Single CAR-Dual target: Intracranial Delivery of Anti-PD-L1 CAR T Cells Effectively Eradicates Glioma and Immunosuppressive Cells in the Tumor Microenvironment.
Ulloa-Navas, M. J.; Luo, Y.; Sanchez-Garavito, J. E.; Qie, Y.; Jones, V. K.; Brooks, M. M.; Aramburu-Berckemeyer, M. M.; Hundal, T.; Gadd, M. E.; Gomez-Palmero, C.; Brim, A. D.; Rivera-Valentin, R.; Basil, A. N.; Tutor-new, F. Q.; Hirdler, J. B.; Irani, S. R.; Dronca, R.; Kharfan-Dabaja, M.; Ren, Y.; Dong, H.; Qin, H.; Quinones-Hinojosa, A.
Show abstract
With the goal to overcome the limited treatment options and poor prognosis of glioblastoma (GBM), we have developed a PD-L1-targeting CAR T cell therapy, MC9999. In vitro experiments with MC9999 CAR T cells derived from GBM patients exhibited potent, antigen-specific cytotoxicity against autologous tumor cells and immunosuppressive cells within the tumor microenvironment (TME). In an orthotopic GBM model using patient-derived brain tumor-initiating cells, the intracranial delivery of MC9999 CAR T cells eradicated established tumors and improved survival. Single-cell RNA sequencing indicated that MC9999 CAR T cells activate interferon pathways, leading to GBM cell apoptosis. Multi-immunohistochemistry confirmed localized PD-L1 expression on tumor cells and TME-residing macrophages, but not in neurons or glia in patient tissue. The local delivery of MC9999 CAR T cells may be a safe, effective approach for simultaneously targeting PD-L1-positive GBM and its immunosuppressive TME and a strategy to overcome immune evasion and enhance the therapeutic potency of CAR T cell therapy against GBM.
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