 2017
                : 8
                : 29
                : 48507-48520
                Affiliations
                1 Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Halle, Germany
                2 Protagen, Dortmund, Germany
                3 Department of Haematology and Oncology, Medical University Innsbruck, Innsbruck, Austria
                4 Experimental Pharmacology and Oncology, Berlin-Buch GmbH, Berlin, Germany
                5 Create Health Translational Cancer Center, Lund University, Lund, Sweden
                6 Roche Pharmaceutical Research and Early Development, Roche Innovation Center, Munich, Germany
                7 Laboratory for Translational Genetics, VIB Center for Cancer Biology, Leuven, Belgium
                8 Institute of Legal Medicine and Core Facility Metabolomics, Medical University of Innsbruck, Innsbruck, Austria
                9 Global Drug Development, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA
                10 Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
                11 Qiagen, Hilden, Germany
                12 CRUK Cambridge Institute, Cambridge, UK
                13 University Medical Center Hamburg-Eppendorf, Department of Tumor Biology Hamburg, Hamburg, Germany
                14 Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, Italy
                15 Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
                16 Perkin Elmer, Hamburg, Germany
                17 Biodesix, Boulder, Colorado, USA
                18 Exosome Diagnostics GmbH, Martinsried, Germany
                19 Hendriks Pharmaceutical Consulting, Purmerend, The Netherlands
                Author notes
                Correspondence to: Barbara Seliger, Barbara.Seliger@ 123456uk-halle.de
                Article
                17397
                10.18632/oncotarget.17397
                5564665
                28501851
                6d299d70-60d1-42c0-9890-b5494eb334d2
                Copyright: © 2017 Quandt et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 8 February 2017
                : 4 April 2017
                Categories
                Review

                Oncology & Radiotherapy
                liquid biopsy,biomarker,tumor,high throughput analysis,immunotherapy
                Oncology & Radiotherapy
                liquid biopsy, biomarker, tumor, high throughput analysis, immunotherapy

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