Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Trials
Published in: Trials 1/2018

Open Access 01-12-2018 | Study protocol

A randomized controlled phase II trial of vaccination with lysate-loaded, mature dendritic cells integrated into standard radiochemotherapy of newly diagnosed glioblastoma (GlioVax): study protocol for a randomized controlled trial

Authors: Marion Rapp, Oliver M. Grauer, Marcel Kamp, Natalie Sevens, Nikola Zotz, Michael Sabel, Rüdiger V. Sorg

Published in: Trials | Issue 1/2018

Login to get access

Abstract

Background

Despite the combination of surgical resection, radio- and chemotherapy, median survival of glioblastoma multiforme (GBM) patients only slightly increased in the last years. Disease recurrence is definite with no effective therapy existing after tumor removal. Dendritic cell (DC) vaccination is a promising active immunotherapeutic approach. There is clear evidence that it is feasible, results in immunological anti-tumoral responses, and appears to be beneficial for survival and quality of life of GBM patients. Moreover, combining it with the standard therapy of GBM may allow exploiting synergies between the treatment modalities. In this randomized controlled trial, we seek to confirm these promising initial results.

Methods

One hundred and thirty-six newly diagnosed, isocitrate dehydrogenase wildtype GBM patients will be randomly allocated (1:1 ratio, stratified by O6-methylguanine-DNA-methyltransferase promotor methylation status) after near-complete resection in a multicenter, prospective phase II trial into two groups: (1) patients receiving the current therapeutic “gold standard” of radio/temozolomide chemotherapy and (2) patients receiving DC vaccination as an add-on to the standard therapy. A recruitment period of 30 months is anticipated; follow-up will be 2 years. The primary objective of the study is to compare overall survival (OS) between the two groups. Secondary objectives are comparing progression-free survival (PFS) and 6-, 12- and 24-month OS and PFS rates, the safety profile, overall and neurological performance and quality of life.

Discussion

Until now, close to 500 GBM patients have been treated with DC vaccination in clinical trials or on a compassionate-use basis. Results have been encouraging, but cannot provide robust evidence of clinical efficacy because studies have been non-controlled or patient numbers have been low. Therefore, a prospective, randomized phase II trial with a sufficiently large number of patients is now mandatory for clear evidence regarding the impact of DC vaccination on PFS and OS in GBM.

Trial registration

Protocol code: GlioVax, date of registration: 17. February 2017.
Trial identifier: EudraCT-Number 2017–000304-14.
German Registry for Clinical Studies, ID: DRKS00013248 (approved primary register in the WHO network) and at ClinicalTrials.​gov, ID: NCT03395587. Registered on 11 March 2017.
Appendix
Available only for authorised users
Literature
1.
Ostrom QT, Bauchet L, Davis FG, Deltour I, Fisher JL, et al. The epidemiology of glioma in adults: a “state of the science” review. Neuro-Oncology. 2014;16:896–913.PubMedPubMedCentralCrossRef
2.
Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10:459–66.PubMedCrossRef
3.
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96.PubMedCrossRef
4.
5.
6.
Hsu FJ, Benike C, Fagnoni F, Liles TM, Czerwinski D, et al. Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat Med. 1996;2:52–8.PubMedCrossRef
7.
Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol. 2006;24:3089–94.PubMedCrossRef
8.
Liau LM, Black KL, Martin NA, Sykes SN, Bronstein JM, et al. Treatment of a patient by vaccination with autologous dendritic cells pulsed with allogeneic major histocompatibility complex class I-matched tumor peptides. Case report. Neurosurg Focus. 2000;e8:9.
9.
Kikuchi T, Akasaki Y, Irie M, Homma S, Abe T, et al. Results of a phase I clinical trial of vaccination of glioma patients with fusions of dendritic and glioma cells. Cancer Immunol Immunother. 2001;50:337–44.PubMedCrossRef
10.
Yu JS, Wheeler CJ, Zeltzer PM, Ying H, Finger DN, et al. Vaccination of malignant glioma patients with peptide-pulsed dendritic cells elicits systemic cytotoxicity and intracranial T-cell infiltration. Cancer Res. 2001;61:842–7.PubMed
11.
Wheeler CJ, Black KL, Liu G, Ying H, Yu JS, et al. Thymic CD8+ T cell production strongly influences tumor antigen recognition and age-dependent glioma mortality. J Immunol. 2003;171:4927–33.PubMedCrossRef
12.
Yamanaka R, Abe T, Yajima N, Tsuchiya N, Homma J, et al. Vaccination of recurrent glioma patients with tumour lysate-pulsed dendritic cells elicits immune responses: results of a clinical phase I/II trial. Br J Cancer. 2003;89:1172–9.PubMedPubMedCentralCrossRef
13.
Caruso DA, Orme LM, Neale AM, Radcliff FJ, Amor GM, et al. Results of a phase 1 study utilizing monocyte-derived dendritic cells pulsed with tumor RNA in children and young adults with brain cancer. Neuro-Oncology. 2004;6:236–46.PubMedPubMedCentralCrossRef
14.
De Vleeschouwer S, Van Calenbergh F, Demaerel P, Flamen P, Rutkowski S, et al. Transient local response and persistent tumor control in a child with recurrent malignant glioma: treatment with combination therapy including dendritic cell therapy. Case report. J Neurosurg. 2004;100:492–7.PubMed
15.
Kikuchi T, Akasaki Y, Abe T, Fukuda T, Saotome H, et al. Vaccination of glioma patients with fusions of dendritic and glioma cells and recombinant human interleukin 12. J Immunother. 2004;27:452–9.PubMedCrossRef
16.
Rutkowski S, De Vleeschouwer S, Kaempgen E, Wolff JE, Kuhl J, et al. Surgery and adjuvant dendritic cell-based tumour vaccination for patients with relapsed malignant glioma, a feasibility study. Br J Cancer. 2004;91:1656–62.PubMedPubMedCentralCrossRef
17.
Wheeler CJ, Das A, Liu G, Yu JS, Black KL. Clinical responsiveness of glioblastoma multiforme to chemotherapy after vaccination. Clin Cancer Res. 2004;10:5316–26.PubMedCrossRef
18.
Yu JS, Liu G, Ying H, Yong WH, Black KL, et al. Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma. Cancer Res. 2004;64:4973–9.PubMedCrossRef
19.
Liau LM, Prins RM, Kiertscher SM, Odesa SK, Kremen TJ, et al. Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment. Clin Cancer Res. 2005;11:5515–25.PubMedCrossRef
20.
Yamanaka R, Homma J, Yajima N, Tsuchiya N, Sano M, et al. Clinical evaluation of dendritic cell vaccination for patients with recurrent glioma: results of a clinical phase I/II trial. Clin Cancer Res. 2005;11:4160–7.PubMedCrossRef
21.
22.
Okada H, Lieberman FS, Walter KA, Lunsford LD, Kondziolka DS, et al. Autologous glioma cell vaccine admixed with interleukin-4 gene transfected fibroblasts in the treatment of patients with malignant gliomas. J Transl Med. 2007;5:67.PubMedPubMedCentralCrossRef
23.
de Vleeschouwer S, Fieuws S, Rutkowski S, Van Calenbergh F, Van Loon J, et al. Postoperative adjuvant dendritic cell-based immunotherapy in patients with relapsed glioblastoma multiforme. Clin Cancer Res. 2008;14:3098–104.PubMedCrossRef
24.
Walker DG, Laherty R, Tomlinson FH, Chuah T, Schmidt C. Results of a phase I dendritic cell vaccine trial for malignant astrocytoma: potential interaction with adjuvant chemotherapy. J Clin Neurosci. 2008;15:114–21.PubMedCrossRef
25.
Wheeler CJ, Black KL, Liu G, Mazer M, Zhang XX, et al. Vaccination elicits correlated immune and clinical responses in glioblastoma multiforme patients. Cancer Res. 2008;68:5955–64.PubMedCrossRef
26.
Sampson JH, Archer GE, Mitchell DA, Heimberger AB, Herndon JE, 2nd, , et al. An epidermal growth factor receptor variant III-targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme. Mol Cancer Ther 2009;8:2773–2779.PubMedPubMedCentralCrossRef
27.
Ardon H, De Vleeschouwer S, Van Calenbergh F, Claes L, Kramm CM, et al. Adjuvant dendritic cell-based tumour vaccination for children with malignant brain tumours. Pediatr Blood Cancer. 2010;54:519–25.PubMed
28.
Ardon H, Van Gool S, Lopes IS, Maes W, Sciot R, et al. Integration of autologous dendritic cell-based immunotherapy in the primary treatment for patients with newly diagnosed glioblastoma multiforme: a pilot study. J Neuro-Oncol. 2010;99:261–72.CrossRef
29.
Chang CN, Huang YC, Yang DM, Kikuta K, Wei KJ, et al. A phase I/II clinical trial investigating the adverse and therapeutic effects of a postoperative autologous dendritic cell tumor vaccine in patients with malignant glioma. J Clin Neurosci. 2011;18:1048–54.PubMedCrossRef
30.
Fadul CE, Fisher JL, Hampton TH, Lallana EC, Li Z, et al. Immune response in patients with newly diagnosed glioblastoma multiforme treated with intranodal autologous tumor lysate-dendritic cell vaccination after radiation chemotherapy. J Immunother. 2011;34:382–9.PubMedPubMedCentralCrossRef
31.
Okada H, Kalinski P, Ueda R, Hoji A, Kohanbash G, et al. Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with {alpha}-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma. J Clin Oncol. 2011;29:330–6.PubMedCrossRef
32.
Prins RM, Soto H, Konkankit V, Odesa SK, Eskin A, et al. Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy. Clin Cancer Res. 2011;17:1603–15.PubMedCrossRef
33.
Akiyama Y, Oshita C, Kume A, Iizuka A, Miyata H, et al. alpha-type-1 polarized dendritic cell-based vaccination in recurrent high-grade glioma: a phase I clinical trial. BMC Cancer. 2012;12:623.PubMedPubMedCentralCrossRef
34.
Ardon H, Van Gool SW, Verschuere T, Maes W, Fieuws S, et al. Integration of autologous dendritic cell-based immunotherapy in the standard of care treatment for patients with newly diagnosed glioblastoma: results of the HGG-2006 phase I/II trial. Cancer Immunol Immunother. 2012;61:2033–44.PubMedCrossRef
35.
Cho DY, Yang WK, Lee HC, Hsu DM, Lin HL, et al. Adjuvant immunotherapy with whole-cell lysate dendritic cells vaccine for glioblastoma multiforme: a phase II clinical trial. World Neurosurg. 2012;77:736–44.PubMedCrossRef
36.
Iwami K, Shimato S, Ohno M, Okada H, Nakahara N, et al. Peptide-pulsed dendritic cell vaccination targeting interleukin-13 receptor alpha2 chain in recurrent malignant glioma patients with HLA-A*24/A*02 allele. Cytotherapy. 2012;14:733–42.PubMedCrossRef
37.
Jie X, Hua L, Jiang W, Feng F, Feng G, et al. Clinical application of a dendritic cell vaccine raised against heat-shocked glioblastoma. Cell Biochem Biophys. 2012;62:91–9.PubMedCrossRef
38.
Valle RD, de Cerio AL, Inoges S, Tejada S, Pastor F, et al. Dendritic cell vaccination in glioblastoma after fluorescence-guided resection. World J Clin Oncol. 2012;3:142–9.PubMedPubMedCentralCrossRef
39.
Phuphanich S, Wheeler CJ, Rudnick JD, Mazer M, Wang H, et al. Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma. Cancer Immunol Immunother. 2013;62:125–35.PubMedCrossRef
40.
Vik-Mo EO, Nyakas M, Mikkelsen BV, Moe MC, Due-Tonnesen P, et al. Therapeutic vaccination against autologous cancer stem cells with mRNA-transfected dendritic cells in patients with glioblastoma. Cancer Immunol Immunother. 2013;62:1499–509.PubMedPubMedCentralCrossRef
41.
Olin MR, Low W, McKenna DH, Haines SJ, Dahlheimer T, et al. Vaccination with dendritic cells loaded with allogeneic brain tumor cells for recurrent malignant brain tumors induces a CD4(+)IL17(+) response. J Immunother Cancer. 2014;2:4.PubMedPubMedCentralCrossRef
42.
Hunn MK, Bauer E, Wood CE, Gasser O, Dzhelali M, et al. Dendritic cell vaccination combined with temozolomide retreatment: results of a phase I trial in patients with recurrent glioblastoma multiforme. J Neuro-Oncol. 2015;121:319–29.CrossRef
43.
Mitchell DA, Batich KA, Gunn MD, Huang MN, Sanchez-Perez L, et al. Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature. 2015;519:366–9.PubMedPubMedCentralCrossRef
44.
Sakai K, Shimodaira S, Maejima S, Udagawa N, Sano K, et al. Dendritic cell-based immunotherapy targeting Wilms’ tumor 1 in patients with recurrent malignant glioma. J Neurosurg. 2015;123(4):989–97.
45.
Akasaki Y, Kikuchi T, Homma S, Koido S, Ohkusa T, et al. Phase I/II trial of combination of temozolomide chemotherapy and immunotherapy with fusions of dendritic and glioma cells in patients with glioblastoma. Cancer Immunol Immunother. 2016;65:1499–509.PubMedCrossRef
46.
Inoges S, Tejada S, de Cerio AL, Gallego Perez-Larraya J, Espinos J, et al. A phase II trial of autologous dendritic cell vaccination and radiochemotherapy following fluorescence-guided surgery in newly diagnosed glioblastoma patients. J Transl Med. 2017;15:104.PubMedPubMedCentralCrossRef
47.
Cao JX, Zhang XY, Liu JL, Li D, Li JL, et al. Clinical efficacy of tumor antigen-pulsed DC treatment for high-grade glioma patients: evidence from a meta-analysis. PLoS One. 2014;9:e107173.PubMedPubMedCentralCrossRef
48.
Kim CH, Woo SJ, Park JS, Kim HS, Park MY, et al. Enhanced antitumour immunity by combined use of temozolomide and TAT-survivin pulsed dendritic cells in a murine glioma. Immunology. 2007;122:615–22.PubMedPubMedCentralCrossRef
49.
Park SD, Kim CH, Kim CK, Park JA, Sohn HJ, et al. Cross-priming by temozolomide enhances antitumor immunity of dendritic cell vaccination in murine brain tumor model. Vaccine. 2007;25:3485–91.PubMedCrossRef
50.
Kim TG, Kim CH, Park JS, Park SD, Kim CK, et al. Immunological factors relating to the antitumor effect of temozolomide chemoimmunotherapy in a murine glioma model. Clin Vaccine Immunol. 2010;17:143–53.PubMedCrossRef
51.
Banissi C, Ghiringhelli F, Chen L, Carpentier AF. Treg depletion with a low-dose metronomic temozolomide regimen in a rat glioma model. Cancer Immunol Immunother. 2009;58:1627–34.PubMedCrossRef
52.
Jordan JT, Sun W, Hussain SF, DeAngulo G, Prabhu SS, et al. Preferential migration of regulatory T cells mediated by glioma-secreted chemokines can be blocked with chemotherapy. Cancer Immunol Immunother. 2008;57:123–31.PubMedCrossRef
53.
Sampson JH, Aldape KD, Archer GE, Coan A, Desjardins A, et al. Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro-Oncology. 2011;13:324–33.PubMedCrossRef
54.
Galea I, Bernardes-Silva M, Forse PA, van Rooijen N, Liblau RS, et al. An antigen-specific pathway for CD8 T cells across the blood-brain barrier. J Exp Med. 2007;204:2023–30.PubMedPubMedCentralCrossRef
55.
Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131:803–20.PubMedCrossRef
56.
Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352:997–1003.PubMedCrossRef
57.
Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, et al. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006;7:392–401.PubMedCrossRef
58.
DeMets DL, Lan KK. Interim analysis: the alpha spending function approach. Stat Med. 1994;13:1341–52.PubMedCrossRef
59.
Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol. 2010;28:1963–72.PubMedCrossRef
60.
Okada H, Weller M, Huang R, Finocchiaro G, Gilbert MR, et al. Immunotherapy response assessment in neuro-oncology: a report of the RANO working group. Lancet Oncol. 2015;16:e534–42.PubMedPubMedCentralCrossRef
61.
Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189–98.PubMedCrossRef
62.
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85:365–76.PubMedCrossRef
63.
Taphoorn MJ, Claassens L, Aaronson NK, Coens C, Mauer M, et al. An international validation study of the EORTC brain cancer module (EORTC QLQ-BN20) for assessing health-related quality of life and symptoms in brain cancer patients. Eur J Cancer. 2010;46:1033–40.PubMedCrossRef
64.
Mehnert A, Müller D, Lehmann C, Koch U. Die deutsche Version des NCCN Distress-Thermometers. Empirische Prüfung eines Screening-Instruments zur Erfassung psychosozialer Belastung bei Krebspatienten. Zeitschrift Psychiatr Psychol Psychother. 2006;54:213–23.
65.
Herrmann C, Buss U, Snaith RP. HADS-D: Hospital Anxiety and Depression Scale—Deutsche Version; Ein Fragebogen zur Erfassung von Angst und Depressivitäit in der somatischen Medizin. Bern: Hans Huber Verlag; 1995.
66.
Rapp M, Ozcan Z, Steiger HJ, Wernet P, Sabel MC, et al. Cellular immunity of patients with malignant glioma: prerequisites for dendritic cell vaccination immunotherapy. J Neurosurg. 2006;105:41–50.PubMedCrossRef
67.
Sorg RV, Ozcan Z, Brefort T, Fischer J, Ackermann R, et al. Clinical-scale generation of dendritic cells in a closed system. J Immunother. 2003;26:374–83.PubMedCrossRef
68.
Jonuleit H, Kuhn U, Muller G, Steinbrink K, Paragnik L, et al. Pro-inflammatory cytokines and prostaglandins induce maturation of potent immunostimulatory dendritic cells under fetal calf serum-free conditions. Eur J Immunol. 1997;27:3135–42.PubMedCrossRef
69.
Mirimanoff RO, Gorlia T, Mason W, Van den Bent MJ, Kortmann RD, et al. Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial. J Clin Oncol. 2006;24:2563–9.PubMedCrossRef
70.
De Vleeschouwer S, Ardon H, Van Calenbergh F, Sciot R, Wilms G, et al. Stratification according to HGG-IMMUNO RPA model predicts outcome in a large group of patients with relapsed malignant glioma treated by adjuvant postoperative dendritic cell vaccination. Cancer Immunol Immunother. 2012;61:2105–12.PubMedCrossRef
71.
Calzascia T, Di Berardino-Besson W, Wilmotte R, Masson F, de Tribolet N, et al. Cutting edge: cross-presentation as a mechanism for efficient recruitment of tumor-specific CTL to the brain. J Immunol. 2003;171:2187–91.PubMedCrossRef
72.
Masson F, Calzascia T, Di Berardino-Besson W, de Tribolet N, Dietrich PY, et al. Brain microenvironment promotes the final functional maturation of tumor-specific effector CD8+ T cells. J Immunol. 2007;179:845–53.PubMedCrossRef
73.
Maes W, Van Gool SW. Experimental immunotherapy for malignant glioma: lessons from two decades of research in the GL261 model. Cancer Immunol Immunother. 2011;60:153–60.PubMedCrossRef
74.
Pellegatta S, Poliani PL, Corno D, Grisoli M, Cusimano M, et al. Dendritic cells pulsed with glioma lysates induce immunity against syngeneic intracranial gliomas and increase survival of tumor-bearing mice. Neurol Res. 2006;28:527–31.PubMedCrossRef
75.
Ni HT, Spellman SR, Jean WC, Hall WA, Low WC. Immunization with dendritic cells pulsed with tumor extract increases survival of mice bearing intracranial gliomas. J Neuro-Oncol. 2001;51:1–9.CrossRef
76.
Liau LM, Black KL, Prins RM, Sykes SN, DiPatre PL, et al. Treatment of intracranial gliomas with bone marrow-derived dendritic cells pulsed with tumor antigens. J Neurosurg. 1999;90:1115–24.PubMedCrossRef
77.
Heimberger AB, Crotty LE, Archer GE, McLendon RE, Friedman A, et al. Bone marrow-derived dendritic cells pulsed with tumor homogenate induce immunity against syngeneic intracerebral glioma. J Neuroimmunol. 2000;103:16–25.PubMedCrossRef
78.
Magana-Maldonado R, Chavez-Cortez EG, Olascoaga-Arellano NK, Lopez-Mejia M, Maldonado-Leal FM, et al. Immunological evasion in glioblastoma. Biomed Res Int. 2016;2016:7487313.PubMedPubMedCentralCrossRef
79.
80.
Fecci PE, Mitchell DA, Whitesides JF, Xie W, Friedman AH, et al. Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res. 2006;66:3294–302.PubMedCrossRef
81.
Dix AR, Brooks WH, Roszman TL, Morford LA. Immune defects observed in patients with primary malignant brain tumors. J Neuroimmunol. 1999;100:216–32.PubMedCrossRef
82.
Morford LA, Elliott LH, Carlson SL, Brooks WH, Roszman TL. T cell receptor-mediated signaling is defective in T cells obtained from patients with primary intracranial tumors. J Immunol. 1997;159:4415–25.PubMed
83.
Brooks WH, Latta RB, Mahaley MS, Roszman TL, Dudka L, et al. Immunobiology of primary intracranial tumors. Part 5: correlation of a lymphocyte index and clinical status. J Neurosurg. 1981;54:331–7.PubMedCrossRef
84.
Braun DP, Penn RD, Flannery AM, Harris JE. Immunoregulatory cell function in peripheral blood leukocytes of patients with intracranial gliomas. Neurosurgery. 1982;10:203–9.PubMed
85.
Grauer OM, Nierkens S, Bennink E, Toonen LW, Boon L, et al. CD4+FoxP3+ regulatory T cells gradually accumulate in gliomas during tumor growth and efficiently suppress antiglioma immune responses in vivo. Int J Cancer. 2007;121:95–105.PubMedCrossRef
86.
Grauer OM, Sutmuller RP, van Maren W, Jacobs JF, Bennink E, et al. Elimination of regulatory T cells is essential for an effective vaccination with tumor lysate-pulsed dendritic cells in a murine glioma model. Int J Cancer. 2008;122:1794–802.PubMedCrossRef
87.
Sampson JH, Heimberger AB, Archer GE, Aldape KD, Friedman AH, et al. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol. 2010;28:4722–9.PubMedPubMedCentralCrossRef
88.
Calzascia T, Masson F, Di Berardino-Besson W, Contassot E, Wilmotte R, et al. Homing phenotypes of tumor-specific CD8 T cells are predetermined at the tumor site by crosspresenting APCs. Immunity. 2005;22:175–84.PubMedCrossRef
89.
Neller MA, Lopez JA, Schmidt CW. Antigens for cancer immunotherapy. Semin Immunol. 2008;20:286–95.PubMedCrossRef
90.
Nishimura T, Iwakabe K, Sekimoto M, Ohmi Y, Yahata T, et al. Distinct role of antigen-specific T helper type 1 (Th1) and Th2 cells in tumor eradication in vivo. J Exp Med. 1999;190:617–27.PubMedPubMedCentralCrossRef
91.
Sallusto F, Schaerli P, Loetscher P, Schaniel C, Lenig D, et al. Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation. Eur J Immunol. 1998;28:2760–9.PubMedCrossRef
92.
Caux C, Ait-Yahia S, Chemin K, de Bouteiller O, Dieu-Nosjean MC, et al. Dendritic cell biology and regulation of dendritic cell trafficking by chemokines. Springer Semin Immunopathol. 2000;22:345–69.PubMedCrossRef
93.
Steinbrink K, Wolfl M, Jonuleit H, Knop J, Enk AH. Induction of tolerance by IL-10-treated dendritic cells. J Immunol. 1997;159:4772–80.PubMed
94.
Grauer O, Poschl P, Lohmeier A, Adema GJ, Bogdahn U. Toll-like receptor triggered dendritic cell maturation and IL-12 secretion are necessary to overcome T-cell inhibition by glioma-associated TGF-beta2. J Neuro-Oncol. 2007;82:151–61.CrossRef
95.
Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annu Rev Immunol. 2003;21:685–711.PubMedCrossRef
96.
Dudek AM, Martin S, Garg AD, Agostinis P. Immature, semi-mature, and fully mature dendritic cells: toward a DC-cancer cells interface that augments anticancer immunity. Front Immunol. 2013;4:438.PubMedPubMedCentralCrossRef
97.
de Vries IJ, Lesterhuis WJ, Scharenborg NM, Engelen LP, Ruiter DJ, et al. Maturation of dendritic cells is a prerequisite for inducing immune responses in advanced melanoma patients. Clin Cancer Res. 2003;9:5091–100.PubMed
98.
Dhodapkar MV, Steinman RM, Krasovsky J, Munz C, Bhardwaj N. Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells. J Exp Med. 2001;193:233–8.PubMedPubMedCentralCrossRef
99.
Eggert AA, Schreurs MW, Boerman OC, Oyen WJ, de Boer AJ, et al. Biodistribution and vaccine efficiency of murine dendritic cells are dependent on the route of administration. Cancer Res. 1999;59:3340–5.PubMed
100.
Eggert AA, van der Voort R, Torensma R, Moulin V, Boerman OC, et al. Analysis of dendritic cell trafficking using EGFP-transgenic mice. Immunol Lett. 2003;89:17–24.PubMedCrossRef
101.
Morse MA, Coleman RE, Akabani G, Niehaus N, Coleman D, et al. Migration of human dendritic cells after injection in patients with metastatic malignancies. Cancer Res. 1999;59:56–8.PubMed
102.
De Vries IJ, Krooshoop DJ, Scharenborg NM, Lesterhuis WJ, Diepstra JH, et al. Effective migration of antigen-pulsed dendritic cells to lymph nodes in melanoma patients is determined by their maturation state. Cancer Res. 2003;63:12–7.PubMed
103.
Macatonia SE, Knight SC, Edwards AJ, Griffiths S, Fryer P. Localization of antigen on lymph node dendritic cells after exposure to the contact sensitizer fluorescein isothiocyanate. Functional and morphological studies. J Exp Med. 1987;166:1654–67.PubMedCrossRef
104.
Ruedl C, Koebel P, Bachmann M, Hess M, Karjalainen K. Anatomical origin of dendritic cells determines their life span in peripheral lymph nodes. J Immunol. 2000;165:4910–6.PubMedCrossRef
105.
Garg S, Oran A, Wajchman J, Sasaki S, Maris CH, et al. Genetic tagging shows increased frequency and longevity of antigen-presenting, skin-derived dendritic cells in vivo. Nat Immunol. 2003;4:907–12.PubMedCrossRef
106.
Verdijk P, Aarntzen EH, Lesterhuis WJ, Boullart AC, Kok E, et al. Limited amounts of dendritic cells migrate into the T-cell area of lymph nodes but have high immune activating potential in melanoma patients. Clin Cancer Res. 2009;15:2531–40.PubMedCrossRef
107.
Lesterhuis WJ, de Vries IJ, Schreibelt G, Lambeck AJ, Aarntzen EH, et al. Route of administration modulates the induction of dendritic cell vaccine-induced antigen-specific T cells in advanced melanoma patients. Clin Cancer Res. 2011;17:5725–35.PubMedCrossRef
108.
Ringel F, Pape H, Sabel M, Krex D, Bock HC, et al. Clinical benefit from resection of recurrent glioblastomas: results of a multicenter study including 503 patients with recurrent glioblastomas undergoing surgical resection. Neuro-Oncology. 2016;18:96–104.PubMedCrossRef
109.
Suchorska B, Weller M, Tabatabai G, Senft C, Hau P, et al. Complete resection of contrast-enhancing tumor volume is associated with improved survival in recurrent glioblastoma-results from the DIRECTOR trial. Neuro-Oncology. 2016;18:549–56.PubMedPubMedCentralCrossRef
110.
111.
Grauer OM, Wesseling P, Adema GJ. Immunotherapy of diffuse gliomas: biological background, current status and future developments. Brain Pathol. 2009;19:674–93.PubMedCrossRef
112.
Dubinski D, Wolfer J, Hasselblatt M, Schneider-Hohendorf T, Bogdahn U, et al. CD4+ T effector memory cell dysfunction is associated with the accumulation of granulocytic myeloid-derived suppressor cells in glioblastoma patients. Neuro-Oncology. 2015;18:807–18.PubMedPubMedCentralCrossRef
113.
Fong B, Jin R, Wang X, Safaee M, Lisiero DN, et al. Monitoring of regulatory T cell frequencies and expression of CTLA-4 on T cells, before and after DC vaccination, can predict survival in GBM patients. PLoS One. 2012;7:e32614.PubMedPubMedCentralCrossRef
114.
Jacobs JF, Idema AJ, Bol KF, Nierkens S, Grauer OM, et al. Regulatory T cells and the PD-L1/PD-1 pathway mediate immune suppression in malignant human brain tumors. Neuro-Oncology. 2009;11:394–402.PubMedPubMedCentralCrossRef
115.
Betts MR, Brenchley JM, Price DA, De Rosa SC, Douek DC, et al. Sensitive and viable identification of antigen-specific CD8+ T cells by a flow cytometric assay for degranulation. J Immunol Methods. 2003;281:65–78.PubMedCrossRef
116.
Dutoit V, Herold-Mende C, Hilf N, Schoor O, Beckhove P, et al. Exploiting the glioblastoma peptidome to discover novel tumour-associated antigens for immunotherapy. Brain. 2012;135:1042–54.PubMedCrossRef
117.
Pollack IF, Jakacki RI, Butterfield LH, Hamilton RL, Panigrahy A, et al. Immune responses and outcome after vaccination with glioma-associated antigen peptides and poly-ICLC in a pilot study for pediatric recurrent low-grade gliomas. Neuro-Oncology. 2016;18:1157–68.PubMedPubMedCentralCrossRef
Metadata
Title
A randomized controlled phase II trial of vaccination with lysate-loaded, mature dendritic cells integrated into standard radiochemotherapy of newly diagnosed glioblastoma (GlioVax): study protocol for a randomized controlled trial
Authors
Marion Rapp
Oliver M. Grauer
Marcel Kamp
Natalie Sevens
Nikola Zotz
Michael Sabel
Rüdiger V. Sorg
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Trials / Issue 1/2018
Electronic ISSN: 1745-6215
DOI
https://doi.org/10.1186/s13063-018-2659-7

Other articles of this Issue 1/2018

Trials 1/2018 Go to the issue

Study protocol

Nerve root block versus surgery (NERVES) for the treatment of radicular pain secondary to a prolapsed intervertebral disc herniation: study protocol for a multi-centre randomised controlled trial

Commentary

Outcome measures in clinical trials of treatments for acute severe haemorrhage

Study protocol

Effect of low-dose ketamine on PerioperAtive depreSsive Symptoms in patients undergoing Intracranial tumOr resectioN (PASSION): study protocol for a randomized controlled trial

Study protocol

A randomized controlled trial testing a hyaluronic acid spacer injection for skin toxicity reduction of brachytherapy accelerated partial breast irradiation (APBI): a study protocol

Research

Financial management of large, multi-center trials in a challenging funding milieu

Research

WASH Benefits Bangladesh trial: management structure for achieving high coverage in an efficacy trial