Skip to main content

Advertisement

SpringerLink
Log in

A Head Start: CAR-T Cell Therapy for Primary Malignant Brain Tumors

  • Neuro-oncology (GJ Lesser, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

Oncology is in the midst of a therapeutic renaissance. The realization of immunotherapy as an efficacious and expanding treatment option has empowered physicians and patients alike. However, despite these remarkable advances, we have only just broached the potential immunotherapy has to offer and have yet to successfully expand these novel modalities to the field of neuro-oncology. In recent years, exciting results in preclinical studies of immune adjuvants, oncolytic viruses, or cell therapy have been met with only fleeting signs of response when taken to early phase trials. Although many have speculated why these innovative approaches result in impaired outcomes, we are left empty-handed in a field plagued by a drought of new therapies. Herein, we will review the recent advances across cellular therapy for primary malignant brain tumors, an approach that lends itself to overcoming the inherent resistance mechanisms which have impeded the success of prior treatment attempts.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References and Recommended Reading

  1. Gittleman H, Boscia A, Ostrom QT, Truitt G, Fritz Y, Kruchko C, et al. Survivorship in adults with malignant brain and other central nervous system tumor from 2000-2014. Neuro-Oncology. 2018;20:VII6–16.

    PubMed  PubMed Central  Google Scholar 

  2. Stupp R, Hegi ME, Mason WP, van den Bent M, Taphoorn MJ, Janzer RC, et al. 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. 2009;10:459–66.

    CAS  PubMed  Google Scholar 

  3. Thakkar JP, Dolecek TA, Horbinski C, Ostrom QT, Lightner DD, Barnholtz-Sloan JS, et al. Epidemiologic and molecular prognostic review of glioblastoma. Cancer Epidemiol Biomark Prev. 2014;23:1985–96.

    CAS  Google Scholar 

  4. Coley WB. Contribution to the knowledge of sarcoma. Ann Surg. 1891;14:199–220.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Wang H, Kaur G, Sankin AI, Chen F, Guan F, Zang X. Immune checkpoint blockade and CAR-T cell therapy in hematologic malignancies. 2019. https://doi.org/10.1186/s13045-019-0746-1.

  6. Nixon NA, Blais N, Ernst S, Kollmannsberger C, Bebb G, Butler M, et al. Current landscape of immunotherapy in the treatment of solid tumours, with future opportunities and challenges. Curr Oncol. 2018;25:e373–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. McGranahan T, Therkelsen KE, Ahmad S, Nagpal S. Current state of immunotherapy for treatment of glioblastoma. Curr Treat Options in Oncol. 2019;20:24. https://doi.org/10.1007/s11864-019-0619-4.

    Article  Google Scholar 

  8. Hodges TR, Ott M, Xiu J, Gatalica Z, Swensen J, Zhou S, et al. Mutational burden, immune checkpoint expression, and mismatch repair in glioma: implications for immune checkpoint immunotherapy. Neuro-Oncology. 2017;19:1047–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Chongsathidkiet P, Jackson C, Koyama S, Loebel F, Cui X, Farber SH, et al. Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors. Nat Med. 2018;24:1459–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Berghoff AS, Kiesel B, Widhalm G, et al. Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma. https://doi.org/10.1093/neuonc/nou307.

  11. Leitinger M, Varosanec MV, Pikija S, Wass RE, Bandke D, Weis S, et al. Fatal necrotizing encephalopathy after treatment with nivolumab for squamous non-small cell lung cancer: case report and review of the literature. Front Immunol. 2018;9. https://doi.org/10.3389/fimmu.2018.00108.

  12. Reardon DA, Omuro A, Brandes AA, et al. OS10.3 Randomized phase 3 study evaluating the efficacy and safety of nivolumab vs bevacizumab in patients with recurrent glioblastoma: CheckMate 143. Neuro-Oncology. 2017;19:iii21–iii21.

    Google Scholar 

  13. Bristol-Myers Squibb Announces Phase 3 CheckMate -498 Study did not meet primary endpoint of overall survival with Opdivo (nivolumab) plus radiation in patients with newly diagnosed MGMT-unmethylated glioblastoma multiforme | BMS Newsroom. https://news.bms.com/press-release/corporatefinancial-news/bristol-myers-squibb-announces-phase-3-checkmate-498-study-did (accessed Feb 13, 2020).

  14. Bristol-Myers Squibb Provides Update on Phase 3 Opdivo (nivolumab) CheckMate -548 Trial in patients with newly diagnosed MGMT-methylated glioblastoma multiforme | BMS Newsroom. https://news.bms.com/press-release/corporatefinancial-news/bristol-myers-squibb-provides-update-phase-3-opdivo-nivolumab- (accessed Feb 13, 2020).

  15. Charles A Janeway J, Travers P, Walport M, Shlomchik MJ. Antigen recognition by T cells. 2001.

    Google Scholar 

  16. Rossjohn J, Gras S, Miles JJ, Turner SJ, Godfrey DI, Mccluskey J. T cell antigen receptor recognition of antigen-presenting molecules. Annu Rev Immunol. 2015;33:169–200.

    CAS  PubMed  Google Scholar 

  17. Huang J, Meyer C, Zhu C. T cell antigen recognition at the cell membrane. Mol Immunol. 2012;52:155–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Davis MM, Krogsgaard M, Huppa JB, Sumen C, Purbhoo MA, Irvine DJ, et al. Dynamics of cell surface molecules during T cell recognition. Annu Rev Biochem. 2003;72:717–42.

    CAS  PubMed  Google Scholar 

  19. Ngoenkam J, Schamel WW, Pongcharoen S. Selected signalling proteins recruited to the T-cell receptor-CD3 complex. Immunology. 2018;153:42–50.

    CAS  PubMed  Google Scholar 

  20. Mak TW, Saunders ME, Jett BD. Primer to the immune response: second edition. Elsevier Inc. 2014. https://doi.org/10.1016/C2009-0-62217-0.

  21. Huang J, Brameshuber M, Zeng X, Xie J, Li QJ, Chien YH, et al. A single peptide-major histocompatibility complex ligand triggers digital cytokine secretion in CD4+ T cells. Immunity. 2013;39:846–57.

    CAS  PubMed  Google Scholar 

  22. Davenport AJ, Cross RS, Watson KA, Liao Y, Shi W, Prince HM, et al. Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity. Proc Natl Acad Sci U S A. 2018;115:E2068–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Alarcón B, Mestre D, Martínez-Martín N. The immunological synapse: a cause or consequence of T-cell receptor triggering? Immunology. 2011;133:420–5.

    PubMed  PubMed Central  Google Scholar 

  24. Watanabe K, Kuramitsu S, Posey AD, June CH. Expanding the therapeutic window for CAR T cell therapy in solid tumors: the knowns and unknowns of CAR T cell biology. Front Immunol. 2018;9:2486.

    PubMed  PubMed Central  Google Scholar 

  25. Kummerow C, Junker C, Kruse K, Rieger H, Quintana A, Hoth M. The immunological synapse controls local and global calcium signals in T lymphocytes. Immunol Rev. 2009;231:132–47.

    CAS  PubMed  Google Scholar 

  26. Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci U S A. 1989;86:10024–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Locke FL, Ghobadi A, Jacobson CA, Miklos DB, Lekakis LJ, Oluwole OO, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial. Lancet Oncol. 2019;20:31–42.

    CAS  PubMed  Google Scholar 

  28. Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380:45–56.

    CAS  PubMed  Google Scholar 

  29. Abramson JS, Gordon LI, Palomba ML, Lunning MA, Arnason JE, Forero-Torres A, et al. Updated safety and long term clinical outcomes in TRANSCEND NHL 001, pivotal trial of lisocabtagene maraleucel (JCAR017) in R/R aggressive NHL. J Clin Oncol. 2018;36:7505–7505.

    Google Scholar 

  30. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378:439–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Ramos CA, Torrano V, Bilgi M, Gerken C, Dakhova O, Mei Z, et al. CD30-chimeric antigen receptor (car) T cells for therapy of Hodgkin lymphoma (HL). Hematol Oncol. 2019;37:168–168.

    Google Scholar 

  32. Grover NS, Savoldo B. Challenges of driving CD30-directed CAR-T cells to the clinic. BMC Cancer. 2019;19:203.

    PubMed  PubMed Central  Google Scholar 

  33. Raje N, Berdeja J, Lin Y, Siegel D, Jagannath S, Madduri D, et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med. 2019;380:1726–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Mailankody S, Htut M, Lee KP, Bensinger W, Devries T, Piasecki J, et al. JCARH125, anti-BCMA CAR T-cell therapy for relapsed/refractory multiple myeloma: initial proof of concept results from a phase 1/2 multicenter study (EVOLVE). Blood. 2018;132:957–957.

    Google Scholar 

  35. Stoiber S, Cadilha BL, Benmebarek M-R, Lesch S, Endres S, Kobold S. Limitations in the design of chimeric antigen receptors for cancer therapy. Cells. 2019;8:472.

    CAS  PubMed Central  Google Scholar 

  36. Qin H, Ramakrishna S, Nguyen S, Fountaine TJ, Ponduri A, Stetler-Stevenson M, et al. Preclinical development of bivalent chimeric antigen receptors targeting both CD19 and CD22. Mol Ther Oncolytics. 2018;11:127–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Darowski D, Kobold S, Jost C, Klein C. Combining the best of two worlds: highly flexible chimeric antigen receptor adaptor molecules (CAR-adaptors) for the recruitment of chimeric antigen receptor T cells. MAbs. 2019;11:621–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Murad JM, Graber DJ, Sentman CL. Advances in the use of natural receptor- or ligand-based chimeric antigen receptors (CARs) in haematologic malignancies. Best Pract Res Clin Haematol. 2018;31:176–83.

    PubMed  PubMed Central  Google Scholar 

  39. Long AH, Haso WM, Shern JF, Wanhainen KM, Murgai M, Ingaramo M, et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med. 2015;21:581–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Hombach AA, Schildgen V, Heuser C, Finnern R, Gilham DE, Abken H. T cell activation by antibody-like immunoreceptors: the position of the binding epitope within the target molecule determines the efficiency of activation of redirected T cells. J Immunol. 2007;178:4650–7.

    CAS  PubMed  Google Scholar 

  41. James SE, Greenberg PD, Jensen MC, Lin Y, Wang J, Till BG, et al. Antigen sensitivity of CD22-specific chimeric TCR is modulated by target epitope distance from the cell membrane. J Immunol. 2008;180:7028–38.

    CAS  PubMed  Google Scholar 

  42. Haso W, Lee DW, Shah NN, Stetler-Stevenson M, Yuan CM, Pastan IH, et al. Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. Blood. 2013;121:1165–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Kulemzin SV, Kuznetsova VV, Mamonkin M, Taranin AV, Gorchakov AA. Engineering chimeric antigen receptors. Acta Nat. 2017;9:6–14.

    CAS  Google Scholar 

  44. Bridgeman JS, Hawkins RE, Bagley S, Blaylock M, Holland M, Gilham DE. The optimal antigen response of chimeric antigen receptors harboring the CD3ζ transmembrane domain is dependent upon incorporation of the receptor into the endogenous TCR/CD3 complex. J Immunol. 2010;184:6938–49.

    CAS  PubMed  Google Scholar 

  45. Van Der Stegen SJC, Hamieh M, Sadelain M. The pharmacology of second-generation chimeric antigen receptors. Nat Rev Drug Discov. 2015;14:499–509.

    PubMed  PubMed Central  Google Scholar 

  46. Weinkove R, George P, Dasyam N, McLellan AD. Selecting costimulatory domains for chimeric antigen receptors: functional and clinical considerations. Clin Transl Immunol. 2019;8:e1049. https://doi.org/10.1002/cti2.1049.

    Article  Google Scholar 

  47. Carpenito C, Milone MC, Hassan R, Simonet JC, Lakhal M, Suhoski MM, et al. Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc Natl Acad Sci U S A. 2009;106:3360–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhao Z, Condomines M, van der Stegen SJC, Perna F, Kloss CC, Gunset G, et al. Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells. Cancer Cell. 2015;28:415–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Kawalekar OU, O’Connor RS, Fraietta JA, Guo L, McGettigan SE, Posey AD Jr, et al. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity. 2016;44:380–90.

    CAS  PubMed  Google Scholar 

  50. Till BG, Jensen MC, Wang J, Chen EY, Wood BL, Greisman HA, et al. Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood. 2008;112:2261–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Jensen MC, Popplewell L, Cooper LJ, DiGiusto D, Kalos M, Ostberg JR, et al. Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. Biol Blood Marrow Transplant. 2010;16:1245–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Savoldo B, Ramos CA, Liu E, Mims MP, Keating MJ, Carrum G, et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest. 2011;121:1822–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Guedan S, Posey AD, Shaw C, et al. Enhancing CAR T cell persistence through ICOS and 4-1BB costimulation. JCI insight. 2018;3. https://doi.org/10.1172/jci.insight.96976.

  54. Zhong XS, Matsushita M, Plotkin J, Riviere I, Sadelain M. Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI 3 kinase/AKT/Bcl-X L activation and CD8 T cell-mediated tumor eradication. Mol Ther. 2010;18:413–20.

    CAS  PubMed  Google Scholar 

  55. Abate-Daga D, Lagisetty KH, Tran E, Zheng Z, Gattinoni L, Yu Z, et al. A novel chimeric antigen receptor against prostate stem cell antigen mediates tumor destruction in a humanized mouse model of pancreatic cancer. Hum Gene Ther. 2014;25:1003–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Kuünkele A, Johnson AJ, Rolczynski LS, et al. Functional tuning of CARs reveals signaling threshold above which CD8+ CTL antitumor potency is attenuated due to cell Fas-FasL-Dependent AICD. Cancer Immunol Res. 2015;3:368–79.

    Google Scholar 

  57. Gomes-Silva D, Mukherjee M, Srinivasan M, Krenciute G, Dakhova O, Zheng Y, et al. Tonic 4-1BB costimulation in chimeric antigen receptors impedes T cell survival and is vector-dependent. Cell Rep. 2017;21:17–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Davenport AJ, Jenkins MR, Cross RS, Yong CS, Prince HM, Ritchie DS, et al. CAR-T cells inflict sequential killing of multiple tumor target cells. Cancer Immunol Res. 2015;3:483–94.

    CAS  PubMed  Google Scholar 

  59. Xiong W, Chen Y, Kang X, Chen Z, Zheng P, Hsu YH, et al. Immunological synapse predicts effectiveness of chimeric antigen receptor cells. Mol Ther. 2018;26:963–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Watanabe K, Terakura S, Martens AC, van Meerten T, Uchiyama S, Imai M, et al. Target antigen density governs the efficacy of anti–CD20-CD28-CD3 ζ chimeric antigen receptor–modified effector CD8 + T cells. J Immunol. 2015;194:911–20.

    CAS  PubMed  Google Scholar 

  61. Walker AJ, Majzner RG, Zhang L, Wanhainen K, Long AH, Nguyen SM, et al. Tumor antigen and receptor densities regulate efficacy of a chimeric antigen receptor targeting anaplastic lymphoma kinase. Mol Ther. 2017;25:2189–201.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Ramakrishna S, Highfill SL, Walsh Z, Nguyen SM, Lei H, Shern JF, et al. Modulation of target antigen density improves CAR T-cell functionality and persistence. Clin Cancer Res. 2019;25:5329–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Debinski W, Slagle B, Gibo DM, Powers SK, Gillespie GY. Expression of a restrictive receptor for interleukin 13 is associated with glial transformation. J Neuro-Oncol. 2000;48:103–11.

    CAS  Google Scholar 

  64. Jarboe JS, Johnson KR, Choi Y, Lonser RR, Park JK. Expression of interleukin-13 receptor α2 in glioblastoma multiforme: implications for targeted therapies. Cancer Res. 2007;67:7983–6.

    CAS  PubMed  Google Scholar 

  65. Brown CE, Badie B, Barish ME, Weng L, Ostberg JR, Chang WC, et al. Bioactivity and safety of IL13Rα2-redirected chimeric antigen receptor CD8+ T cells in patients with recurrent glioblastoma. Clin Cancer Res. 2015;21:4062–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Shah NN, Fry TJ. Mechanisms of resistance to CAR T cell therapy. Nat Rev Clin Oncol. 2019;16:372–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Krebs S, Chow KKH, Yi Z, Rodriguez-Cruz T, Hegde M, Gerken C, et al. T cells redirected to interleukin-13Rα2 with interleukin-13 mutein-chimeric antigen receptors have anti-glioma activity but also recognize interleukin-13Rα1. Cytotherapy. 2014;16:1121–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Brown CE, Starr R, Aguilar B, et al. Clinical development of IL13Rα2-targeting CAR T cells for the treatment of glioblastoma. J Immunother Cancer. 2015;3:1–1.

    Google Scholar 

  69. Jonnalagadda M, Mardiros A, Urak R, Wang X, Hoffman LJ, Bernanke A, et al. Chimeric antigen receptors with mutated IgG4 Fc spacer avoid fc receptor binding and improve T cell persistence and antitumor efficacy. Mol Ther. 2015;23:757–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Wang X, Naranjo A, Brown CE, Bautista C, Wong CLW, Chang WC, et al. Phenotypic and functional attributes of lentivirus-modified CD19-specific human CD8+ central memory T cells manufactured at clinical scale. J Immunother. 2012;35:689–701.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Brown CE, Alizadeh D, Starr R, Weng L, Wagner JR, Naranjo A, et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med. 2016;375:2561–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Krenciute G, Krebs S, Torres D, Wu MF, Liu H, Dotti G, et al. Characterization and functional analysis of scFv-based chimeric antigen receptors to redirect T cells to IL13Rα2-positive glioma. Mol Ther. 2016;24:354–63.

    CAS  PubMed  Google Scholar 

  73. Sugawa N, Ekstrand AJ, James CD, Collins VP. Identical splicing of aberrant epidermal growth factor receptor transcripts from amplified rearranged genes in human glioblastomas. Proc Natl Acad Sci U S A. 1990;87:8602–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Greenall SA, Johns TG. EGFRvIII: the promiscuous mutation. Cell Death Dis. 2016;2:16049. https://doi.org/10.1038/cddiscovery.2016.49.

    Article  CAS  Google Scholar 

  75. Wong AJ, Ruppert JM, Bignerf SH, et al. Structural alterations of the epidermal growth factor receptor gene in human gliomas (oncogene/ampflifcation/reangement/erbB/tumor-spedflc surface molecule). 1992.

  76. Heimberger AB, Suki D, Yang D, Shi W, Aldape K. The natural history of EGFR and EGFRvIII in glioblastoma patients. J Transl Med. 2005;3:38. https://doi.org/10.1186/1479-5876-3-38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. An Z, Aksoy O, Zheng T, Fan QW, Weiss WA. Epidermal growth factor receptor and EGFRvIII in glioblastoma: signaling pathways and targeted therapies. Oncogene. 2018;37:1561–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Gedeon PC, Choi BD, Sampson JH, Bigner DD. Rindopepimut: anti-EGFRvIII peptide vaccine, oncolytic. Drugs Future. 2013;38:147–55.

    PubMed  PubMed Central  Google Scholar 

  79. O’Rourke DM, Nasrallah MP, Desai A, et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med. 2017;9:eaaa0984. https://doi.org/10.1126/scitranslmed.aaa0984.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Johnson LA, Scholler J, Ohkuri T, Kosaka A, Patel PR, McGettigan SE, et al. Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma. Sci Transl Med. 2015;7:275ra22. https://doi.org/10.1126/scitranslmed.aaa4963.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Binder DC, Ladomersky E, Lenzen A, et al. Lessons learned from rindopepimut treatment in patients with EGFRvIII-expressing glioblastoma.

  82. Platten M. EGFRvIII vaccine in glioblastoma-InACT-IVe or not ReACTive enough? Neuro-Oncology. 2017;19:1425–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Okamoto S, Yoshikawa K, Obata Y, Shibuya M, Aoki S, Yoshida J, et al. Monoclonal antibody against the fusion junction of a deletion-mutant epidermal growth factor receptor. Br J Cancer. 1996;73:1366–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. IL13Ralpha2-targeted chimeric antigen receptor (CAR) T cells with or without nivolumab and ipilimumab in treating patients with recurrent or refractory glioblastoma - full text view - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04003649 (accessed Feb 14, 2020).

  85. Genetically modified T-cells in treating patients with recurrent or refractory malignant glioma - full text view - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02208362 (accessed Feb 14, 2020).

  86. Personalized chimeric antigen receptor T cell immunotherapy for patients with recurrent malignant gliomas - full text view - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03423992 (accessed Feb 14, 2020).

  87. EGFR806 CAR T cell immunotherapy for recurrent/refractory solid tumors in children and young adults - full text view - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03618381 (accessed Jan 7, 2020).

  88. CART-EGFRvIII + Pembrolizumab in GBM - full text view - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03726515 (accessed Feb 14, 2020).

  89. Memory-Enriched T Cells in treating patients with recurrent or refractory grade III-IV glioma - full text view - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03389230 (accessed Feb 14, 2020).

  90. T cells expressing HER2-specific chimeric antigen receptors(CAR) for patients with HER2-positive CNS tumors - full text view - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02442297 (accessed Feb 14, 2020).

  91. HER2-specific CAR T cell locoregional immunotherapy for HER2-positive recurrent/refractory pediatric CNS tumors - full text view - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03500991 (accessed Feb 14, 2020).

  92. Intracranial injection of NK-92/5.28.z cells in patients with recurrent HER2-positive glioblastoma - full text view - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03383978 (accessed Feb 14, 2020).

  93. Study of B7-H3-specific CAR T cell locoregional immunotherapy for diffuse intrinsic pontine glioma/diffuse midline glioma and recurrent or refractory pediatric central nervous system tumors - full text view - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04185038 (accessed Feb 14, 2020).

  94. B7-H3 CAR-T for recurrent or refractory glioblastoma - full text view - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04077866 (accessed Feb 14, 2020).

  95. Administering peripheral blood lymphocytes transduced with a CD70-binding chimeric antigen receptor to people with CD70 expressing cancers - full text view - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02830724 (accessed Feb 14, 2020).

  96. CAR-T cell immunotherapy for EphA2 positive malignant glioma patients - full text view - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02575261 (accessed Feb 14, 2020).

  97. CD147-CART cells in patients with recurrent malignant glioma. - full text view - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04045847 (accessed Feb 14, 2020).

  98. Chimeric antigen receptor (CAR) T cells with a Chlorotoxin tumor-targeting domain for the treatment of recurrent or progressive glioblastoma - full text view - ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT04214392 (accessed Feb 14, 2020).

  99. Pilot study of autologous chimeric switch receptor modified T cells in recurrent glioblastoma multiforme - full text view - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02937844 (accessed Feb 14, 2020).

  100. Chen M, Sun R, Shi B, Wang Y, di S, Luo H, et al. Antitumor efficacy of chimeric antigen receptor T cells against EGFRvIII-expressing glioblastoma in C57BL/6 mice. Biomed Pharmacother. 2019;113:108734. https://doi.org/10.1016/j.biopha.2019.108734.

    Article  CAS  PubMed  Google Scholar 

  101. Johns TG, Adams TE, Cochran JR, Hall NE, Hoyne PA, Olsen MJ, et al. Identification of the epitope for the epidermal growth factor receptor-specific monoclonal antibody 806 reveals that it preferentially recognizes an untethered form of the receptor. J Biol Chem. 2004;279:30375–84.

    CAS  PubMed  Google Scholar 

  102. Sivasubramanian A, Chao G, Pressler HM, Wittrup KD, Gray JJ. Structural model of the mAb 806-EGFR complex using computational docking followed by computational and experimental mutagenesis. Structure. 2006;14:401–14.

    CAS  PubMed  Google Scholar 

  103. Reilly EB, Phillips AC, Buchanan FG, et al. Characterization of ABT-806, a humanized tumor-specific anti-EGFR monoclonal antibody. Mol Cancer Ther. 2015;14:1411–51.

    Google Scholar 

  104. Ravanpay AC, Gust J, Johnson AJ, et al. EGFR806-CAR T cells selectively target a tumor-restricted EGFR epitope in glioblastoma. 2019;10:7080–95.

  105. Padhy LC, Shih C, Cowing D, Finkelstein R, Weinberg RA. Identification of a phosphoprotein specifically induced by the transforming DNA of rat neuroblastomas. Cell. 1982;28:865–71.

    CAS  PubMed  Google Scholar 

  106. Wieduwilt MJ, Moasser MM. The epidermal growth factor receptor family: biology driving targeted therapeutics. Cell Mol Life Sci. 2008;65:1566–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Iqbal N, Iqbal N. Human epidermal growth factor receptor 2 (HER2) in cancers: overexpression and therapeutic implications. Mol Biol Int. 2014;2014:1–9.

    Google Scholar 

  108. Mineo JF, Bordron A, Baroncini M, Maurage CA, Ramirez C, Siminski RM, et al. Low HER2-expressing glioblastomas are more often secondary to anaplastic transformation of low-grade glioma. J Neuro-Oncol. 2007;85:281–7.

    Google Scholar 

  109. Carter P, Presta L, Gorman CM, Ridgway JB, Henner D, Wong WL, et al. Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci U S A. 1992;89:4285–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Sliwkowski MX, Lofgren JA, Lewis GD, Hotaling TE, Fendly BM, Fox JA. Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin). Semin Oncol. 1999;26:60–70.

    CAS  PubMed  Google Scholar 

  111. Press MF, Cordon-Cardo C, Slamon DJ. Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissues. Oncogene. 1990;5:953–62.

    CAS  PubMed  Google Scholar 

  112. Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case report of a serious adverse event following the administration of t cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther. 2010;18:843–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Weis W, Harwerth IM, Zwickl M, Hardman N, Groner B, Hynes NE. Construction, bacterial expression and characterization of a bifunctional single-chain antibody-phosphatase fusion protein targeted to the human ERBB-2 receptor. Bio/Technology. 1992;10:1128–32.

    Google Scholar 

  114. Ahmed N, Ratnayake M, Savoldo B, Perlaky L, Dotti G, Wels WS, et al. Regression of experimental medulloblastoma following transfer of HER2-specific T cells. Cancer Res. 2007;67:5957–64.

    CAS  PubMed  Google Scholar 

  115. Ahmed N, Salsman VS, Yvon E, Louis CU, Perlaky L, Wels WS, et al. Immunotherapy for osteosarcoma: genetic modification of T cells overcomes low levels of tumor antigen expression. Mol Ther. 2009;17:1779–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Ahmed N, Salsman VS, Kew Y, Shaffer D, Powell S, Zhang YJ, et al. HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors. Clin Cancer Res. 2010;16:474–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Ahmed N, Brawley VS, Hegde M, Robertson C, Ghazi A, Gerken C, et al. Human epidermal growth factor receptor 2 (HER2) - specific chimeric antigen receptor - modified T cells for the immunotherapy of HER2-positive sarcoma. J Clin Oncol. 2015;33:1688–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Liu X, Zhang N, Shi H. Driving better and safer HER2-specific CARs for cancer therapy. Oncotarget. 2017;8:62730–41.

    PubMed  PubMed Central  Google Scholar 

  119. Yip YL, Smith G, Koch J, Dübel S, Ward RL. Identification of epitope regions recognized by tumor inhibitory and stimulatory anti-ErbB-2 monoclonal antibodies: implications for vaccine design. J Immunol. 2001;166:5271–8.

    CAS  PubMed  Google Scholar 

  120. Guedan S, Calderon H, Posey AD, Maus MV. Engineering and design of chimeric antigen receptors. Mol Ther Methods Clin Dev. 2019;12:145–56.

    CAS  PubMed  Google Scholar 

  121. Liu X, Jiang S, Fang C, Yang S, Olalere D, Pequignot EC, et al. Affinity-tuned ErbB2 or EGFR chimeric antigen receptor T cells exhibit an increased therapeutic index against tumors in mice. Cancer Res. 2015;75:3596–607.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Pule MA, Savoldo B, Myers GD, Rossig C, Russell HV, Dotti G, et al. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med. 2008;14:1264–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Ahmed N, Brawley V, Hegde M, Bielamowicz K, Kalra M, Landi D, et al. HER2-specific chimeric antigen receptor–modified virus-specific T cells for progressive glioblastoma: a phase 1 dose-escalation trial. JAMA Oncol. 2017;3:1094–101.

    PubMed  PubMed Central  Google Scholar 

  124. Wykosky J, Gibo DM, Stanton C, Debinski W. EphA2 as a novel molecular marker and target in glioblastoma multiforme. Mol Cancer Res. 2005;3:541–51.

    CAS  PubMed  Google Scholar 

  125. Chow KK, Naik S, Kakarla S, et al. T cells redirected to EphA2 for the immunotherapy of glioblastoma. Mol Ther. 2013;21:629–37.

    CAS  PubMed  Google Scholar 

  126. Tang X, Zhao S, Zhang Y, Wang Y, Zhang Z, Yang M, et al. B7-H3 as a novel CAR-T therapeutic target for glioblastoma. Mol Ther Oncolytics. 2019;14:279–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Castellanos JR, Purvis IJ, Labak CM, Guda MR, Tsung AJ, Velpula KK, et al. B7-H3 role in the immune landscape of cancer. Am J Clin Exp Immunol. 2017;6:66–75.

    PubMed  PubMed Central  Google Scholar 

  128. Majzner RG, Theruvath JL, Nellan A, Heitzeneder S, Cui Y, Mount CW, et al. CAR T cells targeting B7-H3, a pan-cancer antigen, demonstrate potent preclinical activity against pediatric solid tumors and brain tumors. Clin Cancer Res. 2019;25:2560–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Nehama D, Di Ianni N, Musio S, et al. B7-H3-redirected chimeric antigen receptor T cells target glioblastoma and neurospheres. EBioMedicine. 2019;47:33–43.

    PubMed  PubMed Central  Google Scholar 

  130. Ilieva KM, Cheung A, Mele S, Chiaruttini G, Crescioli S, Griffin M, et al. Chondroitin sulfate proteoglycan 4 and its potential as an antibody immunotherapy target across different tumor types. Front Immunol. 2018;8. https://doi.org/10.3389/fimmu.2017.01911.

  131. Burns WR, Zhao Y, Frankel TL, Hinrichs CS, Zheng Z, Xu H, et al. A high molecular weight melanoma-associated antigen - specific chimeric antigen receptor redirects lymphocytes to target human melanomas. Cancer Res. 2010;70:3027–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Geldres C, Savoldo B, Hoyos V, Caruana I, Zhang M, Yvon E, et al. T lymphocytes redirected against the chondroitin sulfate proteoglycan-4 control the growth of multiple solid tumors both in vitro and in vivo. Clin Cancer Res. 2014;20:962–71.

    CAS  PubMed  Google Scholar 

  133. Tschernia N, Orentas R, Mackall C. Chondroitin sulfate proteoglycan 4 specific chimeric antigen receptor therapy for pediatric solid tumors. J Immunother Cancer. 2014;2:1–2.

    Google Scholar 

  134. Pellegatta S, Savoldo B, Di Ianni N, et al. Constitutive and TNFα-inducible expression of chondroitin sulfate proteoglycan 4 in glioblastoma and neurospheres: implications for CAR-T cell therapy. Sci Transl Med. 2018;10:eaao2731. https://doi.org/10.1126/scitranslmed.aao2731.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Jin L, Ge H, Long Y, Yang C, Chang Y(E), Mu L, et al. CD70, a novel target of CAR T-cell therapy for gliomas. Neuro-Oncology. 2018;20:55–65.

    CAS  PubMed  Google Scholar 

  136. Chahlavi A, Rayman P, Richmond AL, Biswas K, Zhang R, Vogelbaum M, et al. Glioblastomas induce T-lymphocyte death by two distinct pathways involving gangliosides and CD70. Cancer Res. 2005;65:5428–38.

    CAS  PubMed  Google Scholar 

  137. Shaffer DR, Savoldo B, Yi Z, Chow KKH, Kakarla S, Spencer DM, et al. T cells redirected against CD70 for the immunotherapy of CD70-positive malignancies. Blood. 2011;117:4304–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Wang QJ, Yu Z, Hanada KI, Patel K, Kleiner D, Restifo NP, et al. Preclinical evaluation of chimeric antigen receptors targeting CD70-expressing cancers. Clin Cancer Res. 2017;23:2267–76.

    CAS  PubMed  Google Scholar 

  139. Administering peripheral blood lymphocytes transduced with a CD70-binding chimeric antigen receptor to people with CD70 expressing cancers - full text view - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02830724 (accessed Feb 12, 2020).

  140. Wang Y, Chen M, Wu Z, Tong C, Dai H, Guo Y, et al. CD133-directed CAR T cells for advanced metastasis malignancies: a phase I trial. Oncoimmunology. 2018;7:e1440169.

    PubMed  PubMed Central  Google Scholar 

  141. Feng K-C, Guo Y-l, Liu Y, et al. Cocktail treatment with EGFR-specific and CD133-specific chimeric antigen receptor-modified T cells in a patient with advanced cholangiocarcinoma. J Hematol Oncol. 2017;10:1–11.

    Google Scholar 

  142. Stojanovic A, Correia MP, Cerwenka A. The NKG2D/NKG2DL axis in the crosstalk between lymphoid and myeloid cells in health and disease. Front Immunol. 2018;9. https://doi.org/10.3389/fimmu.2018.00827.

  143. Role of NKG2D and its ligands in cancer immunotherapy. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834480/ (accessed Feb 12, 2020).

  144. Yang D, Sun B, Dai H, et al. T cells expressing NKG2D chimeric antigen receptors efficiently eliminate glioblastoma and cancer stem cells. J Immunother Cancer. 2019;7:1–13.

    Google Scholar 

  145. Bielamowicz K, Fousek K, Byrd TT, Samaha H, Mukherjee M, Aware N, et al. Trivalent CAR T cells overcome interpatient antigenic variability in glioblastoma. Neuro-Oncology. 2018;20:506–18.

    CAS  PubMed  Google Scholar 

  146. Krenciute G, Prinzing BL, Yi Z, Wu MF, Liu H, Dotti G, et al. Transgenic expression of IL15 improves antiglioma activity of IL13Rα2-CAR T cells but results in antigen loss variants. Cancer Immunol Res. 2017;5:571–81.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Medical Oncology, UNC-CH, 170 Manning Drive | CB#7305, Chapel Hill, NC, 27599, USA

    Nicholas P. Tschernia MD & Simon Khagi MD

Authors
  1. Nicholas P. Tschernia MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Simon Khagi MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Simon Khagi MD.

Ethics declarations

Conflict of Interest

Nicholas Tschernia declares no potential conflicts of interest relevant to this article were reported.

Simon Khagi declares no potential conflicts of interest relevant to this article were reported.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Neuro-oncology

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tschernia, N.P., Khagi, S. A Head Start: CAR-T Cell Therapy for Primary Malignant Brain Tumors. Curr. Treat. Options in Oncol. 21, 73 (2020). https://doi.org/10.1007/s11864-020-00772-6

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11864-020-00772-6

Keywords

Search

Navigation