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      Therapeutic Immunization against Glioblastoma

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          Abstract

          Glioblastoma is the most common form of brain cancer in adults that produces severe damage to the brain leading to a very poor survival prognosis. The standard of care for glioblastoma is usually surgery, as well as radiotherapy followed by systemic temozolomide chemotherapy, resulting in a median survival time of about 12 to 15 months. Despite these therapeutic efforts, the tumor returns in the vast majority of patients. When relapsing, statistics suggest an imminent death dependent on the size of the tumor, the Karnofsky Performance Status, and the tumor localization. Following the standard of care, the administration of Bevacizumab, inhibiting the growth of the tumor vasculature, is an approved medicinal treatment option approved in the United States, but not in the European Union, as well as the recently approved alternating electric fields (AEFs) generator NovoTTF/Optune. However, it is clear that regardless of the current treatment regimens, glioma patients continue to have dismal prognosis and novel treatments are urgently needed. Here, we describe different approaches of recently developed therapeutic glioma brain cancer vaccines, which stimulate the patient’s immune system to recognize tumor-associated antigens (TAA) on cancer cells, aiming to instruct the immune system to eventually attack and destroy the brain tumor cells, with minimal bystander damage to normal brain cells. These distinct immunotherapies may target particular glioma TAAs which are molecularly defined, but they may also target broad patient-derived tumor antigen preparations intentionally evoking a very broad polyclonal antitumor immune stimulation.

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          Most cited references26

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          Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial.

          Treatment options for recurrent glioblastoma are scarce, with second-line chemotherapy showing only modest activity against the tumour. Despite the absence of well controlled trials, bevacizumab is widely used in the treatment of recurrent glioblastoma. Nonetheless, whether the high response rates reported after treatment with this drug translate into an overall survival benefit remains unclear. We report the results of the first randomised controlled phase 2 trial of bevacizumab in recurrent glioblastoma.
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            A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study.

            The epidermal growth factor receptor variant III deletion mutation, EGFRvIII, is expressed in ∼30% of primary glioblastoma and linked to poor long-term survival. Rindopepimut consists of the unique EGFRvIII peptide sequence conjugated to keyhole limpet hemocyanin. In previous phase II trials (ACTIVATE/ACT II), rindopepimut was well tolerated with robust EGFRvIII-specific immune responses and promising progression-free and overall survival. This multicenter, single-arm phase II clinical trial (ACT III) was performed to confirm these results.
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              Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma

              Background This study evaluated the safety and immune responses to an autologous dendritic cell vaccine pulsed with class I peptides from tumor-associated antigens (TAA) expressed on gliomas and overexpressed in their cancer stem cell population (ICT-107). Methods TAA epitopes included HER2, TRP-2, gp100, MAGE-1, IL13Rα2, and AIM-2. HLA-A1- and/or HLA-A2-positive patients with glioblastoma (GBM) were eligible. Mononuclear cells from leukapheresis were differentiated into dendritic cells, pulsed with TAA peptides, and administered intradermally three times at two-week intervals. Results Twenty-one patients were enrolled with 17 newly diagnosed (ND-GBM) and three recurrent GBM patients and one brainstem glioma. Immune response data on 15 newly diagnosed patients showed 33 % responders. TAA expression by qRT-PCR from fresh-frozen tumor samples showed all patient tumors expressed at least three TAA, with 75 % expressing all six. Correlations of increased PFS and OS with quantitative expression of MAGE1 and AIM-2 were observed, and a trend for longer survival was observed with gp100 and HER2 antigens. Target antigens gp100, HER1, and IL13Rα2 were downregulated in recurrent tumors from 4 HLA-A2+ patients. A decrease in or absence of CD133 expression was seen in five patients who underwent a second resection. At a median follow-up of 40.1 months, six of 16 ND-GBM patients showed no evidence of tumor recurrence. Median PFS in newly diagnosed patients was 16.9 months, and median OS was 38.4 months. Conclusions Expression of four ICT-107 targeted antigens in the pre-vaccine tumors correlated with prolonged overall survival and PFS in ND-GBM patients. The goal of targeting tumor antigens highly expressed on glioblastoma cancer stem cells is supported by the observation of decreased or absent CD133 expression in the recurrent areas of gadolinium-enhanced tumors.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                27 August 2018
                September 2018
                : 19
                : 9
                : 2540
                Affiliations
                [1 ]Epitopoietic Research Corporation ERC-The Netherlands Nistelrooisebaan 3, 5374 RE Schaijk, The Netherlands; a.strik@ 123456ercnetherlands.nl (A.M.S.); r.gloudemans@ 123456ercnetherlands.nl (R.G.-R.); tstath@ 123456hotmail.com (A.S.)
                [2 ]ERC-Belgium Gembloux Isnes, Rue Jean Sonet 10, 5031 Isnes Belgium, Belgium; pretto@ 123456ercbelgium.eu (C.P.); devillers@ 123456ercbelgium.eu (L.D.); dpierre@ 123456ercbelgium.eu (D.P.)
                [3 ]Cell Biology & Immunology Group, Wageningen University, 6708 PB Wageningen, The Netherlands
                [4 ]Chao Family Comprehensive Cancer Center, 101 The City Drive Bldg. 23, Route 81, Orange, CA 92868, USA; jinahec@ 123456uci.edu (J.C.); mdandeka@ 123456uci.edu (M.D.); xkong@ 123456uci.edu (X.-T.K.); dfu@ 123456uci.edu (B.D.F.); fpkhsu@ 123456uci.edu (F.P.K.H); dbota@ 123456uci.edu (D.A.B.)
                [5 ]Department of Neurological Surgery; University of California Irvine, Irvine, CA 92697, USA; Carrilj2@ 123456uci.edu
                [6 ]Department of Neurology, University of California Irvine, Irvine, CA 92697, USA
                [7 ]Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; hofman@ 123456usc.edu
                [8 ]Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; tchen68670@ 123456gmail.com
                [9 ]Department of Molecular, Cell, and Systems Biology, University of California, Riverside, CA 92521, USA; zidovet@ 123456ucr.edu
                [10 ]Department of Neurosurgery, Euroclinics Hospital, 11521 Athens, Greece
                Author notes
                [* ]Correspondence: schijns.virgil@ 123456gmail.com ; Tel.: +32-8172-8610
                Author information
                https://orcid.org/0000-0002-0406-6766
                Article
                ijms-19-02540
                10.3390/ijms19092540
                6163986
                30150597
                e8876458-441f-4306-8e76-e8ee69a149d9
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 14 July 2018
                : 23 August 2018
                Categories
                Review

                Molecular biology
                glioma tumor,brain tumor,immunotherapy,therapeutic vaccine,autologous,allogenic
                Molecular biology
                glioma tumor, brain tumor, immunotherapy, therapeutic vaccine, autologous, allogenic

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