Single CAR-Dual target: Intracranial Delivery of Anti-PD-L1 CAR T Cells Effectively Eradicates Glioma and Immunosuppressive Cells in the Tumor Microenvironment

作者：María José Ulloa-Navas, Yan Luo, Jesus Emiliano Sanchez-Garavito, Yaqing Qie, Vanessa K. Jones, Mieu Brooks, Manuela Maria Aramburu-Berckemeyer, Tanya Hundal, Martha E. Gadd, Cristina Gomez-Palmero, Andrew David Brim, Rocío K. Rivera-Valentín, Aleeshba Basil, Frederick Q Tutor‐New, Jacob B. Hirdler, Sarosh R. Irani, Roxana Dronca, Mohamed A. Kharfan‐Dabaja, Yingxue Ren, Haidong Dong, Hong Qin, Alfredo Quiñones‐Hinojosa · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2024 · DOI：10.1101/2024.11.22.624897 · 被引用次数：1 · 研究领域：CAR-T cell therapy research、Immunotherapy and Immune Responses、Advancements in Semiconductor Devices and Circuit Design

SUMMARY 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.