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      New Strategies Using Antibody Combinations to Increase Cancer Treatment Effectiveness

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          Abstract

          Antibodies have proven their high value in antitumor therapy over the last two decades. They are currently being used as the first-choice to treat some of the most frequent metastatic cancers, like HER2 + breast cancers or colorectal cancers, currently treated with trastuzumab (Herceptin) and bevacizumab (Avastin), respectively. The impressive therapeutic success of antibodies inhibiting immune checkpoints has extended the use of therapeutic antibodies to previously unanticipated tumor types. These anti-immune checkpoint antibodies allowed the cure of patients devoid of other therapeutic options, through the recovery of the patient’s own immune response against the tumor. In this review, we describe how the antibody-based therapies will evolve, including the use of antibodies in combinations, their main characteristics, advantages, and how they could contribute to significantly increase the chances of success in cancer therapy. Indeed, novel combinations will consist of mixtures of antibodies against either different epitopes of the same molecule or different targets on the same tumor cell; bispecific or multispecific antibodies able of simultaneously binding tumor cells, immune cells or extracellular molecules; immunomodulatory antibodies; antibody-based molecules, including fusion proteins between a ligand or a receptor domain and the IgG Fab or Fc fragments; autologous or heterologous cells; and different formats of vaccines. Through complementary mechanisms of action, these combinations could contribute to elude the current limitations of a single antibody which recognizes only one particular epitope. These combinations may allow the simultaneous attack of the cancer cells by using the help of the own immune cells and exerting wider therapeutic effects, based on a more specific, fast, and robust response, trying to mimic the action of the immune system.

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          Vascular Endothelial Growth Factor (VEGF) and Its Receptor (VEGFR) Signaling in Angiogenesis: A Crucial Target for Anti- and Pro-Angiogenic Therapies.

          The vascular endothelial growth factor (VEGF) and its receptor (VEGFR) have been shown to play major roles not only in physiological but also in most pathological angiogenesis, such as cancer. VEGF belongs to the PDGF supergene family characterized by 8 conserved cysteines and functions as a homodimer structure. VEGF-A regulates angiogenesis and vascular permeability by activating 2 receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk1 in mice). On the other hand, VEGF-C/VEGF-D and their receptor, VEGFR-3 (Flt-4), mainly regulate lymphangiogenesis. The VEGF family includes other interesting variants, one of which is the virally encoded VEGF-E and another is specifically expressed in the venom of the habu snake (Trimeresurus flavoviridis). VEGFRs are distantly related to the PDGFR family; however, they are unique with respect to their structure and signaling system. Unlike members of the PDGFR family that strongly stimulate the PI3K-Akt pathway toward cell proliferation, VEGFR-2, the major signal transducer for angiogenesis, preferentially utilizes the PLCγ-PKC-MAPK pathway for signaling. The VEGF-VEGFR system is an important target for anti-angiogenic therapy in cancer and is also an attractive system for pro-angiogenic therapy in the treatment of neuronal degeneration and ischemic diseases.
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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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              Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial.

              Combining biologic monoclonal antibodies with chemotherapeutic cytotoxic drugs provides clinical benefit to patients with advanced or metastatic colorectal cancer, but the optimal choice of the initial biologic therapy in previously untreated patients is unknown.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/473230
                URI : http://frontiersin.org/people/u/471950
                URI : http://frontiersin.org/people/u/395741
                URI : http://frontiersin.org/people/u/204047
                URI : http://frontiersin.org/people/u/173098
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                21 December 2017
                2017
                : 8
                : 1804
                Affiliations
                [1] 1Department of Immunology and Oncology, Centro Nacional de Biotecnologia (CNB-CSIC) , Madrid, Spain
                [2] 2Department of Cellular and Molecular Medicine, Centro de Investigaciones Biologicas (CIB-CSIC) , Madrid, Spain
                Author notes

                Edited by: Nurit Hollander, Tel Aviv University, Israel

                Reviewed by: Daniel Olive, Institut National de la Santé et de la Recherche Médicale, France; Estrella Mariel Levy, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina; William L. Redmond, Earle A. Chiles Research Institute, United States

                *Correspondence: Jose A. Garcia-Sanz, jasanz@ 123456cib.csic.es ; Leonor Kremer, lkremer@ 123456cnb.csic.es

                Both authors contributed equally to this work and should be regarded as senior co-authors.

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

                Article
                10.3389/fimmu.2017.01804
                5742572
                29312320
                585d325c-4375-4088-b043-d92974c148fb
                Copyright © 2017 Corraliza-Gorjón, Somovilla-Crespo, Santamaria, Garcia-Sanz and Kremer.

                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) or licensor 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
                : 11 September 2017
                : 30 November 2017
                Page count
                Figures: 1, Tables: 4, Equations: 0, References: 356, Pages: 31, Words: 25413
                Categories
                Immunology
                Review

                Immunology
                cancer,antibody combinations,oncology,therapeutic antibodies,immunotherapy
                Immunology
                cancer, antibody combinations, oncology, therapeutic antibodies, immunotherapy

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