CNS Drugs

, Volume 34, Issue 2, pp 127–145 | Cite as

Potential of Glioblastoma-Targeted Chimeric Antigen Receptor (CAR) T-Cell Therapy

  • Ryan D. Salinas
  • Joseph S. Durgin
  • Donald M. O’RourkeEmail author
Leading Article


Despite the established efficacy of chimeric antigen receptor (CAR) T-cell therapy in hematologic malignancies, translating CAR T therapy to solid tumors has remained investigational. Glioblastoma, the most aggressive and lethal form of primary brain tumor, has recently been among the malignancies being trialed clinically with CAR T cells. Glioblastoma in particular holds several unique features that have hindered clinical translation, including its vast intertumoral and intratumoral heterogeneity, associated immunosuppressive environment, and lack of clear experimental models to predict response and analyze resistant phenotypes. Here, we review the history of CAR T therapy development, its current progress in treating glioblastoma, as well as the current challenges and future directions in establishing CAR T therapy as a viable alternative to the current standard of care. Tremendous efforts are currently ongoing to identify novel CAR targets and target combinations for glioblastoma, to modify T cells to enhance their efficacy and to enable them to resist tumor-mediated immunosuppression, and to utilize adjunct therapies such as lymphodepletion, checkpoint inhibition, and bi-specific engagers to improve CAR T persistence. Furthermore, new preclinical models of CAR T therapy are being developed that better reflect the clinical features seen in human trials. Current clinical trials that rapidly incorporate key preclinical findings to patient translation are emerging.


Compliance with Ethical Standards


No external funding was used in the preparation of this manuscript.

Conflict of interest

Donald M. O’Rourke has received research grants related to the development of CAR T cells in glioblastoma (Novartis), and holds patents pending and patents filed for CAR T cells in glioblastoma (Novartis, University of Pennsylvania). Ryan D. Salinas and Joseph S. Durgin declare they have no conflicts of interest that might be relevant to the contents of this article.


  1. 1.
    Brentjens RJ, Rivière I, Park JH, Davila ML, Wang X, Stefanski J, et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood. 2011;118:4817–28.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Yip A, Webster RM. The market for chimeric antigen receptor T cell therapies. Nat Rev Drug Discov. 2018;17:161–2.PubMedGoogle Scholar
  3. 3.
    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.PubMedPubMedCentralGoogle Scholar
  4. 4.
    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.PubMedGoogle Scholar
  5. 5.
    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 USA. 1989;86:10024–8.PubMedGoogle Scholar
  6. 6.
    Brocker T. Chimeric Fv-zeta or Fv-epsilon receptors are not sufficient to induce activation or cytokine production in peripheral T cells. Blood. 2000;96:1999–2001.PubMedGoogle Scholar
  7. 7.
    Kershaw MH, Westwood JA, Parker LL, Wang G, Eshhar Z, Mavroukakis SA, et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2006;12:6106–15.Google Scholar
  8. 8.
    Lamers CH, Sleijfer S, van Steenbergen S, van Elzakker P, van Krimpen B, Groot C, et al. Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. Mol Ther J Am Soc Gene Ther. 2013;21:904–12.Google Scholar
  9. 9.
    Park JR, Digiusto DL, Slovak M, Wright C, Naranjo A, Wagner J, et al. Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma. Mol Ther J Am Soc Gene Ther. 2007;15:825–33.Google Scholar
  10. 10.
    Sadelain M, Brentjens R, Rivière I. The promise and potential pitfalls of chimeric antigen receptors. Curr Opin Immunol. 2009;21:215–23.PubMedPubMedCentralGoogle Scholar
  11. 11.
    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.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood. 2012;119:2709–20.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365:725–33.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Kowolik CM, Topp MS, Gonzalez S, Pfeiffer T, Olivares S, Gonzalez N, et al. CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells. Cancer Res. 2006;66:10995–1004.PubMedGoogle Scholar
  15. 15.
    Milone MC, Fish JD, Carpenito C, Carroll RG, Binder GK, Teachey D, et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther J Am Soc Gene Ther. 2009;17:1453–64.Google Scholar
  16. 16.
    van der Stegen SJC, Hamieh M, Sadelain M. The pharmacology of second-generation chimeric antigen receptors. Nat Rev Drug Discov. 2015;14:499–509.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Yan L, Liu B. Critical factors in chimeric antigen receptor-modified T-cell (CAR-T) therapy for solid tumors. OncoTargets Ther. 2019;12:193–204.Google Scholar
  18. 18.
    Li J, Li W, Huang K, Zhang Y, Kupfer G, Zhao Q. Chimeric antigen receptor T cell (CAR-T) immunotherapy for solid tumors: lessons learned and strategies for moving forward. J Hematol Oncol J Hematol Oncol. 2018;11:22.PubMedGoogle Scholar
  19. 19.
    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 Off J Am Soc Clin Oncol. 2015;33:1688–96.Google Scholar
  20. 20.
    Junghans RP, Ma Q, Rathore R, Gomes EM, Bais AJ, Lo ASY, et al. Phase I trial of anti-PSMA designer CAR-T cells in prostate cancer: possible role for interacting interleukin 2-T cell pharmacodynamics as a determinant of clinical response. Prostate. 2016;76:1257–70.PubMedGoogle Scholar
  21. 21.
    Louis CU, Savoldo B, Dotti G, Pule M, Yvon E, Myers GD, et al. Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Blood. 2011;118:6050–6.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Newick K, O’Brien S, Moon E, Albelda SM. CAR T cell therapy for solid tumors. Annu Rev Med. 2017;68:139–52.PubMedGoogle Scholar
  23. 23.
    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.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Katz SC, Burga RA, McCormack E, Wang LJ, Mooring W, Point GR, et al. Phase I hepatic immunotherapy for metastases study of intra-arterial chimeric antigen receptor-modified T-cell therapy for CEA+ liver metastases. Clin Cancer Res Off J Am Assoc Cancer Res. 2015;21:3149–59.Google Scholar
  25. 25.
    Stupp R, Mason WP, Van Den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96.CrossRefGoogle Scholar
  26. 26.
    Hegi ME, Diserens A-C, Gorlia T, Hamou M-F, de Tribolet N, Weller M, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352:997–1003.PubMedGoogle Scholar
  27. 27.
    Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, et al. Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial. JAMA. 2015;314:2535–43.PubMedGoogle Scholar
  28. 28.
    Stupp R, Taillibert S, Kanner A, Read W, Steinberg D, Lhermitte B, et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA. 2017;318:2306–16.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Harder BG, Blomquist MR, Wang J, Kim AJ, Woodworth GF, Winkles JA, et al. Developments in blood–brain barrier penetrance and drug repurposing for improved treatment of glioblastoma. Front Oncol. 2018;8:462.PubMedPubMedCentralGoogle Scholar
  30. 30.
    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.PubMedPubMedCentralGoogle Scholar
  31. 31.
    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.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Goff SL, Morgan RA, Yang JC, Sherry RM, Robbins PF, Restifo NP, et al. Pilot trial of adoptive transfer of chimeric antigen receptor-transduced T cells targeting EGFRvIII in patients with glioblastoma. J Immunother (Hagerstown, MD). 1997;2019(42):126–35.Google Scholar
  33. 33.
    O’Rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mansfield K, Morrissette JJD, 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(399):eaaa0984.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Debinski W, Gibo DM. Molecular expression analysis of restrictive receptor for interleukin 13, a brain tumor-associated cancer/testis antigen. Mol Med. 2000;6:440–9.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Gan HK, Cvrljevic AN, Johns TG. The epidermal growth factor receptor variant III (EGFRvIII): where wild things are altered. FEBS J. 2013;280:5350–70.PubMedGoogle Scholar
  36. 36.
    Sridhar P, Petrocca F. Regional delivery of chimeric antigen receptor (CAR) T-cells for cancer therapy. Cancers. 2017;9(7):E92.PubMedGoogle Scholar
  37. 37.
    Cohen KJ, Pollack IF, Zhou T, Buxton A, Holmes EJ, Burger PC, et al. Temozolomide in the treatment of high-grade gliomas in children: a report from the Children’s Oncology Group. Neuro-Oncol. 2011;13:317–23.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Norelli M, Camisa B, Barbiera G, Falcone L, Purevdorj A, Genua M, et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med. 2018;24:739.PubMedGoogle Scholar
  39. 39.
    Bonifant CL, Jackson HJ, Brentjens RJ, Curran KJ. Toxicity and management in CAR T-cell therapy. Mol Ther Oncolytics. 2016;3:16011.PubMedPubMedCentralGoogle Scholar
  40. 40.
    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.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Brennan CW, Verhaak RGW, McKenna A, Campos B, Noushmehr H, Salama SR, et al. The somatic genomic landscape of glioblastoma. Cell. 2013;155:462–77.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Koka V, Potti A, Forseen SE, Pervez H, Fraiman GN, Koch M, et al. Role of Her-2/neu overexpression and clinical determinants of early mortality in glioblastoma multiforme. Am J Clin Oncol. 2003;26:332–5.PubMedGoogle Scholar
  43. 43.
    Jarboe JS, Johnson KR, Choi Y, Lonser RR, Park JK. Expression of interleukin-13 receptor alpha2 in glioblastoma multiforme: implications for targeted therapies. Cancer Res. 2007;67:7983–6.PubMedGoogle Scholar
  44. 44.
    Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science. 2014;344:1396–401.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17:98–110.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Del Vecchio CA, Giacomini CP, Vogel H, Jensen KC, Florio T, Merlo A, et al. EGFRvIII gene rearrangement is an early event in glioblastoma tumorigenesis and expression defines a hierarchy modulated by epigenetic mechanisms. Oncogene. 2013;32:2670–81.PubMedGoogle Scholar
  47. 47.
    Felsberg J, Hentschel B, Kaulich K, Gramatzki D, Zacher A, Malzkorn B, et al. Epidermal growth factor receptor variant III (EGFRvIII) positivity in EGFR-amplified glioblastomas: prognostic role and comparison between primary and recurrent tumors. Clin Cancer Res Off J Am Assoc Cancer Res. 2017;23:6846–55.Google Scholar
  48. 48.
    Francis JM, Zhang C-Z, Maire CL, Jung J, Manzo VE, Adalsteinsson VA, et al. EGFR variant heterogeneity in glioblastoma resolved through single-nucleus sequencing. Cancer Discov. 2014;4:956–71.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Neftel C, Laffy J, Filbin MG, Hara T, Shore ME, Rahme GJ, et al. An integrative model of cellular states, plasticity, and genetics for glioblastoma. Cell. 2019;178(4):835–849.e21.PubMedGoogle Scholar
  50. 50.
    Hegde M, Mukherjee M, Grada Z, Pignata A, Landi D, Navai SA, et al. Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape. J Clin Investig. 2016;126:3036–52.PubMedGoogle Scholar
  51. 51.
    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-Oncol. 2018;20:506–18.PubMedGoogle Scholar
  52. 52.
    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.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Nehama D, Di Ianni N, Musio S, Du H, Patané M, Pollo B, et al. B7-H3-redirected chimeric antigen receptor T cells target glioblastoma and neurospheres. EBioMedicine. 2019;47:33–43.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Weiss T, Schneider H, Silginer M, Steinle A, Pruschy M, Polić B, et al. NKG2D-dependent antitumor effects of chemotherapy and radiotherapy against glioblastoma. Clin Cancer Res. 2018;24:882–95.PubMedGoogle Scholar
  55. 55.
    Weiss T, Weller M, Guckenberger M, Sentman CL, Roth P. NKG2D-based CAR T cells and radiotherapy exert synergistic efficacy in glioblastoma. Cancer Res. 2018;78:1031–43.PubMedGoogle Scholar
  56. 56.
    Yang D, Sun B, Dai H, Li W, Shi L, Zhang P, et al. T cells expressing NKG2D chimeric antigen receptors efficiently eliminate glioblastoma and cancer stem cells. J Immunother Cancer. 2019;7:171.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Tejero R, Huang Y, Katsyv I, Kluge M, Lin J-Y, Tome-Garcia J, et al. Gene signatures of quiescent glioblastoma cells reveal mesenchymal shift and interactions with niche microenvironment. EBioMedicine. 2019;42:252–69.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Berahovich R, Liu X, Zhou H, Tsadik E, Xu S, Golubovskaya V, et al. Hypoxia selectively impairs CAR-T cells in vitro. Cancers. 2019;11:E602.PubMedGoogle Scholar
  59. 59.
    Cui J, Zhang Q, Song Q, Wang H, Dmitriev P, Sun M, et al. Targeting hypoxia downstream signaling protein, CAIX, for CAR-T cell therapy against glioblastoma. Neuro-Oncol. 2019;21:1436–46.PubMedGoogle Scholar
  60. 60.
    Hatano M, Eguchi J, Tatsumi T, Kuwashima N, Dusak JE, Kinch MS, et al. EphA2 as a glioma-associated antigen: a novel target for glioma vaccines. Neoplasia N Y N. 2005;7:717–22.Google Scholar
  61. 61.
    Zelinski DP, Zantek ND, Stewart JC, Irizarry AR, Kinch MS. EphA2 overexpression causes tumorigenesis of mammary epithelial cells. Cancer Res. 2001;61:2301–6.PubMedGoogle Scholar
  62. 62.
    Chow KK, Naik S, Kakarla S, Brawley VS, Shaffer DR, Yi Z, et al. T cells redirected to EphA2 for the immunotherapy of glioblastoma. Mol Ther. 2013;21:629–37.PubMedGoogle Scholar
  63. 63.
    Pellegatta S, Savoldo B, Ianni ND, Corbetta C, Chen Y, Patané M, 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.PubMedGoogle Scholar
  64. 64.
    Beier D, Hau P, Proescholdt M, Lohmeier A, Wischhusen J, Oefner PJ, et al. CD133+ and CD133-glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res. 2007;67:4010–5.PubMedGoogle Scholar
  65. 65.
    Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 2003;63:5821–8.PubMedGoogle Scholar
  66. 66.
    Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, et al. Identification of human brain tumour initiating cells. Nature. 2004;432:396–401.Google Scholar
  67. 67.
    Zhu X, Prasad S, Gaedicke S, Hettich M, Firat E, Niedermann G. Patient-derived glioblastoma stem cells are killed by CD133-specific CAR T cells but induce the T cell aging marker CD57. Oncotarget. 2015;6:171–84.PubMedGoogle Scholar
  68. 68.
    Martinez M, Moon EK. CAR T cells for solid tumors: new strategies for finding, infiltrating, and surviving in the tumor microenvironment. Front Immunol. 2019;10:128.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Brown CE, Mackall CL. CAR T cell therapy: inroads to response and resistance. Nat Rev Immunol. 2019;19:73–4.PubMedGoogle Scholar
  70. 70.
    Brown CE, Badie B, Barish ME, Weng L, Ostberg JR, Chang W-C, et al. Bioactivity and safety of IL13Rα2-redirected chimeric antigen receptor CD8+ T cells in patients with recurrent glioblastoma. Clin Cancer Res Off J Am Assoc Cancer Res. 2015;21:4062–72.Google Scholar
  71. 71.
    Krenciute G, Prinzing BL, Yi Z, Wu M-F, 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.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Sampson JH, Heimberger AB, Archer GE, Aldape KD, Friedman AH, Friedman HS, et al. 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. 2010;28:4722–9.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Hamieh M, Dobrin A, Cabriolu A, van der Stegen SJC, Giavridis T, Mansilla-Soto J, et al. CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape. Nature. 2019;568:112–6.PubMedPubMedCentralGoogle Scholar
  74. 74.
    See AP, Parker JJ, Waziri A. The role of regulatory T cells and microglia in glioblastoma-associated immunosuppression. J Neurooncol. 2015;123:405–12.PubMedGoogle Scholar
  75. 75.
    Lesniak MS, Gabikian P, Tyler BM, Pardoll DM, Brem H. Dexamethasone mediated inhibition of local IL-2 immunotherapy is dose dependent in experimental brain tumors. J Neurooncol. 2004;70:23–8.PubMedGoogle Scholar
  76. 76.
    Badie B, Schartner JM, Paul J, Bartley BA, Vorpahl J, Preston JK. Dexamethasone-induced abolition of the inflammatory response in an experimental glioma model: a flow cytometry study. J Neurosurg. 2000;93:634–9.PubMedGoogle Scholar
  77. 77.
    Arya SK, Wong-Staal F, Gallo RC. Dexamethasone-mediated inhibition of human T cell growth factor and gamma-interferon messenger RNA. J Immunol (Baltim, MD). 1950;1984(133):273–6.Google Scholar
  78. 78.
    Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Hamid O, Robert C, Daud A, Hodi FS, Hwu W-J, Kefford R, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369:134–44.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124–8.PubMedPubMedCentralGoogle Scholar
  81. 81.
    Abid H, Watthanasuntorn K, Shah O, Gnanajothy R. Efficacy of pembrolizumab and nivolumab in crossing the blood brain barrier. Cureus. 2019;11(4):e4446.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Cloughesy TF, Mochizuki AY, Orpilla JR, Hugo W, Lee AH, Davidson TB, et al. Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nat Med. 2019;25:477–86.PubMedPubMedCentralGoogle Scholar
  83. 83.
    Schalper KA, Rodriguez-Ruiz ME, Diez-Valle R, López-Janeiro A, Porciuncula A, Idoate MA, et al. Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma. Nat Med. 2019;25:470–6.Google Scholar
  84. 84.
    Zhao J, Chen AX, Gartrell RD, Silverman AM, Aparicio L, Chu T, et al. Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma. Nat Med. 2019;25:462–9.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Yin Y, Boesteanu AC, Binder ZA, Xu C, Reid RA, Rodriguez JL, et al. Checkpoint blockade reverses anergy in IL-13Rα2 humanized scFv-based CAR T cells to treat murine and canine gliomas. Mol Ther Oncolytics. 2018;11:20–38.PubMedPubMedCentralGoogle Scholar
  86. 86.
    Shen L, Li H, Bin S, Li P, Chen J, Gu H, et al. The efficacy of third generation anti-HER2 chimeric antigen receptor T cells in combination with PD1 blockade against malignant glioblastoma cells. Oncol Rep. 2019. Scholar
  87. 87.
    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.PubMedPubMedCentralGoogle Scholar
  88. 88.
    Turtle CJ, Berger C, Sommermeyer D, Hanafi L-A, Pender B, Robinson EM, et al. Anti-CD19 chimeric antigen receptor-modified T cell therapy for B cell non-Hodgkin lymphoma and chronic lymphocytic leukemia: fludarabine and cyclophosphamide lymphodepletion improves in vivo expansion and persistence of CAR-T cells and clinical outcomes. Blood. 2015;126:184.Google Scholar
  89. 89.
    Suryadevara CM, Desai R, Abel ML, Riccione KA, Batich KA, Shen SH, et al. Temozolomide lymphodepletion enhances CAR abundance and correlates with antitumor efficacy against established glioblastoma. Oncoimmunology. 2018;7:e1434464.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Ma L, Dichwalkar T, Chang JYH, Cossette B, Garafola D, Zhang AQ, et al. Enhanced CAR-T cell activity against solid tumors by vaccine boosting through the chimeric receptor. Science. 2019;365:162–8.PubMedPubMedCentralGoogle Scholar
  91. 91.
    Sahin A, Sanchez C, Bullain S, Waterman P, Weissleder R, Carter BS. Development of third generation anti-EGFRvIII chimeric T cells and EGFRvIII-expressing artificial antigen presenting cells for adoptive cell therapy for glioma. PLoS One. 2018;13(7):e0199414.PubMedPubMedCentralGoogle Scholar
  92. 92.
    Hu B, Zou Y, Zhang L, Tang J, Niedermann G, Firat E, et al. Nucleofection with plasmid DNA for CRISPR/Cas9-mediated inactivation of programmed cell death protein 1 in CD133-specific CAR T cells. Hum Gene Ther. 2019;30:446–58.PubMedGoogle Scholar
  93. 93.
    Jung I-Y, Kim Y-Y, Yu H-S, Lee M, Kim S, Lee J. CRISPR/Cas9-mediated knockout of DGK improves antitumor activities of human T cells. Cancer Res. 2018;78:4692–703.PubMedGoogle Scholar
  94. 94.
    Shum T, Omer B, Tashiro H, Kruse RL, Wagner DL, Parikh K, et al. Constitutive signaling from an engineered IL7 receptor promotes durable tumor elimination by tumor-redirected T cells. Cancer Discov. 2017;7:1238–47.PubMedPubMedCentralGoogle Scholar
  95. 95.
    Caruso HG, Torikai H, Zhang L, Maiti S, Dai J, Do K-A, et al. Redirecting T-cell specificity to EGFR using mRNA to self-limit expression of chimeric antigen receptor. J Immunother (Hagerstown, MD). 1997;2016(39):205–17.Google Scholar
  96. 96.
    Choi BD, Gedeon PC, Herndon JE, Archer GE, Reap EA, Sanchez-Perez L, et al. Human regulatory T cells kill tumor cells through granzyme-dependent cytotoxicity upon retargeting with a bispecific antibody. Cancer Immunol Res. 2013;1:163.PubMedPubMedCentralGoogle Scholar
  97. 97.
    Choi BD, Yu X, Castano AP, Bouffard AA, Schmidts A, Larson RC, et al. CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity. Nat Biotechnol. 2019;37:1049–58.PubMedGoogle Scholar
  98. 98.
    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.PubMedGoogle Scholar
  99. 99.
    Jiang H, Gao H, Kong J, Song B, Wang P, Shi B, et al. Selective targeting of glioblastoma with EGFRvIII/EGFR bitargeted chimeric antigen receptor T cell. Cancer Immunol Res. 2018;6:1314–26.PubMedGoogle Scholar
  100. 100.
    Wang D, Aguilar B, Starr R, Alizadeh D, Brito A, Sarkissian A, et al. Glioblastoma-targeted CD4+ CAR T cells mediate superior antitumor activity. JCI Insight. 2018;3:99048.PubMedGoogle Scholar
  101. 101.
    Hockey B, Leslie K, Williams D. Dexamethasone for intracranial neurosurgery and anaesthesia. J Clin Neurosci Off J Neurosurg Soc Australas. 2009;16:1389–93.Google Scholar
  102. 102.
    Giles AJ, Hutchinson M-KND, Sonnemann HM, Jung J, Fecci PE, Ratnam NM, et al. Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy. J Immunother Cancer. 2018;6:51.PubMedPubMedCentralGoogle Scholar
  103. 103.
    Brown CE, Aguilar B, Starr R, Yang X, Chang W-C, Weng L, et al. Optimization of IL13Rα2-targeted chimeric antigen receptor T cells for Improved anti-tumor efficacy against glioblastoma. Mol Ther. 2018;26:31–44.PubMedGoogle Scholar
  104. 104.
    Okada H, Weller M, Huang R, Finocchiaro G, Gilbert MR, Wick W, et al. Immunotherapy response assessment in neuro-oncology: a report of the RANO working group. Lancet Oncol. 2015;16:e534–42.PubMedPubMedCentralGoogle Scholar
  105. 105.
    Ren J, Liu X, Fang C, Jiang S, June CH, Zhao Y. Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition. Clin Cancer Res. 2017;23:2255–66.PubMedGoogle Scholar
  106. 106.
    Qasim W, Zhan H, Samarasinghe S, Adams S, Amrolia P, Stafford S, et al. Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Sci Transl Med. 2017;9:eaaj2013.PubMedGoogle Scholar
  107. 107.
    Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM, et al. Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell. 2006;9:391–403.PubMedGoogle Scholar
  108. 108.
    Darmanis S, Sloan SA, Croote D, Mignardi M, Chernikova S, Samghababi P, et al. Single-Cell RNA-Seq analysis of infiltrating neoplastic cells at the migrating front of human glioblastoma. Cell Rep. 2017;21:1399–410.PubMedPubMedCentralGoogle Scholar
  109. 109.
    Ledur PF, Onzi GR, Zong H, Lenz G. Culture conditions defining glioblastoma cells behavior: what is the impact for novel discoveries? Oncotarget. 2017;8:69185–97.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Stockhausen M-T, Broholm H, Villingshøj M, Kirchhoff M, Gerdes T, Kristoffersen K, et al. Maintenance of EGFR and EGFRvIII expressions in an in vivo and in vitro model of human glioblastoma multiforme. Exp Cell Res. 2011;317:1513–26.PubMedGoogle Scholar
  111. 111.
    Schulte A, Günther HS, Martens T, Zapf S, Riethdorf S, Wülfing C, et al. Glioblastoma stem-like cell lines with either maintenance or loss of high-level EGFR amplification, generated via modulation of ligand concentration. Clin Cancer Res Off J Am Assoc Cancer Res. 2012;18:1901–13.Google Scholar
  112. 112.
    Patanè M, Porrati P, Bottega E, Morosini S, Cantini G, Girgenti V, et al. Frequency of NFKBIA deletions is low in glioblastomas and skewed in glioblastoma neurospheres. Mol Cancer. 2013;12:160.PubMedPubMedCentralGoogle Scholar
  113. 113.
    Stec WJ, Rosiak K, Siejka P, Peciak J, Popeda M, Banaszczyk M, et al. Cell line with endogenous EGFRvIII expression is a suitable model for research and drug development purposes. Oncotarget. 2016;7:31907–25.PubMedPubMedCentralGoogle Scholar
  114. 114.
    Cassidy JW, Caldas C, Bruna A. Maintaining tumor heterogeneity in patient-derived tumor xenografts. Cancer Res. 2015;75:2963–8.PubMedPubMedCentralGoogle Scholar
  115. 115.
    Shultz LD, Schweitzer PA, Christianson SW, Gott B, Schweitzer IB, Tennent B, et al. Multiple defects in innate and adaptive immunologic function in NOD/LtSz-scid mice. J Immunol (Baltim, MD). 1950;1995(154):180–91.Google Scholar
  116. 116.
    Candolfi M, Curtin JF, Nichols WS, Muhammad AG, King GD, Pluhar GE, et al. Intracranial glioblastoma models in preclinical neuro-oncology: neuropathological characterization and tumor progression. J Neurooncol. 2007;85:133–48.PubMedPubMedCentralGoogle Scholar
  117. 117.
    Oh T, Fakurnejad S, Sayegh ET, Clark AJ, Ivan ME, Sun MZ, et al. Immunocompetent murine models for the study of glioblastoma immunotherapy. J Transl Med. 2014;12:107.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Halkias J, Yen B, Taylor KT, Reinhartz O, Winoto A, Robey EA, et al. Conserved and divergent aspects of human T-cell development and migration in humanized mice. Immunol Cell Biol. 2015;93:716–26.PubMedPubMedCentralGoogle Scholar
  119. 119.
    Patrizii M, Bartucci M, Pine SR, Sabaawy HE. Utility of glioblastoma patient-derived orthotopic xenografts in drug discovery and personalized therapy. Front Oncol. 2018;8:23.PubMedPubMedCentralGoogle Scholar
  120. 120.
    Pituch KC, Miska J, Krenciute G, Panek WK, Li G, Rodriguez-Cruz T, et al. Adoptive transfer of IL13Rα2-specific chimeric antigen receptor T cells creates a pro-inflammatory environment in glioblastoma. Mol Ther J Am Soc Gene Ther. 2018;26:986–95.Google Scholar
  121. 121.
    Walsh NC, Kenney LL, Jangalwe S, Aryee K-E, Greiner DL, Brehm MA, et al. Humanized mouse models of clinical disease. Annu Rev Pathol. 2017;12:187–215.PubMedGoogle Scholar
  122. 122.
    Sanghera P, Perry J, Sahgal A, Symons S, Aviv R, Morrison M, et al. Pseudoprogression following chemoradiotherapy for glioblastoma multiforme. Can J Neurol Sci J Can Sci Neurol. 2010;37:36–42.Google Scholar
  123. 123.
    Ellingson BM, Chung C, Pope WB, Boxerman JL, Kaufmann TJ. Pseudoprogression, radionecrosis, inflammation or true tumor progression? Challenges associated with glioblastoma response assessment in an evolving therapeutic landscape. J Neurooncol. 2017;134:495–504.PubMedGoogle Scholar
  124. 124.
    Chapelin F, Capitini CM, Ahrens ET. Fluorine-19 MRI for detection and quantification of immune cell therapy for cancer. J Immunother Cancer. 2018;6(1):105.PubMedPubMedCentralGoogle Scholar
  125. 125.
    Jain KK, Sahoo P, Tyagi R, Mehta A, Patir R, Vaishya S, et al. Prospective glioma grading using single-dose dynamic contrast-enhanced perfusion MRI. Clin Radiol. 2015;70:1128–35.PubMedGoogle Scholar
  126. 126.
    Nishikawa R, Sugiyama T, Narita Y, Furnari F, Cavenee WK, Matsutani M. Immunohistochemical analysis of the mutant epidermal growth factor, ΔEGFR, in glioblastoma. Brain Tumor Pathol. 2004;21:53–6.PubMedGoogle Scholar
  127. 127.
    Song D-G, Ye Q, Carpenito C, Poussin M, Wang L-P, Ji C, et al. In vivo persistence, tumor localization, and antitumor activity of CAR-engineered T cells is enhanced by costimulatory signaling through CD137 (4-1BB). Cancer Res. 2011;71:4617–27.PubMedPubMedCentralGoogle Scholar
  128. 128.
    Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6:224ra24.PubMedPubMedCentralGoogle Scholar
  129. 129.
    Nakamura S, Yokoyama K, Yusa N, Ogawa M, Takei T, Kobayashi A, et al. Circulating tumor DNA dynamically predicts response and/or relapse in patients with hematological malignancies. Int J Hematol. 2018;108:402–10.PubMedGoogle Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of Neurosurgery, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Glioblastoma Translational Center of Excellence, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA

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