Dendritic cell vaccination combined with temozolomide retreatment: results of a phase I trial in patients with recurrent glioblastoma multiforme
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There is no standard treatment for recurrent glioblastoma multiforme (GBM). Retreatment with temozolomide (TMZ) is one treatment option. We reasoned this could be more effective if combined with a vaccine that preferentially targeted TMZ-resistant cells. To test the feasibility and safety of such an approach, a phase 1 trial was conducted in which patients with GBM tumors relapsing after standard chemoradiotherapy were retreated with TMZ in combination with a vaccine consisting of monocyte-derived dendritic cells (DC) pulsed with autologous tumor cells that had previously been exposed to TMZ in vivo in the course of primary treatment. Of 14 participants, nine patients completed the initial phase of priming vaccinations and two cycles of TMZ, one proved to have radionecrosis, one rapidly progressed, and in three the yield of DC vaccine was insufficient to proceed with treatment. Other than expected toxicities related to TMZ, there were no adverse events attributable to the combined treatment. Two patients had objective radiological responses. Six month progression-free survival was 22 %, similar to retreatment with TMZ alone. Anti-tumor immune responses were assessed in peripheral blood mononuclear cells using interferon-γ ELISpot, with two patients meeting criteria for a vaccine-induced immune response, one of whom remained disease-free for nearly three years. Another patient with an anti-tumor immune response at baseline that was sustained post-vaccination experienced a 12-month period of progression-free survival. In summary, the combined treatment was safe and well-tolerated but feasibility in the recurrent setting was marginal. Evidence of immune responses in a few patients broadly correlated with better clinical outcome.
KeywordsGlioblastoma multiforme Dendritic cell-based vaccination Temozolomide T cells Chemoresistance Combination therapy
This study was funded by the Cancer Society of New Zealand (Grant 07/143B) with support from the New Zealand Health Research Council (Clinical Fellowship to M.K.H.), the Royal Australasian College of Surgeons (to M.K.H.) and the Surgical Research Trust (to M.K.H.). In addition, the authors wish to acknowledge John Denton and Melanie McConnell for their expert advice, and the New Zealand neurosurgeons and oncologists who supported this study.
Conflict of interest
The authors declare that they have no conflict of interest.
- 1.Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJB, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996. doi: 10.1056/NEJMoa043330 PubMedCrossRefGoogle Scholar
- 3.Perry JR, Bélanger K, Mason WP, Fulton D, Kavan P, Easaw J, Shields C, Kirby S, Macdonald DR, Eisenstat DD, Thiessen B, Forsyth P, Pouliot J-F (2010) Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study. J Clin Oncol 28(12):2051–2057. doi: 10.1200/JCO.2009.26.5520 PubMedCrossRefGoogle Scholar
- 16.Nishioka E, Funasaka Y, Kondoh H, Chakraborty AK, Mishima Y, Ichihashi M (1999) Expression of tyrosinase, TRP-1 and TRP-2 in ultraviolet-irradiated human melanomas and melanocytes: TRP-2 protects melanoma cells from ultraviolet B induced apoptosis. Melanoma Res 9(5):433–443PubMedCrossRefGoogle Scholar
- 23.O’Rourke MGE, Johnson M, Lanagan C, See J, Yang J, Bell JR, Slater GJ, Kerr BM, Crowe B, Purdie DM, Elliott SL, Ellem KAO, Schmidt CW (2003) Durable complete clinical responses in a phase I/II trial using an autologous melanoma cell/dendritic cell vaccine. Cancer Immunol Immunother 52(6):387–395. doi: 10.1007/s00262-003-0375-x PubMedGoogle Scholar
- 28.Kimura T, McKolanis JR, Dzubinski LA, Islam K, Potter DM, Salazar AM, Schoen RE, Finn OJ (2013) MUC1 vaccine for individuals with advanced adenoma of the colon: a cancer immunoprevention feasibility study. Cancer Prev Res (Phila) 6(1):18–26. doi: 10.1158/1940-6207.CAPR-12-0275 CrossRefGoogle Scholar
- 33.Paravati AJ, Heron DE, Landsittel D, Flickinger JC, Mintz A, Chen Y-F, Huq MS (2011) Radiotherapy and temozolomide for newly diagnosed glioblastoma and anaplastic astrocytoma: validation of radiation therapy oncology group-recursive partitioning analysis in the IMRT and temozolomide era. J Neurooncol 104(1):339–349. doi: 10.1007/s11060-010-0499-8 PubMedCentralPubMedCrossRefGoogle Scholar
- 34.De Vleeschouwer S, Ardon H, Van Calenbergh F, Sciot R, Wilms G, Van Loon J, Goffin J, Van Gool S (2012) 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 61(11):2105–2112. doi: 10.1007/s00262-012-1271-z PubMedCrossRefGoogle Scholar
- 35.Liau LM, Prins RM, Kiertscher SM, Odesa SK, Kremen TJ, Giovannone AJ, Lin J-W, 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(15):5515–5525. doi: 10.1158/1078-0432.CCR-05-0464 PubMedCrossRefGoogle Scholar
- 36.Sampson JH, Aldape KD, Archer GE, Coan A, Desjardins A, Friedman AH, Friedman HS, Gilbert MR, Herndon JE, Mclendon RE, Mitchell DA, Reardon DA, Sawaya R, Schmittling R, Shi W, Vredenburgh JJ, Bigner DD, Heimberger AB (2011) Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro-Oncology 13(3):324–333. doi: 10.1093/neuonc/noq157 PubMedCentralPubMedCrossRefGoogle Scholar
- 37.Kim C-H, Woo S-J, Park J-S, Kim H-S, Park M-Y, Park S-D, Hong Y-K, Kim T-G (2007) Enhanced antitumour immunity by combined use of temozolomide and TAT-survivin pulsed dendritic cells in a murine glioma. Immunology 122(4):615–622. doi: 10.1111/j.1365-2567.2007.02680.x PubMedCentralPubMedCrossRefGoogle Scholar
- 38.Gangemi RMR, Griffero F, Marubbi D, Perera M, Capra MC, Malatesta P, Ravetti GL, Zona GL, Daga A, Corte G (2009) SOX2 silencing in glioblastoma tumor-initiating cells causes stop of proliferation and loss of tumorigenicity. Stem Cells 27(1):40–48. doi: 10.1634/stemcells.2008-0493 PubMedCrossRefGoogle Scholar
- 39.Yang Y-P, Chien Y, Chiou G-Y, Cherng J-Y, Wang M-L, Lo W-L, Chang Y-L, Huang P-I, Chen Y-W, Shih Y-H, Chen M-T, Chiou S-H (2012) Inhibition of cancer stem cell-like properties and reduced chemoradioresistance of glioblastoma using microRNA145 with cationic polyurethane-short branch PEI. Biomaterials 33(5):1462–1476. doi: 10.1016/j.biomaterials.2011.10.071 PubMedCrossRefGoogle Scholar
- 40.Ardon H, Van Gool SW, Verschuere T, Maes W, Fieuws S, Sciot R, Wilms G, Demaerel P, Goffin J, Van Calenbergh F, Menten J, Clement P, Debiec-Rychter M, De Vleeschouwer S (2012) 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 61(11):2033–2044. doi: 10.1007/s00262-012-1261-1 PubMedCrossRefGoogle Scholar
- 41.Prins RM, Wang X, Soto H, Young E, Lisiero DN, Fong B, Everson R, Yong WH, Lai A, Li G, Cloughesy TF, Liau LM (2013) Comparison of glioma-associated antigen peptide-loaded versus autologous tumor lysate-loaded dendritic cell vaccination in malignant glioma patients. J Immunother 36(2):152–157. doi: 10.1097/CJI.0b013e3182811ae4 PubMedCentralPubMedCrossRefGoogle Scholar
- 42.Phuphanich S, Wheeler CJ, Rudnick JD, Mazer M, Wang H, Nuño MA, Richardson JE, Fan X, Ji J, Chu RM, Bender JG, Hawkins ES, Patil CG, Black KL, Yu JS (2012) Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma. Cancer Immunol Immunother. doi: 10.1007/s00262-012-1319-0 PubMedCentralPubMedGoogle Scholar