Enhancing Glioblastoma Immunotherapy with Integrated Chimeric Antigen Receptor T Cells through the Re-Education of Tumor-Associated Microglia and Macrophages

• Published in: ACS nano Vol. 18; no. 17; pp. 11165 - 11182
• Main Authors: Zhu, Nianci, Chen, Sijia, Jin, Yu, Wang, Meng, Fang, Luyao, Xue, Lingjing, Hua, Dexiang, Zhang, Ziyao, Jia, Meng, Hao, Meixi, Zhang, Can
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 30-04-2024
• Subjects: Aminopyridines; Animals; Brain Neoplasms - drug therapy; Brain Neoplasms - immunology; Brain Neoplasms - pathology; Brain Neoplasms - therapy; Cell Line, Tumor; Glioblastoma - drug therapy; Glioblastoma - immunology; Glioblastoma - pathology; Glioblastoma - therapy; Humans; Immunotherapy; Immunotherapy, Adoptive; Liposomes - chemistry; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Mice; Microglia - drug effects; Microglia - immunology; Microglia - metabolism; Pyrroles - chemistry; Pyrroles - pharmacology; Receptors, Chimeric Antigen - immunology; Receptors, Chimeric Antigen - metabolism; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Tumor Microenvironment - drug effects; Tumor Microenvironment - immunology; Tumor-Associated Macrophages - drug effects; Tumor-Associated Macrophages - immunology; Tumor-Associated Macrophages - metabolism; blood−brain barrier; cell−drug integrated technology; glioblastoma; re-educated TAMs; CAR-T cells
• ISSN: 1936-0851; 1936-086X
• DOI: 10.1021/acsnano.4c00050

Glioblastoma (GBM) is an aggressive brain cancer that is highly resistant to treatment including chimeric antigen receptor (CAR)-T cells. Tumor-associated microglia and macrophages (TAMs) are major contributors to the immunosuppressive GBM microenvironment, which promotes tumor progression and treatment resistance. Hence, the modulation of TAMs is a promising strategy for improving the immunotherapeutic efficacy of CAR-T cells against GBM. Molecularly targeting drug pexidartinib (PLX) has been reported to re-educate TAMs toward the antitumorigenic M1-like phenotype. Here, we developed a cell–drug integrated technology to reversibly conjugate PLX-containing liposomes (PLX-Lip) to CAR-T cells and establish tumor-responsive integrated CAR-T cells (PLX-Lip/AZO-T cells) as a combination therapy for GBM. We used a mouse model of GBM to show that PLX-Lip was stably maintained on the surface of PLX-Lip/AZO-T cells in circulation and these cells could transmigrate across the blood–brain barrier and deposit PLX-Lip at the tumor site. The uptake of PLX-Lip by TAMs effectively re-educated them into the M1-like phenotype, which in turn boosted the antitumor function of CAR-T cells. GBM tumor growth was completely eradicated in 60% of the mice after receiving PLX-Lip/AZO-T cells and extended their overall survival time beyond 50 days; in comparison, the median survival time of mice in other treatment groups did not exceed 35 days. Overall, we demonstrated the successful fusion of CAR-T cells and small-molecule drugs with the cell–drug integrated technology. These integrated CAR-T cells provided a superior combination strategy for GBM treatment and presented a reference for the construction of integrated cell-based drugs.