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      Novel technologies and emerging biomarkers for personalized cancer immunotherapy

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          Abstract

          The culmination of over a century’s work to understand the role of the immune system in tumor control has led to the recent advances in cancer immunotherapies that have resulted in durable clinical responses in patients with a variety of malignancies. Cancer immunotherapies are rapidly changing traditional treatment paradigms and expanding the therapeutic landscape for cancer patients. However, despite the current success of these therapies, not all patients respond to immunotherapy and even those that do often experience toxicities. Thus, there is a growing need to identify predictive and prognostic biomarkers that enhance our understanding of the mechanisms underlying the complex interactions between the immune system and cancer. Therefore, the Society for Immunotherapy of Cancer (SITC) reconvened an Immune Biomarkers Task Force to review state of the art technologies, identify current hurdlers, and make recommendations for the field. As a product of this task force, Working Group 2 (WG2), consisting of international experts from academia and industry, assembled to identify and discuss promising technologies for biomarker discovery and validation. Thus, this WG2 consensus paper will focus on the current status of emerging biomarkers for immune checkpoint blockade therapy and discuss novel technologies as well as high dimensional data analysis platforms that will be pivotal for future biomarker research. In addition, this paper will include a brief overview of the current challenges with recommendations for future biomarker discovery.

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          Most cited references146

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          Direct multiplexed measurement of gene expression with color-coded probe pairs.

          We describe a technology, the NanoString nCounter gene expression system, which captures and counts individual mRNA transcripts. Advantages over existing platforms include direct measurement of mRNA expression levels without enzymatic reactions or bias, sensitivity coupled with high multiplex capability, and digital readout. Experiments performed on 509 human genes yielded a replicate correlation coefficient of 0.999, a detection limit between 0.1 fM and 0.5 fM, and a linear dynamic range of over 500-fold. Comparison of the NanoString nCounter gene expression system with microarrays and TaqMan PCR demonstrated that the nCounter system is more sensitive than microarrays and similar in sensitivity to real-time PCR. Finally, a comparison of transcript levels for 21 genes across seven samples measured by the nCounter system and SYBR Green real-time PCR demonstrated similar patterns of gene expression at all transcript levels.
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            Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors.

            The success in lung cancer therapy with programmed death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between EGF receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, CTL antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased CTLs and increased markers of T-cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T-cell function and lowering the levels of tumor-promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non-small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape and mechanistically link treatment response to PD-1 inhibition. We show that autochthonous EGFR-driven lung tumors inhibit antitumor immunity by activating the PD-1/PD-L1 pathway to suppress T-cell function and increase levels of proinflammatory cytokines. These findings indicate that EGFR functions as an oncogene through non-cell-autonomous mechanisms and raise the possibility that other oncogenes may drive immune escape. ©2013 AACR.
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              Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment.

              Despite the frequent detection of circulating tumor antigen-specific T cells, either spontaneously or following active immunization or adoptive transfer, immune-mediated cancer regression occurs only in the minority of patients. One theoretical rate-limiting step is whether effector T cells successfully migrate into metastatic tumor sites. Affymetrix gene expression profiling done on a series of metastatic melanoma biopsies revealed a major segregation of samples based on the presence or absence of T-cell-associated transcripts. The presence of lymphocytes correlated with the expression of defined chemokine genes. A subset of six chemokines (CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10) was confirmed by protein array and/or quantitative reverse transcription-PCR to be preferentially expressed in tumors that contained T cells. Corresponding chemokine receptors were found to be up-regulated on human CD8(+) effector T cells, and transwell migration assays confirmed the ability of each of these chemokines to promote migration of CD8(+) effector cells in vitro. Screening by chemokine protein array identified a subset of melanoma cell lines that produced a similar broad array of chemokines. These melanoma cells more effectively recruited human CD8(+) effector T cells when implanted as xenografts in nonobese diabetic/severe combined immunodeficient mice in vivo. Chemokine blockade with specific antibodies inhibited migration of CD8(+) T cells. Our results suggest that lack of critical chemokines in a subset of melanoma metastases may limit the migration of activated T cells, which in turn could limit the effectiveness of antitumor immunity.
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                Author and article information

                Contributors
                jiandayuanusa@gmail.com
                pritih@gene.com
                Raphael.Clynes@bms.com
                Periklis.Foukas@chuv.ch
                Alexandre.Harari@chuv.ch
                thomas.kleen@epiontis.com
                p.kvistborg@nki.nl
                crimaccalli@gmail.com
                maecker@stanford.edu
                david.page2@providence.org
                hrobins@adaptivebiotech.com
                wenru.song@gmail.com
                edward.stack@perkinelmer.com
                ewang@sidra.org
                whitesidetl@upmc.edu
                zhaoy@ctep.nci.nih.gov
                heinz.zwierzina@i-med.ac.at
                butterfieldl@upmc.edu
                bernard.fox@providence.org
                Journal
                J Immunother Cancer
                J Immunother Cancer
                Journal for Immunotherapy of Cancer
                BioMed Central (London )
                2051-1426
                19 January 2016
                19 January 2016
                2016
                : 4
                : 3
                Affiliations
                [ ]Memorial Sloan-Kettering Cancer Center, 1275 New York Ave Box 386, New York, NY 10065 USA
                [ ]Genentech, Inc., 1 DNA Way South, San Francisco, CA 94080 USA
                [ ]Bristol-Myers Squibb, 3551 Lawrenceville Road, Princeton, NJ 08648 USA
                [ ]Center of Experimental Therapeutics and Ludwig Institute of Cancer Research, University Hospital of Lausanne, Rue du Bugnon 21, 1011 Lausanne, Switzerland
                [ ]Department of Pathology, University of Athens Medical School, “Attikon” University Hospital, 1st Rimini St, 12462 Haidari, Greece
                [ ]Epiontis GmbH, Rudower Chaussee 29, 12489 Berlin, Germany
                [ ]Netherlands Cancer Institute, Postbus 90203, 1006 BE Amsterdam, Netherlands
                [ ]Italian Network for Biotherapy of Tumors (NIBIT)-Laboratory, c/o Medical Oncology and Immunotherapy, University Hospital of Siena, V.le Bracci,16, Siena, 53100 Italy
                [ ]Stanford University Medical Center, 299 Campus Drive, Stanford, CA 94303 USA
                [ ]Earle A. Chiles Research Institute, Providence Cancer Center, 4805 NE Glisan Street, Portland, OR 97213 USA
                [ ]Adaptive Technologies, Inc., 1551 Eastlake Avenue East Suite 200, Seattle, WA 98102 USA
                [ ]AstraZeneca, One MedImmune Way, Gaithersburg, MD 20878 USA
                [ ]PerkinElmer, 68 Elm Street, Hopkinton, MA 01784 USA
                [ ]Sidra Medical and Research Center, PO Box 26999, Doha, Qatar
                [ ]University of Pittsburgh Cancer Institute, 5117 Centre Ave, Suite 1.27, Pittsburgh, PA 15213 USA
                [ ]National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20850 USA
                [ ]Innsbruck Medical University, Medizinische Klinik, Anichstrasse 35, Innsbruck, A-6020 Austria
                [ ]Department of Medicine, Surgery and Immunology, University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Pittsburgh, PA 15213 USA
                Article
                107
                10.1186/s40425-016-0107-3
                4717548
                26788324
                87c71850-8fe7-45b9-b60b-d45c38e0086c
                © Yuan et al. 2016

                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
                : 19 November 2015
                : 5 January 2016
                Categories
                Review
                Custom metadata
                © The Author(s) 2016

                immune checkpoint blockade,cancer immunotherapy,biomarkers,task force,immune monitoring,technology,bioinformatics

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