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      Phase Ib study evaluating a self-adjuvanted mRNA cancer vaccine (RNActive®) combined with local radiation as consolidation and maintenance treatment for patients with stage IV non-small cell lung cancer

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          Abstract

          Background

          Advanced non-small cell lung cancer (NSCLC) represents a significant unmet medical need. Despite advances with targeted therapies in a small subset of patients, fewer than 20% of patients survive for more than two years after diagnosis. Cancer vaccines are a promising therapeutic approach that offers the potential for durable responses through the engagement of the patient’s own immune system. CV9202 is a self-adjuvanting mRNA vaccine that targets six antigens commonly expressed in NSCLC (NY-ESO-1, MAGEC1, MAGEC2, 5 T4, survivin, and MUC1).

          Methods/Design

          The trial will assess the safety and tolerability of CV9202 vaccination combined with local radiation designed to enhance immune responses and will include patients with stage IV NSCLC and a response or stable disease after first-line chemotherapy or therapy with an EGFR tyrosine kinase inhibitor. Three histological and molecular subtypes of NSCLC will be investigated (squamous and non-squamous cell with/without EGFR mutations). All patients will receive two initial vaccinations with CV9202 prior to local radiotherapy (5 GY per day for four successive days) followed by further vaccinations until disease progression. The primary endpoint of the study is the number of patients experiencing Grade >3 treatment-related adverse events. Pharmacodynamic analyses include the assessment of immune responses to the antigens encoded by CV9202 and others not included in the panel (antigen spreading) and standard efficacy assessments.

          Discussion

          RNActive self-adjuvanted mRNA vaccines offer the potential for simultaneously inducing immune responses to a wide panel of antigens commonly expressed in tumors. This trial will assess the feasibility of this approach in combination with local radiotherapy in NSCLC patients.

          Trial registration

          Clinicaltrials.gov: NCT01915524/EudraCT No.: 2012-004230-41

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          Most cited references38

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          Combining radiotherapy and cancer immunotherapy: a paradigm shift.

          The therapeutic application of ionizing radiation has been largely based on its cytocidal power combined with the ability to selectively target tumors. Radiotherapy effects on survival of cancer patients are generally interpreted as the consequence of improved local control of the tumor, directly decreasing systemic spread. Experimental data from multiple cancer models have provided sufficient evidence to propose a paradigm shift, whereby some of the effects of ionizing radiation are recognized as contributing to systemic antitumor immunity. Recent examples of objective responses achieved by adding radiotherapy to immunotherapy in metastatic cancer patients support this view. Therefore, the traditional palliative role of radiotherapy in metastatic disease is evolving into that of a powerful adjuvant for immunotherapy. This combination strategy adds to the current anticancer arsenal and offers opportunities to harness the immune system to extend survival, even among metastatic and heavily pretreated cancer patients. We briefly summarize key evidence supporting the role of radiotherapy as an immune adjuvant. A critical appraisal of the current status of knowledge must include potential immunosuppressive effects of radiation that can hamper its capacity to convert the irradiated tumor into an in situ, individualized vaccine. Moreover, we discuss some of the current challenges to translate this knowledge to the clinic as more trials testing radiation with different immunotherapies are proposed.
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            Maximizing tumor immunity with fractionated radiation.

            Technologic advances have led to increased clinical use of higher-sized fractions of radiation dose and higher total doses. How these modify the pathways involved in tumor cell death, normal tissue response, and signaling to the immune system has been inadequately explored. Here we ask how radiation dose and fraction size affect antitumor immunity, the suppression thereof, and how this might relate to tumor control. Mice bearing B16-OVA murine melanoma were treated with up to 15 Gy radiation given in various-size fractions, and tumor growth followed. The tumor-specific immune response in the spleen was assessed by interferon-γ enzyme-linked immunospot (ELISPOT) assay with ovalbumin (OVA) as the surrogate tumor antigen and the contribution of regulatory T cells (Tregs) determined by the proportion of CD4(+)CD25(hi)Foxp3(+) T cells. After single doses, tumor control increased with the size of radiation dose, as did the number of tumor-reactive T cells. This was offset at the highest dose by an increase in Treg representation. Fractionated treatment with medium-size radiation doses of 7.5 Gy/fraction gave the best tumor control and tumor immunity while maintaining low Treg numbers. Radiation can be an immune adjuvant, but the response varies with the size of dose per fraction. The ultimate challenge is to optimally integrate cancer immunotherapy into radiation therapy. Copyright © 2012 Elsevier Inc. All rights reserved.
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              Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1.

              Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR-mutant lung cancers. Here, we modeled disease progression using EGFR-mutant human tumor cell lines. Although five of six models displayed alterations already found in humans, one harbored an unexpected secondary NRAS Q61K mutation; resistant cells were sensitive to concurrent EGFR and MEK inhibition but to neither alone. Prompted by this finding and because RAS/RAF/MEK mutations are known mediators of acquired resistance in other solid tumors (colon cancers, gastrointestinal stromal tumors, and melanomas) responsive to targeted therapies, we analyzed the frequency of secondary KRAS/NRAS/BRAF/MEK1 gene mutations in the largest collection to date of lung cancers with acquired resistance to EGFR TKIs. No recurrent NRAS, KRAS, or MEK1 mutations were found in 212, 195, or 146 patient samples, respectively, but 2 of 195 (1%) were found to have mutations in BRAF (G469A and V600E). Ectopic expression of mutant NRAS or BRAF in drug-sensitive EGFR-mutant cells conferred resistance to EGFR TKIs that was overcome by addition of a MEK inhibitor. Collectively, these positive and negative results provide deeper insight into mechanisms of acquired resistance to EGFR TKIs in lung cancer and inform ongoing clinical trials designed to overcome resistance. In the context of emerging knowledge about mechanisms of acquired resistance to targeted therapies in various cancers, our data highlight the notion that, even though solid tumors share common signaling cascades, mediators of acquired resistance must be elucidated for each disease separately in the context of treatment.
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                Author and article information

                Contributors
                Sebastian@med.uni-frankfurt.de
                Alexandros.Papachristofilou@usb.ch
                Christian.Weiss@kgu.de
                Martin.Frueh@kssg.ch
                Richard.Cathomas@ksgr.ch
                Wolfgang.Hilbe@uibk.ac.at
                thomas.wehler@unimedizin-mainz.de
                Gerd.Rippin@Rippin-consulting.com
                Sven.Koch@curevac.com
                Birgit.Scheel@curevac.com
                Mariola.Fotin-Mleczek@curevac.com
                Regina.Heidenreich@curevac.com
                Karl-Josef.Kallen@curevac.com
                Ulrike.Gnad-Vogt@curevac.com
                Alfred.Zippelius@usb.ch
                Journal
                BMC Cancer
                BMC Cancer
                BMC Cancer
                BioMed Central (London )
                1471-2407
                6 October 2014
                6 October 2014
                2014
                : 14
                : 1
                : 748
                Affiliations
                [ ]Department of Hematology and Oncology, Johann-Wolfgang-Goethe-Universität, Frankfurt, Germany
                [ ]Department of Radiation Oncology, University Hospital Basel, Basel, Switzerland
                [ ]Department of Radiation Therapy and Oncology, Goethe University, Frankfurt am Main, Germany
                [ ]Department of Medical Oncology and Hematology, Kantonsspital St Gallen, St Gallen, Switzerland
                [ ]Medical Oncology, Kantonsspital Graubünden, Chur, Switzerland
                [ ]Department of General Internal Medicine, Oncology, University Hospital, Innsbruck, Austria
                [ ]Third Department of Internal Medicine, University Hospital Mainz, Mainz, Germany
                [ ]Rippin Consulting, Solingen, Germany
                [ ]CureVac GmbH, Tübingen, Germany
                [ ]Department of Oncology, University Hospital Basel, Petersgraben 4, CH - 4031 Basel, Switzerland
                Article
                4926
                10.1186/1471-2407-14-748
                4195907
                25288198
                d9288921-eca5-40ad-96a5-69baf1d4d8d0
                © Sebastian et al.; licensee BioMed Central Ltd. 2014

                This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 29 November 2013
                : 25 September 2014
                Categories
                Study Protocol
                Custom metadata
                © The Author(s) 2014

                Oncology & Radiotherapy
                non-small cell lung cancer,cv9202,mrna vaccine,rnactive,local radiotherapy
                Oncology & Radiotherapy
                non-small cell lung cancer, cv9202, mrna vaccine, rnactive, local radiotherapy

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