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Chimeric Antigen Receptor (CAR) T Cell Therapy for Glioblastoma

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Abstract

Glioblastoma (GBM) are the most common and aggressive primary brain tumors in adults. Current mainstay treatments include surgery, chemotherapy, and radiation; however, these are ineffective. As a result, immunotherapy treatment strategies are being developed to harness the body’s natural defense mechanisms against gliomas. Adoptive cell therapy with chimeric antigen receptor (CAR) T cells uses patients’ own T cells that are genetically modified to target tumor-associated antigens. These cells are harvested from patients, engineered to target specific proteins expressed by the tumor and re-injected into the patient with the goal of destroying tumor cells. In this mini review, we outline the history of CAR T cell therapy, describe current antigen targets, and review challenges this treatment faces specifically in targeting GBM.

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References

  • Abramson, J. S., McGree, B., Noyes, S., et al. (2017). Anti-CD19 CAR T cells in CNS diffuse large-B-cell lymphoma. New England Journal of Medicine, 377(8), 783–784.

    PubMed  Google Scholar 

  • Ahmed, N., Brawley, V., Hegde, M., et al. (2017). HER2-specific chimeric antigen receptor-modified virus-specific T cells for progressive glioblastoma: A phase 1 dose-escalation trial. JAMA Oncology, 3(8), 1094–1101.

    PubMed  PubMed Central  Google Scholar 

  • Ahmed, N., Salsman, V. S., Kew, Y., et al. (2010). HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors. Clinical Cancer Research, 16(2), 474–485.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Almasbak, H., Aarvak, T., & Vemuri, M. C. (2016). CAR T cell therapy: A game changer in cancer treatment. Journal of Immunology Research, 2016, 5474602.

    PubMed  PubMed Central  Google Scholar 

  • Bielamowicz, K., Fousek, K., Byrd, T. T., et al. (2018). Trivalent CAR T cells overcome interpatient antigenic variability in glioblastoma. Neuro-Oncology, 20(4), 506–518.

    CAS  PubMed  Google Scholar 

  • Brown, C. E., Alizadeh, D., Starr, R., et al. (2016). Regression of glioblastoma after chimeric antigen receptor T-cell therapy. New England Journal of Medicine, 375(26), 2561–2569.

    CAS  PubMed  Google Scholar 

  • Brown, C. E., Badie, B., Barish, M. E., et al. (2015). Bioactivity and safety of IL13Ralpha2-redirected chimeric antigen receptor CD8+ T cells in patients with recurrent glioblastoma. Clinical Cancer Research, 21(18), 4062–4072.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Brown, C. E., Warden, C. D., Starr, R., et al. (2013). Glioma IL13Ralpha2 is associated with mesenchymal signature gene expression and poor patient prognosis. PLoS ONE, 8(10), e77769.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Brown, D. V., Stylli, S. S., Kaye, A. H., & Mantamadiotis, T. (2019). Multilayered heterogeneity of glioblastoma stem cells: Biological and clinical significance. Advances in Experimental Medicine and Biology, 1139, 1–21.

    CAS  PubMed  Google Scholar 

  • Chmielewski, M., & Abken, H. (2020). TRUCKS, the fourth-generation CAR T cells: Current developments and clinical translation. Advances in Cell and Gene Therapy, 3(3), e84.

    Google Scholar 

  • Choi, B. D., Maus, M. V., June, C. H., & Sampson, J. H. (2019). Immunotherapy for glioblastoma: Adoptive T-cell strategies. Clinical Cancer Research, 25(7), 2042–2048.

    CAS  PubMed  Google Scholar 

  • Chong, E. A., Melenhorst, J. J., Lacey, S. F., et al. (2017). PD-1 blockade modulates chimeric antigen receptor (CAR)-modified T cells: Refueling the CAR. Blood, 129(8), 1039–1041.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Curran, K. J., Seinstra, B. A., Nikhamin, Y., et al. (2015). Enhancing antitumor efficacy of chimeric antigen receptor T cells through constitutive CD40L expression. Molecular Therapy, 23(4), 769–778.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dubinski, D., Wolfer, J., Hasselblatt, M., et al. (2016). CD4+ T effector memory cell dysfunction is associated with the accumulation of granulocytic myeloid-derived suppressor cells in glioblastoma patients. Neuro-Oncology, 18(6), 807–818.

    CAS  PubMed  Google Scholar 

  • Ekstrand, A. J., Sugawa, N., James, C. D., & Collins, V. P. (1992). Amplified and rearranged epidermal growth factor receptor genes in human glioblastomas reveal deletions of sequences encoding portions of the N- and/or C-terminal tails. Proceedings of the National Academy of Sciences of the United States of America, 89(10), 4309–4313.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Firor, A. E., Jares, A., & Ma, Y. (2015). From humble beginnings to success in the clinic: Chimeric antigen receptor-modified T-cells and implications for immunotherapy. Experimental Biology and Medicine (Maywood, N.J.), 240(8), 1087–1098.

    CAS  Google Scholar 

  • Gauthier, J., & Turtle, C. J. (2018). Insights into cytokine release syndrome and neurotoxicity after CD19-specific CAR-T cell therapy. Current Research in Translational Medicine, 66(2), 50–52.

    PubMed  PubMed Central  Google Scholar 

  • Genssler, S., Burger, M. C., Zhang, C., et al. (2016). Dual targeting of glioblastoma with chimeric antigen receptor-engineered natural killer cells overcomes heterogeneity of target antigen expression and enhances antitumor activity and survival. Oncoimmunology, 5(4), e1119354.

    PubMed  Google Scholar 

  • Goff, S. L., Morgan, R. A., Yang, J. C., et al. (2019). Pilot trial of adoptive transfer of chimeric antigen receptor-transduced T cells targeting EGFRvIII in patients with glioblastoma. Journal of Immunotherapy, 42(4), 126–135.

    CAS  PubMed  Google Scholar 

  • Gousias, K., Markou, M., Voulgaris, S., et al. (2009). Descriptive epidemiology of cerebral gliomas in northwest Greece and study of potential predisposing factors, 2005–2007. Neuroepidemiology, 33(2), 89–95.

    CAS  PubMed  Google Scholar 

  • Gross, G., Waks, T., & Eshhar, Z. (1989). Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proceedings of the National Academy of Sciences of the United States of America, 86(24), 10024–10028.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gust, J., Hay, K. A., Hanafi, L. A., et al. (2017). Endothelial activation and blood–brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discovery, 7(12), 1404–1419.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hao, C., Parney, I. F., Roa, W. H., Turner, J., Petruk, K. C., & Ramsay, D. A. (2002). Cytokine and cytokine receptor mRNA expression in human glioblastomas: Evidence of Th1, Th2 and Th3 cytokine dysregulation. Acta Neuropathologica, 103(2), 171–178.

    CAS  PubMed  Google Scholar 

  • Hart, D. N., & Fabre, J. W. (1981). Demonstration and characterization of Ia-positive dendritic cells in the interstitial connective tissues of rat heart and other tissues, but not brain. Journal of Experimental Medicine, 154(2), 347–361.

    CAS  PubMed  Google Scholar 

  • Hegde, M., Corder, A., Chow, K. K., et al. (2013). Combinational targeting offsets antigen escape and enhances effector functions of adoptively transferred T cells in glioblastoma. Molecular Therapy, 21(11), 2087–2101.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hombach, A., Wieczarkowiecz, A., Marquardt, T., et al. (2001). Tumor-specific T cell activation by recombinant immunoreceptors: CD3 zeta signaling and CD28 costimulation are simultaneously required for efficient IL-2 secretion and can be integrated into one combined CD28/CD3 zeta signaling receptor molecule. The Journal of Immunology, 167(11), 6123–6131.

    CAS  PubMed  Google Scholar 

  • Hong, J. J., Rosenberg, S. A., Dudley, M. E., et al. (2010). Successful treatment of melanoma brain metastases with adoptive cell therapy. Clinical Cancer Research, 16(19), 4892–4898.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hussain, S. F., Yang, D., Suki, D., Aldape, K., Grimm, E., & Heimberger, A. B. (2006). The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses. Neuro-Oncology, 8(3), 261–279.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Iorgulescu, J. B., Gokhale, P. C., Speranza, M. C., et al. (2021). Concurrent dexamethasone limits the clinical benefit of immune checkpoint blockade in glioblastoma. Clinical Cancer Research, 27(1), 276–287.

    CAS  PubMed  Google Scholar 

  • Jensen, M. C., Popplewell, L., Cooper, L. J., et al. (2010). Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. Biology of Blood and Marrow Transplantation, 16(9), 1245–1256.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Joshi, B. H., Plautz, G. E., & Puri, R. K. (2000). Interleukin-13 receptor alpha chain: A novel tumor-associated transmembrane protein in primary explants of human malignant gliomas. Cancer Research, 60(5), 1168–1172.

    CAS  PubMed  Google Scholar 

  • Kershaw, M. H., Westwood, J. A., Parker, L. L., et al. (2006). A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clinical Cancer Research, 12(20 Pt 1), 6106–6115.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Koka, V., Potti, A., Forseen, S. E., et al. (2003). Role of Her-2/neu overexpression and clinical determinants of early mortality in glioblastoma multiforme. American Journal of Clinical Oncology, 26(4), 332–335.

    PubMed  Google Scholar 

  • Lamers, C. H., Sleijfer, S., Vulto, A. G., et al. (2006). Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: First clinical experience. Journal of Clinical Oncology, 24(13), e20-22.

    PubMed  Google Scholar 

  • Larjavaara, S., Mantyla, R., Salminen, T., et al. (2007). Incidence of gliomas by anatomic location. Neuro-Oncology, 9(3), 319–325.

    PubMed  PubMed Central  Google Scholar 

  • Lee, D. W., Gardner, R., Porter, D. L., et al. (2014). Current concepts in the diagnosis and management of cytokine release syndrome. Blood, 124(2), 188–195.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liu, G., Ying, H., Zeng, G., Wheeler, C. J., Black, K. L., & Yu, J. S. (2004). HER-2, gp100, and MAGE-1 are expressed in human glioblastoma and recognized by cytotoxic T cells. Cancer Research, 64(14), 4980–4986.

    CAS  PubMed  Google Scholar 

  • Liu, H., Jacobs, B. S., Liu, J., et al. (2000). Interleukin-13 sensitivity and receptor phenotypes of human glial cell lines: Non-neoplastic glia and low-grade astrocytoma differ from malignant glioma. Cancer Immunology, Immunotherapy, 49(6), 319–324.

    CAS  PubMed  Google Scholar 

  • Lupu, R., Colomer, R., Kannan, B., & Lippman, M. E. (1992). Characterization of a growth factor that binds exclusively to the erbB-2 receptor and induces cellular responses. Proceedings of the National Academy of Sciences of the United States of America, 89(6), 2287–2291.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Maude, S. L., Laetsch, T. W., Buechner, J., et al. (2018). Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. New England Journal of Medicine, 378(5), 439–448.

    CAS  PubMed  Google Scholar 

  • Migliorini, D., Dietrich, P. Y., Stupp, R., Linette, G. P., Posey, A. D., Jr., & June, C. H. (2018). CAR T-cell therapies in glioblastoma: A first look. Clinical Cancer Research, 24(3), 535–540.

    CAS  PubMed  Google Scholar 

  • Neelapu, S. S., Locke, F. L., Bartlett, N. L., et al. (2017). Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. New England Journal of Medicine, 377(26), 2531–2544.

    CAS  PubMed  Google Scholar 

  • Neftel, C., Laffy, J., Filbin, M. G., et al. (2019). An integrative model of cellular states, plasticity, and genetics for glioblastoma. Cell, 178(4), 835-849 e821.

    CAS  PubMed  PubMed Central  Google Scholar 

  • O’Rourke, D. M., Nasrallah, M. P., Desai, A., et al. (2017). A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Science Translational Medicine. https://doi.org/10.1126/scitranslmed.aaa0984

    Article  PubMed  PubMed Central  Google Scholar 

  • Ostrom, Q. T., Bauchet, L., Davis, F. G., et al. (2014). The epidemiology of glioma in adults: A “state of the science” review. Neuro-Oncology, 16(7), 896–913.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Park, J. H., Riviere, I., Gonen, M., et al. (2018). Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. New England Journal of Medicine, 378(5), 449–459.

    CAS  PubMed  Google Scholar 

  • Pegram, H. J., Lee, J. C., Hayman, E. G., et al. (2012). Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. Blood, 119(18), 4133–4141.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Petersen, C. T., & Krenciute, G. (2019). Next generation CAR T cells for the immunotherapy of high-grade glioma. Frontiers in Oncology, 9, 69.

    PubMed  PubMed Central  Google Scholar 

  • Press, M. F., Cordon-Cardo, C., & Slamon, D. J. (1990). Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissues. Oncogene, 5(7), 953–962.

    CAS  PubMed  Google Scholar 

  • Rapoport, A. P., Stadtmauer, E. A., Binder-Scholl, G. K., et al. (2015). NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nature Medicine, 21(8), 914–921.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ricklefs, F. L., Alayo, Q., Krenzlin, H., et al. (2018). Immune evasion mediated by PD-L1 on glioblastoma-derived extracellular vesicles. Science Advances, 4(3), eaar2766.

    PubMed  PubMed Central  Google Scholar 

  • Sampson, J. H., Heimberger, A. B., Archer, G. E., et al. (2010). Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. Journal of Clinical Oncology, 28(31), 4722–4729.

    PubMed  PubMed Central  Google Scholar 

  • Santomasso, B. D., Park, J. H., Salloum, D., et al. (2018). Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia. Cancer Discovery, 8(8), 958–971.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sims, J. S., Grinshpun, B., Feng, Y., et al. (2016). Diversity and divergence of the glioma-infiltrating T-cell receptor repertoire. Proceedings of the National Academy of Sciences of the United States of America, 113(25), E3529-3537.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sugawa, N., Ekstrand, A. J., James, C. D., & Collins, V. P. (1990). Identical splicing of aberrant epidermal growth factor receptor transcripts from amplified rearranged genes in human glioblastomas. Proceedings of the National Academy of Sciences of the United States of America, 87(21), 8602–8606.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Thaci, B., Brown, C. E., Binello, E., Werbaneth, K., Sampath, P., & Sengupta, S. (2014). Significance of interleukin-13 receptor alpha 2-targeted glioblastoma therapy. Neuro-Oncology, 16(10), 1304–1312.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tu, M., Wange, W., Cai, L., Zhu, P., Gao, Z., & Zheng, W. (2016). IL-13 receptor alpha2 stimulates human glioma cell growth and metastasis through the Src/PI3K/Akt/mTOR signaling pathway. Tumour Biology, 37(11), 14701–14709.

    CAS  PubMed  Google Scholar 

  • Verhaak, R. G., Hoadley, K. A., Purdom, E., et al. (2010). Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell, 17(1), 98–110.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang, D., Starr, R., Chang, W. C., et al. (2020). Chlorotoxin-directed CAR T cells for specific and effective targeting of glioblastoma. Science Translational Medicine. https://doi.org/10.1126/scitranslmed.aaw2672

    Article  PubMed  PubMed Central  Google Scholar 

  • Wikstrand, C. J., McLendon, R. E., Friedman, A. H., & Bigner, D. D. (1997). Cell surface localization and density of the tumor-associated variant of the epidermal growth factor receptor, EGFRvIII. Cancer Research, 57(18), 4130–4140.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr. Julie Ostberg and Ms. Andrea Lynch for their assistance in manuscript preparation.

Funding

Funding for COH clinical trial by Mustang Biol, Inc.

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Authors and Affiliations

  1. Division of Neurosurgery, City of Hope National Medical Center, Duarte, CA, 91010, USA

    Lisa Feldman & Behnam Badie

  2. Departments of Cancer Immunotherapy & Tumor Immunology and Hematology & Hematopoietic Call Transplantation, City of Hope National Medical Center, Duarte, CA, 91010, USA

    Christine Brown

  3. Division of Neurosurgery, City of Hope National Medical Center, MOB 2001, 1500 East Duarte Road, Duarte, CA, 91010, USA

    Lisa Feldman

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  1. Lisa Feldman
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LF drafted the manuscript. BB and CB revised the manuscript critically for important intellectual content and approved the version to be published.

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Correspondence to Lisa Feldman.

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Lisa Feldman has no financial relationships to disclose. None. Christine Brown receives licensing (IP and royalties) and consulting payments from Mustang Bio., Inc. Behnam Badie receives licensing (IP and royalties) payments from Mustang Bio., Inc.

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Feldman, L., Brown, C. & Badie, B. Chimeric Antigen Receptor (CAR) T Cell Therapy for Glioblastoma. Neuromol Med 24, 35–40 (2022). https://doi.org/10.1007/s12017-021-08689-5

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