Immunotherapies for Brain Cancer: From Preclinical Models to Human Trials

  • Thomas J. Wilson
  • Marianela Candolfi
  • Hikmat Assi
  • Mariela Moreno Ayala
  • Yohei Mineharu
  • Shawn L. Hervey-Jumper
  • Pedro R. Lowenstein
  • Maria G. Castro
Part of the Tumors of the Central Nervous System book series (TCNS, volume 13)


Glioblastoma Multiforme (GBM) is the most common and aggressive primary brain tumor. Every year ~22,000 patients are diagnosed with GBM in the US, and less than 5% survive 5 years post-diagnosis. Thus, novel therapeutic approaches are urgently needed to improve the outcome in these patients. Immunotherapy has the potential of stimulating the immune system to eliminate GBM cells that might have spread throughout the brain. Here we will discuss the latest advances in preclinical immunotherapy for glioma, which involve the local delivery of pro-inflammatory cytokines, such as Flt3L, Type I IFNs, IL-2, IL-4, and IL-12 using gene therapy vectors and neural stem cells, or the blockade of immune-suppressive mediators such as TGF-beta, FasL and phosphorylated STAT3. Novel immunotherapeutic approaches have also been assessed in clinical trials implemented in GBM patients. These involve the systemic or local adoptive transfer of autologous immune cells activated ex vivo back into the patient, and the administration of dendritic cell vaccines loaded with tumor peptides or cells, which induce active immunity against GBM. Preclinical and clinical findings so far indicate that immunotherapy improves anti-tumor immunity in preclinical GBM models and patients, which makes it a valuable adjuvant in the treatment of GBM.


Malignant Glioma Glioblastoma Multiforme Anaplastic Astrocytoma Antitumor Immunity Methylated MGMT Promoter 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by National Institutes of Health/National Institute of Neurological Disorders & Stroke (NIH/NINDS) Grants 1UO1-NS052465, UO1-NS052465-04S1, 1RO1-NS074387 and 1RO1-NS 057711 to M.G.C.; NIH/NINDS Grants 1R21-NS 084275 and 1RO1- NS 061107 to P.R.L. T32 NS 007222, T32 CA 009676, T32 GM 007863, UL1TR000433; and the Department of Neurosurgery, University of Michigan School of Medicine. M.C. and M.M.A. were supported by the National Council of Science and Technology (CONICET, Argentina) PIP CONICET 114-201101-00353. We are grateful to Dr. K. Murasko for her academic leadership and M. Dahlgren, D. Tomford and S. Napolitan for superb administrative support.


  1. Aboody KS, Brown A, Rainov NG, Bower KA, Liu S, Yang W, Small JE, Herrlinger U, Ourednik V, Black PM, Breakefield XO, Snyder EY (2000) Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc Natl Acad Sci U S A 97:12846–12851PubMedCentralPubMedCrossRefGoogle Scholar
  2. Abou-Ghazal M, Yang DS, Qiao W, Reina-Ortiz C, Wei J, Kong LY, Fuller GN, Hiraoka N, Priebe W, Sawaya R, Heimberger AB (2008) The incidence, correlation with tumor-infiltrating inflammation, and prognosis of phosphorylated STAT3 expression in human gliomas. Clin Cancer Res 14:8228–8235PubMedCentralPubMedCrossRefGoogle Scholar
  3. Badie B, Schartner J, Prabakaran S, Paul J, Vorpahl J (2001) Expression of Fas ligand by microglia: possible role in glioma immune evasion. J Neuroimmunol 120:19–24PubMedCrossRefGoogle Scholar
  4. Biglari A, Bataille D, Naumann U, Weller M, Zirger J, Castro MG, Lowenstein PR (2004) Effects of ectopic decorin in modulating intracranial glioma progression in vivo, in a rat syngeneic model. Cancer Gene Ther 11:721–732PubMedCentralPubMedCrossRefGoogle Scholar
  5. Candolfi M, Yagiz K, Foulad D, Alzadeh GE, Tesarfreund M, Muhammad AK, Puntel M, Kroeger KM, Liu C, Lee S, Curtin JF, King GD, Lerner J, Sato K, Mineharu Y, Xiong W, Lowenstein PR, Castro MG (2009) Release of HMGB1 in response to proapoptotic glioma killing strategies: efficacy and neurotoxicity. Clin Cancer Res 15:4401–4414PubMedCentralPubMedCrossRefGoogle Scholar
  6. Candolfi M, King G, Yagiz K, Curtin J, Mineharu Y, Muhammad AG, Foulad D, Kroeger KM, Barnett N, Josien R, Lowenstein PR, Castro MG (2012) Plasmacytoid dendritic cells in the tumor microenvironment: immune targets for glioma therapeutics. Neoplasia 14(8):757–770Google Scholar
  7. Curtin JF, Candolfi M, Xiong W, Lowenstein PR, Castro MG (2008) Turning the gene tap off; implications of regulating gene expression for cancer therapeutics. Mol Cancer Ther 7:439–448PubMedCentralPubMedCrossRefGoogle Scholar
  8. Curtin JF, Liu N, Candolfi M, Xiong W, Assi H, Yagiz K, Edwards MR, Michelsen KS, Kroeger KM, Liu C, Muhammad AK, Clark MC, Arditi M, Comin-Anduix B, Ribas A, Lowenstein PR, Castro MG (2009) HMGB1 mediates endogenous TLR2 activation and brain tumor regression. PLoS Med 6:e10PubMedCrossRefGoogle Scholar
  9. De Bonis P, Albanese A, Lofrese G, de Waure C, Mangiola A, Pettorini BL, Pompucci A, Balducci M, Fiorentino A, Lauriola L, Anile C, Maira G (2011) Postoperative infection may influence survival in patients with glioblastoma: simply a myth? Neurosurgery 69:864–868; discussion 868–869PubMedCrossRefGoogle Scholar
  10. Dillman RO, Duma CM, Ellis RA, Cornforth AN, Schiltz PM, Sharp SL, DePriest MC (2009) Intralesional lymphokine-activated killer cells as adjuvant therapy for primary glioblastoma. J Immunother 32:914–919PubMedCrossRefGoogle Scholar
  11. Doucette TA, Kong LY, Yang Y, Ferguson SD, Yang J, Wei J, Qiao W, Fuller GN, Bhat KP, Aldape K, Priebe W, Bogler O, Heimberger AB, Rao G (2012) Signal transducer and activator of transcription 3 promotes angiogenesis and drives malignant progression in glioma. Neuro Oncol 14(9):1136–1145PubMedCentralPubMedCrossRefGoogle Scholar
  12. Fisher JL, Schwartzbaum JA, Wrensch M, Wiemels JL (2007) Epidemiology of brain tumors. Neurol Clin 25:867–890, viiPubMedCrossRefGoogle Scholar
  13. Haghighat P, Timiryasova TM, Chen B, Kajioka EH, Gridley DS, Fodor I (2000) Antitumor effect of IL-2, p53, and bax gene transfer in C6 glioma cells. Anticancer Res 20:1337–1342PubMedGoogle Scholar
  14. 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 352:997–1003PubMedCrossRefGoogle Scholar
  15. Hussain SF, Kong LY, Jordan J, Conrad C, Madden T, Fokt I, Priebe W, Heimberger AB (2007) A novel small molecule inhibitor of signal transducers and activators of transcription 3 reverses immune tolerance in malignant glioma patients. Cancer Res 67:9630–9636PubMedCrossRefGoogle Scholar
  16. Iwata-Kajihara T, Sumimoto H, Kawamura N, Ueda R, Takahashi T, Mizuguchi H, Miyagishi M, Takeda K, Kawakami Y (2011) Enhanced cancer immunotherapy using STAT3-depleted dendritic cells with high Th1-inducing ability and resistance to cancer cell-derived inhibitory factors. J Immunol 187:27–36PubMedCrossRefGoogle Scholar
  17. Jansen T, Tyler B, Mankowski JL, Recinos VR, Pradilla G, Legnani F, Laterra J, Olivi A (2010) FasL gene knock-down therapy enhances the antiglioma immune response. Neuro Oncol 12:482–489PubMedCentralPubMedGoogle Scholar
  18. Kim HA, Park JH, Cho SH, Lee J, Lee M (2011) Glia/ischemia tissue dual specific gene expression vector for glioblastoma gene therapy. J Control Release 152(Suppl 1):e146–e148PubMedCrossRefGoogle Scholar
  19. Kohsaka S, Wang L, Yachi K, Mahabir R, Narita T, Itoh T, Tanino M, Kimura T, Nishihara H, Tanaka S (2012) STAT3 inhibition overcomes temozolomide resistance in glioblastoma by downregulating MGMT expression. Mol Cancer Ther 11:1289–1299PubMedCrossRefGoogle Scholar
  20. Kortylewski M, Kujawski M, Wang T, Wei S, Zhang S, Pilon-Thomas S, Niu G, Kay H, Mulé J, Kerr WG, Jove R, Pardoll D, Yu H (2005) Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med 11:1314–1321PubMedCrossRefGoogle Scholar
  21. Kujawski M, Zhang C, Herrmann A, Reckamp K, Scuto A, Jensen M, Deng J, Forman S, Figlin R, Yu H (2010) Targeting STAT3 in adoptively transferred T cells promotes their in vivo expansion and antitumor effects. Cancer Res 70:9599–9610PubMedCentralPubMedCrossRefGoogle Scholar
  22. 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 11:5515–5525PubMedCrossRefGoogle Scholar
  23. Mineharu Y, King GD, Muhammad AK, Bannykh S, Kroeger KM, Liu C, Lowenstein PR, Castro MG (2011) Engineering the brain tumor microenvironment enhances the efficacy of dendritic cell vaccination: implications for clinical trial design. Clin Cancer Res 17:4705–4718PubMedCentralPubMedCrossRefGoogle Scholar
  24. Mineharu Y, Muhammad A, Yagiz K, Candolfi M, Kroeger K, Xiong W, Puntel M, Liu C, Levy E, Lugo C, Kocharian A, Allison J, Curran M, Lowenstein P, Castro M (2012) Gene therapy mediated reprogramming tumor infiltrating T cells using IL-2 and inhibiting NF-κB signaling improves the efficacy of immunotherapy in a brain cancer model. Neurotherapeutics 9(4):827–843Google Scholar
  25. Naumann U, Maass P, Gleske AK, Aulwurm S, Weller M, Eisele G (2008) Glioma gene therapy with soluble transforming growth factor-beta receptors II and III. Int J Oncol 33:759–765PubMedGoogle Scholar
  26. Okada H, Giezeman-Smits KM, Tahara H, Attanucci J, Fellows WK, Lotze MT, Chambers WH, Bozik ME (1999) Effective cytokine gene therapy against an intracranial glioma using a retrovirally transduced IL-4 plus HSVtk tumor vaccine. Gene Ther 6:219–226PubMedCrossRefGoogle Scholar
  27. Plautz GE, Barnett GH, Miller DW, Cohen BH, Prayson RA, Krauss JC, Luciano M, Kangisser DB, Shu S (1998) Systemic T cell adoptive immunotherapy of malignant gliomas. J Neurosurg 89:42–51PubMedCrossRefGoogle Scholar
  28. Saito R, Mizuno M, Nakahara N, Tsuno T, Kumabe T, Yoshimoto T, Yoshida J (2004) Vaccination with tumor cell lysate-pulsed dendritic cells augments the effect of IFN-beta gene therapy for malignant glioma in an experimental mouse intracranial glioma. Int J Cancer 111:777–782PubMedCrossRefGoogle Scholar
  29. Sampson JH, Archer GE, Mitchell DA, Heimberger AB, Herndon JE 2nd, Lally-Goss D, McGehee-Norman S, Paolino A, Reardon DA, Friedman AH, Friedman HS, Bigner DD (2009) Mol Cancer Ther 8(10):2773–2779PubMedCentralPubMedCrossRefGoogle Scholar
  30. Sampson JH, Heimberger AB, Archer GE, Aldape KD, Friedman AH, Friedman HS, Gilbert MR, Herndon JE 2nd, McLendon RE, Mitchell DA, Reardon DA, Sawaya R, Schmittling RJ, Shi W, Vredenburgh JJ, Bigner DD (2010) 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 28:4722–4729PubMedCentralPubMedCrossRefGoogle Scholar
  31. Sanai N, Polley MY, McDermott MW, Parsa AT, Berger MS (2011) An extent of resection threshold for newly diagnosed glioblastomas. J Neurosurg 115:3–8PubMedCrossRefGoogle Scholar
  32. Schneider T, Becker A, Ringe K, Reinhold A, Firsching R, Sabel BA (2008) Brain tumor therapy by combined vaccination and antisense oligonucleotide delivery with nanoparticles. J Neuroimmunol 195:21–27PubMedCrossRefGoogle Scholar
  33. Stander M, Naumann U, Dumitrescu L, Heneka M, Loschmann P, Gulbins E, Dichgans J, Weller M (1998) Decorin gene transfer-mediated suppression of TGF-beta synthesis abrogates experimental malignant glioma growth in vivo. Gene Ther 5:1187–1194PubMedCrossRefGoogle Scholar
  34. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, 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 352:987–996PubMedCrossRefGoogle Scholar
  35. Tsuboi K, Saijo K, Ishikawa E, Tsurushima H, Takano S, Morishita Y, Ohno T (2003) Effects of local injection of ex vivo expanded autologous tumor-specific T lymphocytes in cases with recurrent malignant gliomas. Clin Cancer Res 9:3294–3302PubMedGoogle Scholar
  36. Tsugawa T, Kuwashima N, Sato H, Fellows-Mayle WK, Dusak JE, Okada K, Papworth GD, Watkins SC, Gambotto A, Yoshida J, Pollack IF, Okada H (2004) Sequential delivery of interferon-alpha gene and DCs to intracranial gliomas promotes an effective antitumor response. Gene Ther 11:1551–1558PubMedCrossRefGoogle Scholar
  37. Tsurushima H, Yuan X, Dillehay LE, Leong KW (2007) Radioresponsive tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene therapy for malignant brain tumors. Cancer Gene Ther 14:706–716PubMedCrossRefGoogle Scholar
  38. Vetter M, Hofer MJ, Roth E, Pircher HP, Pagenstecher A (2009) Intracerebral interleukin 12 induces glioma rejection in the brain predominantly by CD8+ T cells and independently of interferon-gamma. J Neuropathol Exp Neurol 68:525–534PubMedCrossRefGoogle Scholar
  39. Wang T, Niu G, Kortylewski M, Burdelya L, Shain K, Zhang S, Bhattacharya R, Gabrilovich D, Heller R, Coppola D, Dalton W, Jove R, Pardoll D, Yu H (2004) Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med 10:48–54PubMedCrossRefGoogle Scholar
  40. 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 68:5955–5964PubMedCrossRefGoogle Scholar
  41. Yamanaka R, Homma J, Yajima N, Tsuchiya N, Sano M, Kobayashi T, Yoshida S, Abe T, Narita M, Takahashi M, Tanaka R (2005) Clinical evaluation of dendritic cell vaccination for patients with recurrent glioma: results of a clinical phase I/II trial. Clin Cancer Res 11:4160–4167PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Thomas J. Wilson
    • 1
  • Marianela Candolfi
    • 2
  • Hikmat Assi
    • 3
  • Mariela Moreno Ayala
    • 4
    • 5
  • Yohei Mineharu
    • 3
  • Shawn L. Hervey-Jumper
    • 1
  • Pedro R. Lowenstein
    • 3
  • Maria G. Castro
    • 3
  1. 1.Department of Neurosurgery, School of MedicineUniversity of MichiganAnn ArborUSA
  2. 2.Instituto de Investigaciones BiomédicasINBIOMED, Facultad de Medicina, Universidad de Buenos AiresBuenos AiresArgentina
  3. 3.Department of Neurosurgery, Department of Cell and Developmental Biology, School of MedicineUniversity of MichiganAnn ArborUSA
  4. 4.Instituto de Investigaciones BiomédicasNational Council of Science and Technology – University of Buenos AiresBuenos AiresArgentina
  5. 5.University of Buenos Aires School of MedicineBuenos AiresArgentina

Personalised recommendations