. 2015 Oct; 17 Suppl 7:vii32-vii40.
doi: 10.1093/neuonc/nov178.

Immunotherapy for neuro-oncology: the critical rationale for combinatorial therapy

David A Reardon 1 Mark R Gilbert 1 Wolfgang Wick 1 Linda Liau 1 
  • PMID: 26516225
  •     127 References
  •     9 citations


A successful therapeutic paradigm established historically in oncology involves combining agents with potentially complementary mechanisms of antitumor activity into rationally designed regimens. For example, cocktails of cytotoxic agents, which were carefully designed based on mechanisms of action, dose, and scheduling considerations, have led to dramatic improvements in survival including cures for childhood leukemia, Hodgkin's lymphoma, and several other complex cancers. Outcome for glioblastoma, the most common primary malignant CNS cancer, has been more modest, but nonetheless our current standard of care derives from confirmation that combination therapy surpasses single modality therapy. Immunotherapy has recently come of age for medical oncology with exciting therapeutic benefits achieved by several types of agents including vaccines, adoptive T cells, and immune checkpoint inhibitors against several types of cancers. Nonetheless, most benefits are relatively short, while others are durable but are limited to a minority of treated patients. Critical factors limiting efficacy of immunotherapeutics include insufficient immunogenicity and/or inadequate ability to overcome immunosuppressive factors exploited by tumors. The paradigm of rationally designed combinatorial regimens, originally established by cytotoxic therapy for oncology, may also prove relevant for immunotherapy. Realization of the true therapeutic potential of immunotherapy for medical oncology and neuro-oncology patients may require development of combinatorial regimens that optimize immunogenicity and target tumor adaptive immunosuppressive factors.

Keywords: glioblastoma; immune checkpoint; immunotherapy; programmed-death 1; vaccine.

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Combining radiation and immunotherapy: a new systemic therapy for solid tumors?
Chad Tang, Xiaohong Wang, +14 authors, James W Welsh.
Cancer Immunol Res, 2014 Sep 05; 2(9). PMID: 25187273    Free PMC article.
Highly Cited. Review.
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Radiat Res, 2006 Dec 08; 166(6). PMID: 17149971
Sipuleucel-T immunotherapy for castration-resistant prostate cancer.
Philip W Kantoff, Celestia S Higano, +11 authors, IMPACT Study Investigators.
N Engl J Med, 2010 Sep 08; 363(5). PMID: 20818862
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Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide.
M E Christine Lutsiak, Roshanak T Semnani, +3 authors, Helen Sabzevari.
Blood, 2004 Dec 14; 105(7). PMID: 15591121
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CTLA-4 blockade enhances antitumor immunity of intratumoral injection of immature dendritic cells into irradiated tumor in a mouse colon cancer model.
Cheol-Hun Son, Jae-Ho Bae, +7 authors, You-Soo Park.
J Immunother, 2013 Dec 10; 37(1). PMID: 24316550
Secretion of vascular endothelial growth factor by oral squamous cell carcinoma cells skews endothelial cells to suppress T-cell functions.
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Hum Immunol, 2009 Jun 02; 70(6). PMID: 19480853    Free PMC article.
Individual patient-specific immunity against high-grade glioma after vaccination with autologous tumor derived peptides bound to the 96 KD chaperone protein.
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Clin Cancer Res, 2012 Aug 09; 19(1). PMID: 22872572
Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas.
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Costimulatory protein 4IgB7H3 drives the malignant phenotype of glioblastoma by mediating immune escape and invasiveness.
Dieter Lemke, Philipp-Niclas Pfenning, +8 authors, Wolfgang Wick.
Clin Cancer Res, 2011 Nov 15; 18(1). PMID: 22080438
Radiation enhances regulatory T cell representation.
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Glia, 2005 Apr 09; 51(4). PMID: 15818597
Angiogenesis and immunity: a bidirectional link potentially relevant for the monitoring of antiangiogenic therapy and the development of novel therapeutic combination with immunotherapy.
Eric Tartour, H Pere, +11 authors, S Oudard.
Cancer Metastasis Rev, 2011 Jan 21; 30(1). PMID: 21249423
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Bevacizumab plus ipilimumab in patients with metastatic melanoma.
F Stephen Hodi, Donald Lawrence, +20 authors, David McDermott.
Cancer Immunol Res, 2014 May 20; 2(7). PMID: 24838938    Free PMC article.
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Treg depletion with a low-dose metronomic temozolomide regimen in a rat glioma model.
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Cancer Immunol Immunother, 2009 Feb 18; 58(10). PMID: 19221744
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma.
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J Exp Med, 2013 Jul 31; 210(9). PMID: 23897981    Free PMC article.
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Exploiting the mutanome for tumor vaccination.
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Cancer Res, 2012 Jan 13; 72(5). PMID: 22237626
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Enhanced antitumour immunity by combined use of temozolomide and TAT-survivin pulsed dendritic cells in a murine glioma.
Chang-Hyun Kim, Sun-Je Woo, +5 authors, Tai-Gyu Kim.
Immunology, 2007 Jul 25; 122(4). PMID: 17645496    Free PMC article.
CCL2/CCR2-dependent recruitment of functional antigen-presenting cells into tumors upon chemotherapy.
Yuting Ma, Stephen R Mattarollo, +15 authors, Guido Kroemer.
Cancer Res, 2013 Dec 05; 74(2). PMID: 24302580
Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo.
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Blood, 1998 Dec 03; 92(11). PMID: 9834220
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Angiotensinogen and HLA class II predict bevacizumab response in recurrent glioblastoma patients.
Thomas Urup, Signe Regner Michaelsen, +9 authors, Ulrik Lassen.
Mol Oncol, 2016 Jun 06; 10(8). PMID: 27262894    Free PMC article.
REST represses miR-124 and miR-203 to regulate distinct oncogenic properties of glioblastoma stem cells.
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Neuro Oncol, 2017 Jan 04; 19(4). PMID: 28040710    Free PMC article.
The development of dendritic cell vaccine-based immunotherapies for glioblastoma.
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Non-tumor cell IDO1 predominantly contributes to enzyme activity and response to CTLA-4/PD-L1 inhibition in mouse glioblastoma.
Lijie Zhai, Erik Ladomersky, +8 authors, Derek A Wainwright.
Brain Behav Immun, 2017 Feb 10; 62. PMID: 28179106    Free PMC article.
Reconfigurable Microfluidic Magnetic Valve Arrays: Towards a Radiotherapy-Compatible Spheroid Culture Platform for the Combinatorial Screening of Cancer Therapies.
Alexandre R Brunet, Frédérique Labelle, Philip Wong, Thomas Gervais.
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Predictors of Response to Autologous Dendritic Cell Therapy in Glioblastoma Multiforme.
Chia-Ing Jan, Wan-Chen Tsai, +5 authors, Der-Yang Cho.
Front Immunol, 2018 Jun 19; 9. PMID: 29910795    Free PMC article.
Combination therapy to checkmate Glioblastoma: clinical challenges and advances.
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Highly Cited. Review.
Efficacy of ruthenium coordination complex-based Rutherrin in a preclinical rat glioblastoma model.
Manjunatha Akathatti Munegowda, Carl Fisher, +6 authors, Lothar Lilge.
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OncoPDSS: an evidence-based clinical decision support system for oncology pharmacotherapy at the individual level.
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