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      Externally-Controlled Systems for Immunotherapy: From Bench to Bedside

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          Abstract

          Immunotherapy is a very promising therapeutic approach against cancer that is particularly effective when combined with gene therapy. Immuno-gene therapy approaches have led to the approval of four advanced therapy medicinal products (ATMPs) for the treatment of p53-deficient tumors (Gendicine and Imlygic), refractory acute lymphoblastic leukemia (Kymriah) and large B-cell lymphomas (Yescarta). In spite of these remarkable successes, immunotherapy is still associated with severe side effects for CD19+ malignancies and is inefficient for solid tumors. Controlling transgene expression through an externally administered inductor is envisioned as a potent strategy to improve safety and efficacy of immunotherapy. The aim is to develop smart immunogene therapy-based-ATMPs, which can be controlled by the addition of innocuous drugs or agents, allowing the clinicians to manage the intensity and durability of the therapy. In the present manuscript, we will review the different inducible, versatile and externally controlled gene delivery systems that have been developed and their applications to the field of immunotherapy. We will highlight the advantages and disadvantages of each system and their potential applications in clinics.

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          Most cited references128

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          Cytokines in clinical cancer immunotherapy

          Cytokines are soluble proteins that mediate cell-to-cell communication. Based on the discovery of the potent anti-tumour activities of several pro-inflammatory cytokines in animal models, clinical research led to the approval of recombinant interferon-alpha and interleukin-2 for the treatment of several malignancies, even if efficacy was only modest. These early milestones in immunotherapy have been followed by the recent addition to clinical practice of antibodies that inhibit immune checkpoints, as well as chimeric antigen receptor T cells. A renewed interest in the anti-tumour properties of cytokines has led to an exponential increase in the number of clinical trials that explore the safety and efficacy of cytokine-based drugs, not only as single agents, but also in combination with other immunomodulatory drugs. These second-generation drugs under clinical development include known molecules with novel mechanisms of action, new targets, and fusion proteins that increase half-life and target cytokine activity to the tumour microenvironment or to the desired effector immune cells. In addition, the detrimental activity of immunosuppressive cytokines can be blocked by antagonistic antibodies, small molecules, cytokine traps or siRNAs. In this review, we provide an overview of the novel trends in the cytokine immunotherapy field that are yielding therapeutic agents for clinical trials.
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            Cancer immunotherapy: the beginning of the end of cancer?

            These are exciting times for cancer immunotherapy. After many years of disappointing results, the tide has finally changed and immunotherapy has become a clinically validated treatment for many cancers. Immunotherapeutic strategies include cancer vaccines, oncolytic viruses, adoptive transfer of ex vivo activated T and natural killer cells, and administration of antibodies or recombinant proteins that either costimulate cells or block the so-called immune checkpoint pathways. The recent success of several immunotherapeutic regimes, such as monoclonal antibody blocking of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD1), has boosted the development of this treatment modality, with the consequence that new therapeutic targets and schemes which combine various immunological agents are now being described at a breathtaking pace. In this review, we outline some of the main strategies in cancer immunotherapy (cancer vaccines, adoptive cellular immunotherapy, immune checkpoint blockade, and oncolytic viruses) and discuss the progress in the synergistic design of immune-targeting combination therapies.
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              Optical Control of Mammalian Endogenous Transcription and Epigenetic States

              The dynamic nature of gene expression enables cellular programming, homeostasis, and environmental adaptation in living systems. Dissection of causal gene functions in cellular and organismal processes therefore necessitates approaches that enable spatially and temporally precise modulation of gene expression. Recently, a variety of microbial and plant-derived light-sensitive proteins have been engineered as optogenetic actuators, enabling high precision spatiotemporal control of many cellular functions 1-11 . However, versatile and robust technologies that enable optical modulation of transcription in the mammalian endogenous genome remain elusive. Here, we describe the development of Light-Inducible Transcriptional Effectors (LITEs), an optogenetic two-hybrid system integrating the customizable TALE DNA-binding domain 12-14 with the light-sensitive cryptochrome 2 protein and its interacting partner CIB1 from Arabidopsis thaliana. LITEs do not require additional exogenous chemical co-factors, are easily customized to target many endogenous genomic loci, and can be activated within minutes with reversibility 3,4,6,7,15 . LITEs can be packaged into viral vectors and genetically targeted to probe specific cell populations. We have applied this system in primary mouse neurons, as well as in the brain of awake mice in vivo to mediate reversible modulation of mammalian endogenous gene expression as well as targeted epigenetic chromatin modifications. The LITE system establishes a novel mode of optogenetic control of endogenous cellular processes and enables direct testing of the causal roles of genetic and epigenetic regulation in normal biological processes and disease states.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                04 September 2020
                2020
                : 11
                : 2044
                Affiliations
                [1] 1Gene and Cell Therapy Unit, Genomic Medicine Department, Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research (GENYO) , Granada, Spain
                [2] 2LentiStem Biotech, Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research (GENYO) , Granada, Spain
                Author notes

                Edited by: Jose A. Garcia-Sanz, Consejo Superior de Investigaciones Científicas (CSIC), Spain

                Reviewed by: Stephen Gottschalk, St. Jude Children's Research Hospital, United States; Ana Gutierrez Del Arroyo, Queen Mary University of London, United Kingdom

                *Correspondence: Francisco Martin francisco.martin@ 123456genyo.es

                This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology

                †These authors have contributed equally to this work

                Article
                10.3389/fimmu.2020.02044
                7498544
                33013864
                f8172298-b9c5-4baf-ad27-44fa27bc23eb
                Copyright © 2020 Tristán-Manzano, Justicia-Lirio, Maldonado-Pérez, Cortijo-Gutiérrez, Benabdellah and Martin.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 25 May 2020
                : 28 July 2020
                Page count
                Figures: 2, Tables: 3, Equations: 0, References: 147, Pages: 17, Words: 14123
                Funding
                Funded by: Instituto de Salud Carlos III 10.13039/501100004587
                Award ID: PI12/01097
                Award ID: PI15/02015
                Award ID: PI18/00330
                Award ID: PI18/00337
                Funded by: Consejería de Salud, Junta de Andalucía" 10.13039/501100010566
                Award ID: 2016000073332-TRA
                Award ID: 2016000073391-TRA
                Award ID: PAIDI-Bio326
                Award ID: PI-0014-2016
                Award ID: PI-57069
                Categories
                Immunology
                Review

                Immunology
                immunotherapy,gene therapy,externally controlled,inducible,atmps,transgene expression,cancer,autoimmunity

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