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      Targeting Angiogenesis With Peptide Vaccines

      review-article
      1 , 2 , *
      Frontiers in Immunology
      Frontiers Media S.A.
      angiogenesis, peptide vaccines, adjuvant, cancer, VEGF, EMMPRIN

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          Abstract

          Most cancer peptide vaccinations tested so far are capable of eliciting a strong immune response, but demonstrate poor clinical benefits. Since peptide vaccination is safe and well-tolerated, and several indications suggest that it has clear potential advantages over other modalities of treatment, it is important to investigate the reasons for these clinical failures. In this review, the current state of the art in targeting angiogenic proteins via peptide vaccines is presented, and the underlying reasons for both the successes and the failures are analyzed. The review highlights a number of areas critical for future success, including choice of target antigens, types of peptides used, delivery methods and use of proper adjuvants, and suggests ways to achieve better clinical results in the future.

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          Most cited references68

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          Coinhibitory Pathways in Immunotherapy for Cancer.

          The immune system is capable of recognizing tumors and eliminates many early malignant cells. However, tumors evolve to evade immune attack, and the tumor microenvironment is immunosuppressive. Immune responses are regulated by a number of immunological checkpoints that promote protective immunity and maintain tolerance. T cell coinhibitory pathways restrict the strength and duration of immune responses, thereby limiting immune-mediated tissue damage, controlling resolution of inflammation, and maintaining tolerance to prevent autoimmunity. Tumors exploit these coinhibitory pathways to evade immune eradication. Blockade of the PD-1 and CTLA-4 checkpoints is proving to be an effective and durable cancer immunotherapy in a subset of patients with a variety of tumor types, and additional combinations are further improving response rates. In this review we discuss the immunoregulatory functions of coinhibitory pathways and their translation to effective immunotherapies for cancer.
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            Synergistic effect of immune checkpoint blockade and anti-angiogenesis in cancer treatment

            Immune checkpoint inhibitor (ICI) activates host’s anti-tumor immune response by blocking negative regulatory immune signals. A series of clinical trials showed that ICI could effectively induce tumor regression in a subset of advanced cancer patients. In clinical practice, a main concerning for choosing ICI is the low response rate. Even though multiple predictive biomarkers such as PD-L1 expression, mismatch-repair deficiency, and status of tumor infiltrating lymphocytes have been adopted for patient selection, frequent resistance to ICI monotherapy has not been completely resolved. However, some recent studies indicated that ICI resistance could be alleviated by combination therapy with anti-angiogenesis treatment. Actually, anti-angiogenesis therapy not only prunes blood vessel which is essential to cancer growth and metastasis, but also reprograms the tumor immune microenvironment. Preclinical studies demonstrated that the efficacy of combination therapy of ICI and anti-angiogenesis was superior to monotherapy. In mice model, combination therapy could effectively increase the ratio of anti-tumor/pro-tumor immune cell and decrease the expression of multiple immune checkpoints more than PD-1. Based on exciting results from preclinical studies, many clinical trials were deployed to investigate the synergistic effect of the combination therapy and acquired promising outcome. This review summarized the latest understanding of ICI combined anti-angiogenesis therapy and highlighted the advances of relevant clinical trials.
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              Antiangiogenic therapy: impact on invasion, disease progression, and metastasis.

              Antiangiogenic drugs targeting the VEGF pathway have slowed metastatic disease progression in some patients, leading to progression-free survival (PFS) and overall survival benefits compared with controls. However, the results are more modest than predicted by most preclinical testing and benefits in PFS are frequently not accompanied by overall survival improvements. Questions have emerged about the basis of drug resistance and the limitations of predictive preclinical models, and also about whether the nature of disease progression following antiangiogenic therapy is different to classic cytotoxic therapies-in particular whether therapy may lead to more invasive or metastatic behavior. In addition, because of recent clinical trial failures of antiangiogenic therapy in patients with early-stage disease, and the fact that there are hundreds of trials underway in perioperative neoadjuvant and adjuvant settings, there is now greater awareness about the lack of appropriate preclinical testing that preceded these studies. Improved preclinical assessment of all stages of metastatic disease should be a priority for future antiangiogenic drug discovery and development. © 2011 Macmillan Publishers Limited. All rights reserved
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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
                08 August 2019
                2019
                : 10
                : 1924
                Affiliations
                [1] 1Immunotherapy Laboratory, Carmel Medical Center , Haifa, Israel
                [2] 2The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology , Haifa, Israel
                Author notes

                Edited by: Nurit Hollander, Tel Aviv University, Israel

                Reviewed by: Cristina Maccalli, Sidra Medical and Research Center, Qatar; Lorenzo Mortara, University of Insubria, Italy

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

                Article
                10.3389/fimmu.2019.01924
                6694838
                31440262
                b8087500-1961-4988-9ce7-436cca13d3de
                Copyright © 2019 Rahat.

                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
                : 06 June 2019
                : 30 July 2019
                Page count
                Figures: 0, Tables: 2, Equations: 0, References: 80, Pages: 11, Words: 9602
                Funding
                Funded by: Israel Science Foundation 10.13039/501100003977
                Funded by: Israel Cancer Association 10.13039/501100003975
                Categories
                Immunology
                Review

                Immunology
                angiogenesis,peptide vaccines,adjuvant,cancer,vegf,emmprin
                Immunology
                angiogenesis, peptide vaccines, adjuvant, cancer, vegf, emmprin

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