Molecular Neurobiology

, Volume 55, Issue 11, pp 8236–8242 | Cite as

Role of Chimeric Antigen Receptor T Cell Therapy in Glioblastoma Multiforme

  • Vishal Jindal


Glioblastoma multiforme (GBM) is the most common primary malignant cancer of brain, which is extremely aggressive and carries a dreadful prognosis. Current treatment protocol runs around radiotherapy, surgical resection, and temozolomide with median overall survival of around 12–15 months. Due to its heterogeneity and mutational load, immunotherapy with chimeric antigen receptor (CAR) T cell therapy can be a promising treatment option for recurrent glioblastoma. Initial phase 1 studies have shown that this therapy is safe without dose-limiting side effects and it also has a better clinical outcome. Therefore, CAR T cell therapy can be a great future tool in our armamentarium to treat advanced GBM. In this article, we have explained the structure, mechanism of action, and rationale of CAR T cell therapy in GBM; we also discussed various antigenic targets and clinical outcome of initial studies of this novel therapy.


Glioblastoma multiforme Chimeric antigen receptor Adoptive T cell therapy 



Special thanks to Dr. Manisha Dhananjaya.

Compliance with Ethical Standards

Conflict of Interest

The author declares that there is no conflict of interest.


  1. 1.
    Iacob G, Dinca E (2009) Current data and strategy in glioblastoma multiforme. J Med Life 2(4):386–393PubMedPubMedCentralGoogle Scholar
  2. 2.
    Bush NA, Chang SM, Berger MS (2017) Current and future strategies for treatment of glioma. Neurosurg Rev 40(1):1–14. CrossRefPubMedGoogle Scholar
  3. 3.
    Tanaka S, Louis DN, Curry WT, Batchelor TT, Dietrich J (2013) Diagnostic and therapeutic avenues for glioblastoma: no longer a dead end? Nat Rev Clin Oncol 10(1):14–26. CrossRefPubMedGoogle Scholar
  4. 4.
    Krebs S, Rodriguez-Cruz TG, Derenzo C et al (2013) Genetically modified T cells to target glioblastoma. Front Oncol 3:322. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Munn DH, Bronte V (2016) Immune suppressive mechanisms in the tumor microenvironment. Curr Opin Immunol 39:1–6. CrossRefPubMedGoogle Scholar
  6. 6.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJB, Belanger K, Brandes AA et al (2005) European Organisation for research and treatment of cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996CrossRefGoogle Scholar
  7. 7.
    Verhoeff JJC, van Tellingen O, Claes A, Stalpers LJA, van Linde ME, Richel DJ, Leenders WPJ, van Furth WR (2009) Concerns about anti-angiogenic treatment in patients with glioblastoma multiforme. BMC Cancer 9:444CrossRefGoogle Scholar
  8. 8.
    Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE et al (2014) Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371:1507–1517CrossRefGoogle Scholar
  9. 9.
    Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, Sommermeyer D, Melville K et al (2016) CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest 126:2123–2138CrossRefGoogle Scholar
  10. 10.
    Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, Bagg A, Marcucci KT et al (2015) Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med 7:303ra139CrossRefGoogle Scholar
  11. 11.
    Kochenderfer JN, Dudley ME, Kassim SH, Somerville RPT, Carpenter RO, Stetler-Stevenson M, Yang JC, Phan GQ et al (2015) Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol 33:540–549CrossRefGoogle Scholar
  12. 12.
    Kershaw MH, Westwood JA, Parker LL, Wang G, Eshhar Z, Mavroukakis SA et al (2006) A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res 12(Pt 1):6106–6115CrossRefGoogle Scholar
  13. 13.
    Beatty GL, Haas AR, Maus MV, Torigian DA, Soulen MC, Plesa G et al (2006) Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies. Cancer Immunol Res 2:112–120CrossRefGoogle Scholar
  14. 14.
    Ahmed N, Brawley VS, Hegde M, Robertson C, Ghazi A, Gerken C, Liu E, Dakhova O et al (2015) Human epidermal growth factor receptor 2 (HER2)-specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-positive sarcoma. J Clin Oncol 33:1688–1696CrossRefGoogle Scholar
  15. 15.
    Brown CE, Alizadeh D, Starr R, Weng L, Wagner JR, Naranjo A et al (2016) Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med 375:2561–2569CrossRefGoogle Scholar
  16. 16.
    Campoli M, Ferrone S (2008) HLA antigen changes in malignant cells: epigenetic mechanisms and biologic significance. Oncogene 27:5869–5885CrossRefGoogle Scholar
  17. 17.
    Chang CC, Campoli M, Ferrone S (2005) Classical and nonclassical HLA class I antigen and NK cell-activating ligand changes in malignant cells: current challenges and future directions. Adv Cancer Res 93:189–234CrossRefGoogle Scholar
  18. 18.
    Zhao Z, Condomines M, van der Stegen SJ, Perna F, Kloss CC, Gunset G et al (2015) Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells. Cancer Cell 28(4):415–428. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Sadelain M, Brentjens R, Rivière I (2013) The basic principles of chimeric antigen receptor design. Cancer Discov 3(4):388–398. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Chmielewski M, Hombach AA, Abken H (2013) Antigen-specific T-cell activation independently of the MHC: chimeric antigen receptor-redirected T cells. Front Immunol 4:371. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Riddell SR, Sommermeyer D, Berger C, Liu LS, Balakrishnan A, Salter A, Hudecek M et al (2014) Adoptive therapy with chimeric antigen receptor-modified T cells of defined subset composition. Cancer J 20:141–144. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kershaw MH, Westwood JA, Slaney CY, Darcy PK (2014) Clinical application of genetically modified T cells in cancer therapy. Clin Transl Immunol 3(5):e16CrossRefGoogle Scholar
  23. 23.
    Pereira BI, Akbar AN (2016) Convergence of innate and adaptive immunity during human aging. Front Immunol 7:445PubMedPubMedCentralGoogle Scholar
  24. 24.
    Yasukawa M, Ohminami H, Arai J, Kasahara Y, Ishida Y, Fujita S (2000) Granule exocytosis, and not the fas/fas ligand system, is the main pathway of cytotoxicity mediated by alloantigen-specific CD4(+) as well as CD8(+)cytotoxic T lymphocytes in humans. Blood 95(7):2352–2355PubMedGoogle Scholar
  25. 25.
    Hombach A, Kohler H, Rappl G, Abken H (2006) Human CD4+ T cells lyse target cells via granzyme/perforin upon circumvention of MHC class II restriction by an antibody-like immunoreceptor. J Immunol 177(8):5668–5675CrossRefGoogle Scholar
  26. 26.
    Maus MV, Grupp SA, Porter DL, June CH (2014) Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood 123(17):2625–2635. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Pegram HJ, Park JH, Brentjens RJ (2014) CD28z CARs and armored CARs. Cancer J 20(2):127–133. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Zhang RD, Price JE, al FT (1992) Differential permeability of the blood-brain barrier in experimental brain metastases produced by human neoplasms implanted into nude mice. Am J Pathol 141:1115PubMedPubMedCentralGoogle Scholar
  29. 29.
    Stewart DJ (1994) A critique of the role of the blood-brain barrier in the chemotherapy of human brain tumors. J Neuro-Oncol 20(2):121–139. CrossRefGoogle Scholar
  30. 30.
    Lockman PR, Mittapalli RK, Taskar KS, Rudraraju V, Gril B, Bohn KA, Adkins CE, Roberts A et al (2010) Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer. Clin Cancer Res: Off J Am Assoc Cancer Res 16(23):5664–5678. CrossRefGoogle Scholar
  31. 31.
    Batich KA, Swartz AM, Sampson JH (2015) Enhancing dendritic cell-based vaccination for highly aggressive glioblastoma. Expert Opin Biol Ther 15(1):79–94CrossRefGoogle Scholar
  32. 32.
    Azad TD, Razavi SM, Jin B et al (2015) Glioblastoma antigen discovery-foundations for immunotherapy. Neurooncol 123(3):347–358CrossRefGoogle Scholar
  33. 33.
    Everson RG, Antonios JP, Lisiero DN, Soto H, Scharnweber R, Garrett MC, Yong WH, Li N et al (2016) Efficacy of systemic adoptive transfer immunotherapy targeting NY-ESO-1 for glioblastoma. Neuro-Oncology 18(3):368–378CrossRefGoogle Scholar
  34. 34.
    Lin Y, Okada H (2016) Cellular immunotherapy for malignant gliomas. Expert Opin Biol Ther 16(10):1265–1275CrossRefGoogle Scholar
  35. 35.
    Hynes NE, MacDonald G (2009) ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol 21(2):177–184. CrossRefPubMedGoogle Scholar
  36. 36.
    Hynes NE, Lane HA (2005) ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5(5):341–354. CrossRefPubMedGoogle Scholar
  37. 37.
    Olayioye MA, Neve RM, Lane HA, Hynes NE (2000) The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J 19(13):3159–3167. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Yano S, Kondo K, Yamaguchi M, Richmond G, Hutchison M, Wakeling A et al (2002) Distribution and function of EGFR in human tissue and the effect of EGFR tyrosine kinase inhibition. Anticancer Res 23(5A):3639–3650 56Google Scholar
  39. 39.
    Sasada T, Azuma K, Ohtake J, Fujimoto Y (2016) Immune responses to epidermal growth factor receptor (EGFR) and their application for cancer treatment. Front Pharmacol 7:405. CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Villa GR, Mischel PS (2016) Old player, new partner: EGFRvIII and cytokine receptor signaling in glioblastoma. Nat Neurosci 19(6):765–767CrossRefGoogle Scholar
  41. 41.
    Wong AJ, Ruppert JM, Bigner SH, Grzeschik CH, Humphrey PA, Bigner DS, Vogelstein B (1992) Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci USA 1992 89(7):2965–2969CrossRefGoogle Scholar
  42. 42.
    Greenall SA, Donoghue JF, Van Sinderen M, Dubljevic V, Budiman S, Devlin M et al (2015) EGFRvIII-mediated transactivation of receptor tyrosine kinases in glioma: mechanism and therapeutic implications. Oncogene 8(34(41)):5277–5287. CrossRefGoogle Scholar
  43. 43.
    Inda M-M, Bonavia R, Mukasa A, Narita Y, Sah DWY, Vandenberg S, Brennan C, Johns TG et al (2010) Tumor heterogeneity is an active process maintained by a mutant EGFR-induced cytokine circuit in glioblastoma. Genes Dev 24(16):1731–1745. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Jahani-Asl A, Yin H, Soleimani VD, Haque T, Luchman HA, Chang NC, Sincennes MC, Puram SV et al (2016) Control of glioblastoma tumorigenesis by feed-forward cytokine signaling. Nat Neurosci 19(6):798–806. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Brown CE, Warden CD, Starr R, Deng X, Badie B, Yuan YC, Forman SJ, Barish ME (2013) Glioma IL13Ralpha2 is associated with mesenchymal signature gene expression and poor patient prognosis. PLoS One 8(10):e77769CrossRefGoogle Scholar
  46. 46.
    Liu H, Jacobs BS, Liu J, Prayson RA, Estes ML, Barnett GH, Barna BP (2000) Interleukin-13 sensitivity and receptor phenotypes of human glial cell lines: non-neoplastic glia and low-grade astrocytoma differ from malignant glioma. Cancer Immunol Immunother 49(6):319–324CrossRefGoogle Scholar
  47. 47.
    Rahaman SO, Vogelbaum MA, Haque SJ (2005) Aberrant Stat3 signaling by interleukin-4 in malignant glioma cells: involvement of IL-13Ralpha2. Cancer Res 65(7):2956–2963CrossRefGoogle Scholar
  48. 48.
    Fujisawa T, Joshi B, Nakajima A, Puri RK (2009) A novel role of interleukin-13 receptor alpha2 in pancreatic cancer invasion and metastasis. Cancer Res 69(22):8678–8685CrossRefGoogle Scholar
  49. 49.
    Fujisawa T, Joshi BH, Puri RK (2012) IL-13 regulates cancer invasion and metastasis through IL-13Ralpha2 via ERK/AP-1 pathway in mouse model of human ovarian cancer. Int J Cancer 131(2):344–356 34CrossRefGoogle Scholar
  50. 50.
    Fichtner-Feigl S, Terabe M, Kitani A, Young CA, Fuss I, Geissler EK, Schlitt HJ, Berzofsky JA et al (2008) Restoration of tumor immunosurveillance via targeting of interleukin-13 receptor-alpha 2. Cancer Res 68(9):3467–3475CrossRefGoogle Scholar
  51. 51.
    Debinski W, Gibo DM, Hulet SW, Connor JR, Gillespie GY (1999) Receptor for interleukin 13 is a marker and therapeutic target for human high-grade gliomas. Clin Cancer Res 5(5):985–990 70PubMedGoogle Scholar
  52. 52.
    Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2(2):127–137. CrossRefPubMedGoogle Scholar
  53. 53.
    Cho HS, Mason K, Ramyar KX, Stanley AM, Gabelli SB, Denney DW Jr, Leahy DJ (2003) Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 421(6924):756–760. CrossRefPubMedGoogle Scholar
  54. 54.
    Wong YF, Cheung TH, Lam SK, Lu HJ, Zhuang YL, Chan MY, Chung TK (1995) Prevalence and significance of HER-2/neu amplification in epithelial ovarian cancer. Gynecol Obstet Investig 40:209–212CrossRefGoogle Scholar
  55. 55.
    Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin W, Stuart S et al (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244(4905):707–712. CrossRefPubMedGoogle Scholar
  56. 56.
    Gorlick R, Huvos AG, Heller G, Aledo A, Beardsley GP, Healey JH, Meyers PA (1999) Expression of HER2/erbB-2 correlates with survival in osteosarcoma. J Clin Oncol 17(9):2781–2788. CrossRefPubMedGoogle Scholar
  57. 57.
    Zhang JG, Kruse CA, Driggers L, Hoa N, Wisoff J, Allen JC, Zagzag D, Newcomb EW et al (2008) Tumor antigen precursor protein profiles of adult and pediatric brain tumors identify potential targets for immunotherapy. J Neuro-Oncol 88(1):65–76. CrossRefGoogle Scholar
  58. 58.
    Hegde M, Mukherjee M, Grada Z, Pignata A, Landi D, Navai SA, Wakefield A, Fousek K et al (2016) Tandem CAR T cells targeting HER2 and IL13Ralpha2 mitigate tumor antigen escape. J Clin Invest 126:3036–3052CrossRefGoogle Scholar
  59. 59.
    Morgan RA, Johnson LA, Davis JL, Zheng Z, Woolard KD, Reap EA, Feldman SA, Chinnasamy N et al (2012) Recognition of glioma stem cells by genetically modified T cells targeting EGFRvIII and development of adoptive cell therapy for glioma. Hum Gene Ther 23(10):1043–1053. CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Miao H, Choi BD, Suryadevara CM, Sanchez-Perez L, Yang S, De Leon G et al (2014) EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma. PLoS One 9(4):e94281. CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    O'Rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mansfield K, Morrissette JJD et al (2017) A single dose of peripherally infused EGFRvIIIdirected CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med 9:eaaa0984CrossRefGoogle Scholar
  62. 62.
    Yaghoubi SS, Jensen MC, Satyamurthy N, Paik D, Czernin J, Gambh SS (2009) Non-invasive detection of therapeutic cytolytic T cells in patients with [18-F]FHBG positron emission tomography in a glioma patient. Nat Clin Pract Oncol 6:53–58CrossRefGoogle Scholar
  63. 63.
    Brown CE, Badie B, Barish ME, Weng L, Julie R, Chang W et al (2016) Bioactivity and safety of IL13Ra2-redirected chimeric antigen receptor CD8+ T cells in patients with recurrent glioblastoma. Clin Cancer Res 21:4062–4072CrossRefGoogle Scholar
  64. 64.
    Ahmed N, Brawley V, Hegde M, Bielamowicz K, Kalra M, Landi D, Robertson C, Gray TL et al (2017) HER2-specific chimeric antigen receptor-modified virus-specific T cells for progressive glioblastoma: a phase 1 dose-escalation trial. JAMA Oncol 3:1094–1101CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Internal MedicineSaint Vincent HospitalWorcesterUSA
  2. 2.WorcesterUSA

Personalised recommendations