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      Immunomodulation Mediated by Anti-angiogenic Therapy Improves CD8 T Cell Immunity Against Experimental Glioma

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          Abstract

          Glioblastoma (GBM) is a lethal cancer of the central nervous system with a median survival rate of 15 months with treatment. Thus, there is a critical need to develop novel therapies for GBM. Immunotherapy is emerging as a promising therapeutic strategy. However, current therapies for GBM, in particular anti-angiogenic therapies that block vascular endothelial growth factor (VEGF), may have undefined consequences on the efficacy of immunotherapy. While this treatment is primarily prescribed to reduce tumor vascularization, multiple immune cell types also express VEGF receptors, including the most potent antigen-presenting cell, the dendritic cell (DC). Therefore, we assessed the role of anti-VEGF therapy in modifying DC function. We found that VEGF blockade results in a more mature DC phenotype in the brain, as demonstrated by an increase in the expression of the co-stimulatory molecules B7-1, B7-2, and MHC II. Furthermore, we observed reduced levels of the exhaustion markers PD-1 and Tim-3 on brain-infiltrating CD8 T cells, indicating improved functionality. Thus, anti-angiogenic therapy has the potential to be used in conjunction with and enhance immunotherapy for GBM.

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          Recent therapeutic advances in the treatment of colorectal cancer.

          Metastatic colorectal cancer is a prevalent disease for which novel targeted therapies and biologically based combinations are under development. Cytotoxic chemotherapy doublets (FOLFOX, FOLFIRI) and triplets (FOLFOXIRI) in combination with biologics are standard regimens, and efforts are ongoing to delineate the optimal sequence for each patient based on unique underlying tumor biology. Molecular profiling of metastatic colorectal cancer (including mutational analysis for KRAS, NRAS, BRAF, PIK3CA, and others) has become increasingly important for identification of prognostic and predictive biomarkers, as well as for insights into the biology that drives the tumor. Large comprehensive analyses such as that of The Cancer Genome Atlas have provided important clues into carcinogenesis and discerned potentially druggable targets for metastatic colorectal cancer. Novel therapeutic agents currently under investigation for subtypes of this disease include immunotherapies such as anti-programmed cell death receptor antibody, cancer stem cell inhibitors, targeted combinations such as BRAF and PI3K inhibitors, and the anti-RAS reovirus Reolysin®.
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            Current Vaccine Trials in Glioblastoma: A Review

            Glioblastoma (GBM) is the most common primary brain tumor, and despite aggressive therapy with surgery, radiation, and chemotherapy, average survival remains at about 1.5 years. The highly infiltrative and invasive nature of GBM requires that alternative treatments for this disease be widespread and targeted to tumor cells. Immunotherapy in the form of tumor vaccines has the potential to meet this need. Vaccines against GBM hold the promise of triggering specific and systemic antitumor immune responses that may be the key to eradicating this unrelenting cancer. In this review, we will discuss past and present clinical trials of various GBM vaccines and their potential impact on the future care of GBM patients. There have been many promising phase I and phase II GBM vaccine studies that have led to ongoing and upcoming phase III trials. If the results of these randomized trials show a survival benefit, immunotherapy will become a standard part of the treatment of this devastating disease.
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              Value of bevacizumab in treatment of colorectal cancer: A meta-analysis.

              To assess the efficacy and safety of bevacizumab in the treatment of colorectal cancer.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                20 August 2018
                2018
                : 8
                : 320
                Affiliations
                [1] 1Department of Immunology, Mayo Clinic , Rochester, MN, United States
                [2] 2Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic , Rochester, MN, United States
                [3] 3Department of Ophthalmology, Mayo Clinic , Rochester, MN, United States
                [4] 4Department of Neurology, Mayo Clinic , Rochester, MN, United States
                [5] 5Department of Molecular Medicine, Mayo Clinic , Rochester, MN, United States
                Author notes

                Edited by: Shiv K. Gupta, Mayo Clinic, United States

                Reviewed by: Thomas Daubon, Institut National de la Santé et de la Recherche Médicale (INSERM), France; Sujuan Guo, Dana–Farber Cancer Institute, United States

                *Correspondence: Aaron J. Johnson Johnson.aaron2@ 123456mayo.edu

                This article was submitted to Cancer Molecular Targets and Therapeutics, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2018.00320
                6124655
                30211113
                149ce9c3-b82f-4b16-be12-33ee1d5cdbcf
                Copyright © 2018 Malo, Khadka, Ayasoufi, Jin, AbouChehade, Hansen, Iezzi, Pavelko and Johnson.

                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
                : 15 June 2018
                : 26 July 2018
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 18, Pages: 6, Words: 3802
                Categories
                Oncology
                Original Research

                Oncology & Radiotherapy
                glioblastoma,anti-angiogenic therapy,immunotherapy,vaccine,combination therapy

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