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Cancer Immunology, Immunotherapy
Published in: Cancer Immunology, Immunotherapy 11/2012

01-11-2012 | Original article

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

Authors: Hilko Ardon, Stefaan W. Van Gool, Tina Verschuere, Wim Maes, Steffen Fieuws, Raf Sciot, Guido Wilms, Philippe Demaerel, Jan Goffin, Frank Van Calenbergh, Johan Menten, Paul Clement, Maria Debiec-Rychter, Steven De Vleeschouwer

Published in: Cancer Immunology, Immunotherapy | Issue 11/2012

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Abstract

Purpose

Dendritic cell (DC)-based tumor vaccination has rendered promising results in relapsed high-grade glioma patients. In the HGG-2006 trial (EudraCT 2006-002881-20), feasibility, toxicity, and clinical efficacy of the full integration of DC-based tumor vaccination into standard postoperative radiochemotherapy are studied in 77 patients with newly diagnosed glioblastoma.

Patients and methods

Autologous DC are generated after leukapheresis, which is performed before the start of radiochemotherapy. Four weekly induction vaccines are administered after the 6-week course of concomitant radiochemotherapy. During maintenance chemotherapy, 4 boost vaccines are given. Feasibility and progression-free survival (PFS) at 6 months (6mo-PFS) are the primary end points. Overall survival (OS) and immune profiling, rather than monitoring, as assessed in patients’ blood samples, are the secondary end points. Analysis has been done on intent-to-treat basis.

Results

The treatment was feasible without major toxicity. The 6mo-PFS was 70.1 % from inclusion. Median OS was 18.3 months. Outcome improved significantly with lower EORTC RPA classification. Median OS was 39.7, 18.3, and 10.7 months for RPA classes III, IV, and V, respectively. Patients with a methylated MGMT promoter had significantly better PFS (p = 0.0027) and OS (p = 0.0082) as compared to patients with an unmethylated status. Exploratory “immunological profiles” were built to compare to clinical outcome, but no statistical significant evidence was found for these profiles to predict clinical outcome.

Conclusion

Full integration of autologous DC-based tumor vaccination into standard postoperative radiochemotherapy for newly diagnosed glioblastoma seems safe and possibly beneficial. These results were used to power the currently running phase IIb randomized clinical trial.
Appendix
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Literature
1.
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoom MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer EA, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Eng J Med 352:987–996CrossRef
2.
Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO (2009) 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 10:459–466PubMedCrossRef
3.
Ardon H, Van Gool S, Lopes IS, Maes W, Sciot R, Wilms G, Demaerel P, Bijttebier P, Claes L, Goffin J, Van Calenbergh F, De Vleeschouwer S (2010) Integration of autologous dendritic cell-based immunotherapy in the primary treatment for patients with newly diagnosed glioblastoma multiforme: a pilot study. J Neurooncol 99:261–272PubMedCrossRef
4.
De Vleeschouwer S, Fieuws S, Rutkowski S, Van Calenbergh F, Van Loon J, Goffin J, Sciot R, Wilms G, Demaerel P, Warmuth-Metz M, Soerensen N, Wolff JE, Wagner S, Kaempgen E, Van Gool SW (2008) Postoperative adjuvant dendritic cell-based immunotherapy in patients with relapsed glioblastoma multiforme. Clin Cancer Res 14:3098–3104PubMedCrossRef
5.
Sampson JH, Archer GE, Mitchell DA, Heimberger AB, Herndon JE, Lally-Goss D, McGehee-Norman S, Paolino A, Reardon DA, Friedman AH, Friedman HS, Bigner DD (2009) An epidermal growth factor receptor variant III-targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme. Mol Cancer Ther 8:2773–2779PubMedCrossRef
6.
Wheeler CJ, Black KL, Liu G, Mazer M, Zhang XX, Pepkowitz S, Goldfinger D, Ng H, Irvin D, Yu JS (2008) Vaccination elicits correlated immune and clinical responses in glioblastoma multiforme patients. Cancer Res 68:5955–5964PubMedCrossRef
7.
Ardon H, De Vleeschouwer S, Van Calenbergh F, Claes L, Kramm CM, Rutkowski S, Wolff JE, Van Gool SW (2010) Adjuvant dendritic cell-based tumour vaccination for children with malignant brain tumours. Pediatr Blood Cancer 54:519–525PubMed
8.
De Vleeschouwer S, Van Calenbergh F, Demaerel P, Flamen P, Rutkowski S, Kaempgen E, Wolff JEA, Plets C, Sciot R, Van Gool SW (2004) Transient local response and persistent tumor control of recurrent malignant glioma treated with combination therapy including dendritic cell therapy. J Neurosurg (pediatrics) 100:492–497CrossRef
9.
Grauer OM, Wesseling P, Adema GJ (2009) Immunotherapy of diffuse gliomas: biological background, current status and future developments. Brain Pathol 19:674–693PubMedCrossRef
10.
Liau LM, Prins RM, Kiertscher SM, Odesa SK, Kremen TJ, Giovannone AJ, Lin JW, Chute DJ, Mischel PS, Cloughesy TF, Roth MD (2005) 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 11:5515–5525PubMedCrossRef
11.
Rutkowski S, De Vleeschouwer S, Kaempgen E, Wolff JEA, Kuhl J, Demaerel P, Warmuth-Metz M, Flamen P, Van Calenbergh F, Plets C, Sorensen N, Opitz A, Van Gool SW (2004) Surgery and adjuvant dendritic cell-based tumour vaccination for patients with relapsed malignant glioma, a feasibility study. Br J Cancer 91:1656–1662PubMed
12.
Van Gool S, Maes W, Ardon H, Verschuere T, Van Cauter S, De Vleeschouwer S (2009) Dendritic cell therapy of high-grade gliomas. Brain Pathol 19:694–712PubMedCrossRef
13.
Walker DG, Laherty R, Tomlinson FH, Chuah T, Schmidt C (2008) Results of a phase I dendritic cell vaccine trial for malignant astrocytoma: potential interaction with adjuvant chemotherapy. J Clin Neurosci 15:114–121PubMedCrossRef
14.
North RJ (1984) Gamma-irradiation facilitates the expression of adoptive immunity against established tumors by eliminating suppressor T cells. Cancer Immunol Immunother 16:175–181PubMedCrossRef
15.
16.
Jameson SC (2002) Maintaining the norm: T-cell homeostasis. Nat Rev Immunol 2:547–556PubMed
17.
Porter DL, June CH (2005) T-cell reconstitution and expansion after hematopoietic stem cell transplantation: ‘T’ it up! Bone Marrow Transplant 35:935–942PubMedCrossRef
18.
Banissi C, Ghiringhelli F, Chen L, Carpentier AF (2009) Treg depletion with a low-dose metronomic temozolomide regimen in a rat glioma model. Cancer Immunol Immunother 58:1627–1634PubMedCrossRef
19.
Jordan JT, Sun W, Hussain SF, DeAngulo G, Prabhu SS, Heimberger AB (2008) Preferential migration of regulatory T cells mediated by glioma-secreted chemokines can be blocked with chemotherapy. Cancer Immunol Immunother 57:123–131PubMedCrossRef
20.
Park SD, Kim CH, Kim CK, Park JA, Sohn HJ, Hong YK, Kim TG (2007) Cross-priming by temozolomide enhances antitumor immunity of dendritic cell vaccination in murine brain tumor model. Vaccine 25:3485–3491PubMedCrossRef
21.
Kim TG, Kim CH, Park JS, Park SD, Kim CK, Chung DS, Hong YK (2010) Immunological factors relating to the antitumor effect of temozolomide chemoimmunotherapy in a murine glioma model. Clin Vaccine Immunol 17:143–153PubMedCrossRef
22.
Garg AD, Nowis D, Golab J, Vandenabeele P, Krysko DV, Agostinis P (2010) Immunogenic cell death, DAMPs and anticancer therapeutics: an emerging amalgamation. Biochim Biophys Acta 1805:53–71PubMed
23.
Wheeler CJ, Das A, Liu G, Yu JS, Black KL (2004) Clinical responsiveness of glioblastoma multiforme to chemotherapy after vaccination. Clin Cancer Res 10:5316–5326PubMedCrossRef
24.
Liu G, Akasaki Y, Khong HT, Wheeler CJ, Das A, Black KL, Yu JS (2005) Cytotoxic T cell targeting of TRP-2 sensitizes human malignant glioma to chemotherapy. Oncogene 24:5226–5234PubMedCrossRef
25.
Mirimanoff RO, Gorlia T, Mason W, van den Bent MJ, Kortmann RD, Fisher B, Reni M, Brandes AA, Curschmann J, Villa S, Cairncross G, Allgeier A, Lacombe D, Stupp R (2006) Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial. J Clin Oncol 24:2563–2569PubMedCrossRef
26.
Ardon H, Verbinnen B, Maes W, Beez T, Van Gool S, De Vleeschouwer S (2010) Technical advancement in regulatory T cell isolation and characterization using CD127 expression in patients with malignant glioma treated with autologous dendritic cell vaccination. J Immunol Methods 352:169–173PubMedCrossRef
27.
Weller M, Stupp R, Reifenberger G, Brandes AA, van den Bent MJ, Wick W, Hegi ME (2010) MGMT promoter methylation in malignant gliomas: ready for personalized medicine? Nat Rev Neurol 6:39–51PubMedCrossRef
28.
Gorlia T, van den Bent MJ, Hegi ME, Mirimanoff RO, Weller M, Cairncross JG, Eisenhauer E, Belanger K, Brandes AA, Allgeier A, Lacombe D, Stupp R (2008) Nomograms for predicting survival of patients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981-22981/CE.3. Lancet Oncol 9:29–38PubMedCrossRef
29.
Stummer W, Tonn JC, Mehdorn HM, Nestler U, Franz K, Goetz C, Bink A, Pichlmeier U (2010) Counterbalancing risks and gains from extended resections in malignant glioma surgery: a supplemental analysis from the randomized 5-aminolevulinic acid glioma resection study. J Neurosurg 114:613–623PubMed
30.
Muller AJ, Prendergast GC (2005) Marrying immunotherapy with chemotherapy: why say IDO? Cancer Res 65:8065–8068PubMedCrossRef
31.
Nowak AK, Robinson BW, Lake RA (2003) Synergy between chemotherapy and immunotherapy in the treatment of established murine solid tumors. Cancer Res 63:4490–4496PubMed
32.
Masucci GV, Mansson-Brahme E, Ragnarsson-Olding B, Nilsson B, Wagenius G, Hansson J (2006) Alternating chemo-immunotherapy with temozolomide and low-dose interleukin-2 in patients with metastatic melanoma. Melanoma Res 16:357–363PubMedCrossRef
33.
Grossman SA, Ye X, Chamberlain M, Mikkelsen T, Batchelor T, Desideri S, Piantadosi S, Fisher J, Fine HA (2009) Talampanel with standard radiation and temozolomide in patients with newly diagnosed glioblastoma: a multicenter phase II trial. J Clin Oncol 27:4155–4161PubMedCrossRef
34.
Grossman SA, Ye X, Piantadosi S, Desideri S, Nabors LB, Rosenfeld M, Fisher J (2010) Survival of patients with newly diagnosed glioblastoma treated with radiation and temozolomide in research studies in the United States. Clin Cancer Res 16:2443–2449PubMedCrossRef
35.
Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003PubMedCrossRef
36.
Rivera AL, Pelloski CE, Gilbert MR, Colman H, De La CC, Sulman EP, Bekele BN, Aldape KD (2010) MGMT promoter methylation is predictive of response to radiotherapy and prognostic in the absence of adjuvant alkylating chemotherapy for glioblastoma. Neuro Oncol 12:116–121PubMedCrossRef
37.
Hegi ME, Liu L, Herman JG, Stupp R, Wick W, Weller M, Mehta MP, Gilbert MR (2008) Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity. J Clin Oncol 26:4189–4199PubMedCrossRef
38.
Clavreul A, Piard N, Tanguy JY, Gamelin E, Rousselet MC, Leynia P, Menei P (2010) Autologous tumor cell vaccination plus infusion of GM-CSF by a programmable pump in the treatment of recurrent malignant gliomas. J Clin Neurosci 17:842–848PubMedCrossRef
39.
Sloan AE, Dansey R, Zamorano L, Barger G, Hamm C, Diaz F, Baynes R, Wood G (2000) Adoptive immunotherapy in patients with recurrent malignant glioma: preliminary results of using autologous whole-tumor vaccine plus granulocyte-macrophage colony-stimulating factor and adoptive transfer of anti-CD3-activated lymphocytes. Neurosurg Focus 9:e9PubMedCrossRef
40.
Wallenfriedman MA, Conrad JA, DelaBarre L, Graupman PC, Lee G, Garwood M, Gregerson DS, Jean WC, Hall WA, Low WC (1999) Effects of continuous localized infusion of granulocyte-macrophage colony-stimulating factor and inoculations of irradiated glioma cells on tumor progression. J Neurosurg 90:1064–1071PubMedCrossRef
Metadata
Title
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
Authors
Hilko Ardon
Stefaan W. Van Gool
Tina Verschuere
Wim Maes
Steffen Fieuws
Raf Sciot
Guido Wilms
Philippe Demaerel
Jan Goffin
Frank Van Calenbergh
Johan Menten
Paul Clement
Maria Debiec-Rychter
Steven De Vleeschouwer
Publication date
01-11-2012
Publisher
Springer-Verlag
Published in
Cancer Immunology, Immunotherapy / Issue 11/2012
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-012-1261-1

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