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      First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma

      research-article
      1 , , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 59 , 20 , 20 , 21 , 22 , 22 , 23 , 24 , 25 , 26 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 44 , 45 , 46 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 58 , 1 , 1 , 57 , 58 ,
      Journal of Translational Medicine
      BioMed Central
      Glioblastoma, Immunotherapy, Dendritic cell, Vaccine

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          Abstract

          Background

          Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax ®-L) to standard therapy for newly diagnosed glioblastoma.

          Methods

          After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS).

          Results

          For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone.

          Conclusions

          Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival.

          Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1; initially registered 19 September 2002

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          Most cited references17

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          Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial.

          Cilengitide is a selective αvβ3 and αvβ5 integrin inhibitor. Data from phase 2 trials suggest that it has antitumour activity as a single agent in recurrent glioblastoma and in combination with standard temozolomide chemoradiotherapy in newly diagnosed glioblastoma (particularly in tumours with methylated MGMT promoter). We aimed to assess cilengitide combined with temozolomide chemoradiotherapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter.
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            Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials.

            Despite notable technical advances in therapy for malignant gliomas during the past decade, improved patient survival has not been clearly documented, suggesting that pretreatment prognostic factors influence outcome more than minor modifications in therapy. Age, performance status, and tumor histopathology have been identified as the pretreatment variables most predictive of survival outcome. However, an analysis of the association of survival with both pretreatment characteristics and treatment-related variables is necessary to assure reliable evaluation of new approaches for treatment of malignant glioma. This study of malignant glioma patients used a non-parametric statistical technique to examine the associations of both pretreatment patient and tumor characteristics and treatment-related variables with survival duration. This technique was used to identify subgroups with survival rates sufficiently different to create improvements in the design and stratification of clinical trials. We used a recursive partitioning technique to analyze survival in 1578 patients entered in three Radiation Therapy Oncology Group malignant glioma trials from 1974 to 1989 that used several radiation therapy (RT) regimens with and without chemotherapy or a radiation sensitizer. This approach creates a regression tree according to prognostic variables that classifies patients into homogeneous subsets by survival. Twenty-six pretreatment characteristics and six treatment-related variables were analyzed. The years). Patients younger than 50 years old were categorized by histology (astrocytomas with anaplastic or atypical foci [AAF] versus glioblastoma multiforme [GBM]) and subsequently by normal or abnormal mental status for AAF patients and by performance status for those with GBM. For patients aged 50 years or older, performance status was the most important variable, with normal or abnormal mental status creating the only significant split in the poorer performance status group. Treatment-related variables produced a subgroup showing significant differences only for better performance status GBM patients over age 50 (by extent of surgery and RT dose). Median survival times were 4.7-58.6 months for the 12 subgroups resulting from this analysis, which ranged in size from 32 to 256 patients. This approach permits examination of the interaction between prognostic variables not possible with other forms of multivariate analysis. The recursive partitioning technique can be employed to refine the stratification and design of malignant glioma trials.
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              Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy.

              To assess the feasibility, safety, and toxicity of autologous tumor lysate-pulsed dendritic cell (DC) vaccination and toll-like receptor (TLR) agonists in patients with newly diagnosed and recurrent glioblastoma. Clinical and immune responses were monitored and correlated with tumor gene expression profiles. Twenty-three patients with glioblastoma (WHO grade IV) were enrolled in this dose-escalation study and received three biweekly injections of glioma lysate-pulsed DCs followed by booster vaccinations with either imiquimod or poly-ICLC adjuvant every 3 months until tumor progression. Gene expression profiling, immunohistochemistry, FACS, and cytokine bead arrays were performed on patient tumors and peripheral blood mononuclear cells. DC vaccinations are safe and not associated with any dose-limiting toxicity. The median overall survival from the time of initial surgical diagnosis of glioblastoma was 31.4 months, with a 1-, 2-, and 3-year survival rate of 91%, 55%, and 47%, respectively. Patients whose tumors had mesenchymal gene expression signatures exhibited increased survival following DC vaccination compared with historic controls of the same genetic subtype. Tumor samples with a mesenchymal gene expression signature had a higher number of CD3(+) and CD8(+) tumor-infiltrating lymphocytes compared with glioblastomas of other gene expression signatures (P = 0.006). Autologous tumor lysate-pulsed DC vaccination in conjunction with TLR agonists is safe as adjuvant therapy in newly diagnosed and recurrent glioblastoma patients. Our results suggest that the mesenchymal gene expression profile may identify an immunogenic subgroup of glioblastoma that may be more responsive to immune-based therapies. ©2010 AACR.
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                Author and article information

                Contributors
                lliau@mednet.ucla.edu
                k.ashkan@nhs.net
                david.tran@neurosurgery.ufl.edu
                Campian.jian@wustl.edu
                John.trusheim@Mpls-clinic.com
                Charles.cobbs@swedish.org
                jheth@med.umich.edu
                msalacz@kumc.edu
                SATAYLOR@kumc.edu
                DandrS1@sutterhealth.org
                Fi2146@cumc.columbia.edu
                edropcho@iupui.edu
                ymoshel@ansdocs.com
                Kevin_Walter@URMC.Rochester.edu
                Clement_Pillainayagam@rush.edu
                Ra615@cinj.rutgers.edu
                tripatrr@UCMAIL.UC.EDU
                Samuel.Goldlust@hackensackmeridian.org
                dbota@uci.edu
                JDuic@nyuwinthrop.org
                Jgrewal8@gmail.com
                helinzano@Lifespan.org
                Steven.Toms@lifespan.org
                Kevin.Lillehei@ucdenver.edu
                TMIKKEL1@hfhs.org
                TWALBER1@hfhs.org
                sabram@howellallen.com
                brennera@uthscsa.edu
                Steven.Brem@uphs.upenn.edu
                ewend@unchealth.unc.edu
                skhagi@med.unc.edu
                JPortnow@coh.org
                lyndon.kim@jefferson.edu
                wgloudon@gmail.com
                Reid.thompson@Vanderbilt.Edu
                davigan@bidmc.harvard.edu
                Karen.Fink@BSWHealth.org
                FGEOFFROY@illinoiscancercare.com
                lindhors@musc.edu
                Jose.Lutzky@msmc.com
                Andrew.Sloan@UHhospitals.org
                Gabriele.Schackert@uniklinikum-dresden.de
                Dietmar.Krex@uniklinikum-dresden.de
                meisel@bergmannstrost.com
                jwu3@tuftsmedicalcenter.org
                raphael.davis@stonybrookmedicine.edu
                cduma@mac.com
                Arnold.Etame@moffitt.org
                David.Mathieu@USherbrooke.ca
                KesariS@jwci.org
                dpiccioni@ucsd.edu
                westphal@uke.de
                DBaskin@houstonmethodist.org
                pnew@houstonmethodist.org
                mlacroix1@geisinger.edu
                s-a.may@skc.de
                tpluard@saint-lukes.org
                Victor.C.Tse@kp.org
                Richard.M.Green@kp.org
                jlvillano@uky.edu
                mpearlman@carepointhc.com
                kevin.petrecca@mcgill.ca
                mschulder@northwell.edu
                ltaylor@uw.edu
                amaida@nwbio.com
                rprins@mednet.ucla.edu
                tcloughesy@mednet.ucla.edu
                paul.mulholland@nhs.net
                marnix@nwbio.com
                Journal
                J Transl Med
                J Transl Med
                Journal of Translational Medicine
                BioMed Central (London )
                1479-5876
                29 May 2018
                29 May 2018
                2018
                : 16
                : 142
                Affiliations
                [1 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, University of California Los Angeles (UCLA) David Geffen School of Medicine & Jonsson Comprehensive Cancer Center, ; Los Angeles, CA USA
                [2 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, King’s College London School of Medical Education, ; London, UK
                [3 ]ISNI 0000 0004 1936 8091, GRID grid.15276.37, University of Florida, ; Gainesville, FL USA
                [4 ]ISNI 0000 0001 2355 7002, GRID grid.4367.6, Washington University, ; St. Louis, MO USA
                [5 ]ISNI 0000 0000 8795 611X, GRID grid.413195.b, Abbott Northwestern Hospital, ; Minneapolis, MN USA
                [6 ]ISNI 0000 0004 0463 5388, GRID grid.281044.b, Swedish Medical Center, , Swedish Neuroscience Institute, ; Seattle, WA USA
                [7 ]ISNI 0000000086837370, GRID grid.214458.e, University of Michigan Medical School, ; Ann Arbor, MI USA
                [8 ]ISNI 0000 0004 0408 2680, GRID grid.468219.0, University of Kansas Cancer Center, ; Kansas City, KS USA
                [9 ]GRID grid.430769.f, Sutter Institute for Medical Research, ; Sacramento, CA USA
                [10 ]ISNI 0000 0001 2285 2675, GRID grid.239585.0, Columbia University Medical Center, ; New York, NY USA
                [11 ]ISNI 0000 0001 2287 3919, GRID grid.257413.6, Indiana University Simon Cancer Center, ; Indianapolis, IN USA
                [12 ]ISNI 0000 0000 8945 8587, GRID grid.417328.b, Overlook Medical Center, ; Summit, NJ USA
                [13 ]ISNI 0000 0004 1936 9166, GRID grid.412750.5, University of Rochester Medical Center, ; Rochester, NY USA
                [14 ]ISNI 0000 0001 0705 3621, GRID grid.240684.c, Rush University Medical Center, ; Rochester, USA
                [15 ]ISNI 0000 0004 1936 8796, GRID grid.430387.b, Rutgers Cancer Institute, ; New Brunswick, NJ USA
                [16 ]ISNI 0000 0000 9881 9161, GRID grid.413561.4, University of Cincinnati Medical Center, ; Cincinnati, OH USA
                [17 ]ISNI 0000 0004 0407 6328, GRID grid.239835.6, Hackensack University Medical Center, ; Hackensack, NJ USA
                [18 ]ISNI 0000 0004 0434 883X, GRID grid.417319.9, UC Irvine Medical Center, ; Irvine, CA USA
                [19 ]ISNI 0000 0001 0228 085X, GRID grid.281603.e, Winthrop-University Hospital, ; Mineola, NY USA
                [20 ]ISNI 0000 0001 0557 9478, GRID grid.240588.3, Rhode Island Hospital, ; Providence, RI USA
                [21 ]ISNI 0000 0000 9908 7089, GRID grid.413085.b, University of Colorado Hospital, ; Aurora, CO USA
                [22 ]ISNI 0000 0000 8523 7701, GRID grid.239864.2, Henry Ford Health System, ; Detroit, MI USA
                [23 ]St. Thomas Research Institute, Nashville, TN USA
                [24 ]ISNI 0000 0001 0629 5880, GRID grid.267309.9, University of Texas Health Science Center, ; San Antonio, TX USA
                [25 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, University of Pennsylvania Perelman School of Medicine, ; Philadelphia, PA USA
                [26 ]ISNI 0000 0001 1034 1720, GRID grid.410711.2, University of North Carolina, ; Chapel Hill, NC USA
                [27 ]ISNI 0000 0004 0421 8357, GRID grid.410425.6, City of Hope National Medical Center, ; Duarte, CA USA
                [28 ]ISNI 0000 0001 2166 5843, GRID grid.265008.9, Thomas Jefferson University, ; Philadelphia, PA USA
                [29 ]ISNI 0000 0004 0450 7802, GRID grid.416692.e, St. Joseph Hospital, ; Newport Beach, CA USA
                [30 ]ISNI 0000 0001 2264 7217, GRID grid.152326.1, Vanderbilt University, ; Nashville, TN USA
                [31 ]ISNI 0000 0000 9011 8547, GRID grid.239395.7, Beth Israel Deaconess Medical Center, ; Boston, MA USA
                [32 ]ISNI 0000 0001 2167 9807, GRID grid.411588.1, Baylor University Medical Center, ; Dallas, TX USA
                [33 ]GRID grid.428927.2, Illinois CancerCare, ; Peoria, IL USA
                [34 ]ISNI 0000 0001 2189 3475, GRID grid.259828.c, Medical University of South Carolina, ; Charleston, SC USA
                [35 ]ISNI 0000 0004 0430 4458, GRID grid.410396.9, Mount Sinai Comprehensive Cancer Center, ; Miami, FL USA
                [36 ]ISNI 0000 0000 9149 4843, GRID grid.443867.a, University Hospitals Case Medical Center, ; Cleveland, OH USA
                [37 ]ISNI 0000 0001 1091 2917, GRID grid.412282.f, University Hospital Carl-Gustav-Carus of Technical University, ; Dresden, Germany
                [38 ]BG-Klinikum Bergmannstrost, Halle, Germany
                [39 ]ISNI 0000 0000 8934 4045, GRID grid.67033.31, Tufts University School of Medicine, ; Boston, MA USA
                [40 ]ISNI 0000 0001 2216 9681, GRID grid.36425.36, Stony Brook University, ; Stony Brook, NY USA
                [41 ]ISNI 0000 0000 9755 6590, GRID grid.414587.b, Hoag Cancer Center, ; Newport Beach, CA USA
                [42 ]ISNI 0000 0000 9891 5233, GRID grid.468198.a, H. Lee Moffit Cancer Center and Research Institute, ; Tampa, FL USA
                [43 ]ISNI 0000 0000 9064 6198, GRID grid.86715.3d, CHUS-Hopital Fleurimont, Sherbrooke University, ; Sherbrooke, QC Canada
                [44 ]ISNI 0000 0001 2107 4242, GRID grid.266100.3, UCSD Health System, UC San Diego, ; San Diego, CA USA
                [45 ]ISNI 0000 0001 2180 3484, GRID grid.13648.38, Neurochirurgische Klinik University Clinic Hamburg-Eppendorf, ; Hamburg, Germany
                [46 ]ISNI 0000 0004 0445 0041, GRID grid.63368.38, Houston Methodist, ; Houston, TX USA
                [47 ]ISNI 0000 0004 0394 1447, GRID grid.280776.c, Geisinger Health System, ; Danville, PA USA
                [48 ]ISNI 0000 0004 0389 4214, GRID grid.459629.5, Klinikum Chemnitz GGMBH, ; Chemnitz, Germany
                [49 ]ISNI 0000 0004 0383 1037, GRID grid.419820.6, Saint Luke’s Cancer Institute, ; Kansas City, MO USA
                [50 ]ISNI 0000 0000 9957 7758, GRID grid.280062.e, Kaiser Permanente Northern California, ; Redwood City, CA USA
                [51 ]ISNI 0000 0000 9957 7758, GRID grid.280062.e, Kaiser Permanente Southern California, ; Los Angeles, CA USA
                [52 ]ISNI 0000 0004 1936 8438, GRID grid.266539.d, University of Kentucky College of Medicine, ; Lexington, KY USA
                [53 ]ISNI 0000 0004 0480 7493, GRID grid.433646.0, Colorado Neurological Institute, ; Englewood, CO USA
                [54 ]ISNI 0000 0004 1936 8649, GRID grid.14709.3b, Montreal Neurological Institute and Hospital, McGill University, ; Montreal, Canada
                [55 ]ISNI 0000 0004 1936 8753, GRID grid.137628.9, Northwell Hofstra School of Medicine, ; Lake Success, NY USA
                [56 ]ISNI 0000000122986657, GRID grid.34477.33, Department of Neurology, Alvord Brain Tumor Center, , University of Washington, ; Seattle, WA USA
                [57 ]ISNI 0000000121901201, GRID grid.83440.3b, University College Hospitals, ; London, UK
                [58 ]GRID grid.436541.1, Northwest Biotherapeutics Inc., ; Bethesda, MD USA
                [59 ]ISNI 0000 0004 1936 8753, GRID grid.137628.9, NYU Winthrop Hospital, ; Mineola, NY USA
                Author information
                http://orcid.org/0000-0002-8831-8456
                Article
                1507
                10.1186/s12967-018-1507-6
                5975654
                29843811
                4efc3b1d-8e53-4011-9a41-22d95881dc8c
                © The Author(s) 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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
                : 27 April 2018
                : 7 May 2018
                Categories
                Research
                Custom metadata
                © The Author(s) 2018

                Medicine
                glioblastoma,immunotherapy,dendritic cell,vaccine
                Medicine
                glioblastoma, immunotherapy, dendritic cell, vaccine

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