Liu Junchen, Dai Kun, Saliu Muhammad Auwal, Salisu Mansur Dabai, Gan Jiangyu, Afolabi Lukman Olalekan, Yan Dehong, Zhang Guizhong, Liu Maoxuan, Wan Xiaochun
Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
University of Chinese Academy of Sciences, Beijing, China.
Front Immunol. 2025 Jan 14;15:1519777. doi: 10.3389/fimmu.2024.1519777. eCollection 2024.
Chimeric antigen receptor T-cell (CAR-T) therapies have shown promise in glioblastoma clinical studies, but responses remain inconsistent due to heterogeneous tumor antigen expression and immune evasion post-treatment. NKG2D CAR-T cells have demonstrated a favorable safety profile in patients with hematologic tumors, and showed robust antitumor efficacy in various xenograft models, including glioblastoma. However, malignant glioma cells evade immunological surveillance by reducing NKG2D ligands expression or cleavage. To enhance the effectiveness of NKG2D CAR-T therapy, we investigated the potential of combining NKG2D CAR-T with approved drugs that cross the blood-brain barrier and augment NKG2D ligands expression in glioma cells. We found that sodium valproate (VPA), an antiepileptic drug, significantly increased surface NKG2D ligands expression on glioblastoma cells at a sublethal concentration. VPA treatment enhanced the susceptibility of glioblastoma cells to NKG2D CAR-T mediated cytotoxicity in both 2D monolayer and 3D tumor spheroid models . Moreover, VPA-treated glioblastoma cells stimulated CAR-T cells to produce higher levels of inflammatory cytokines (IL-2, IFN-γ, and IL-6). Mechanistically, VPA upregulated NKG2D ligands expression via the PI3K/Akt signaling pathway. Additionally, VPA treatment augmented the antitumor activity of NKG2D CAR-T cells in a glioblastoma xenograft model . These preclinical results suggest that combining VPA with NKG2D CAR-T therapy represents a promising strategy for improving glioblastoma treatment, warranting further clinical investigation.
嵌合抗原受体T细胞（CAR-T）疗法在胶质母细胞瘤临床研究中已显示出前景，但由于肿瘤抗原表达异质性和治疗后免疫逃逸，反应仍然不一致。NKG2D CAR-T细胞在血液系统肿瘤患者中已显示出良好的安全性，并在包括胶质母细胞瘤在内的各种异种移植模型中表现出强大的抗肿瘤功效。然而，恶性胶质瘤细胞通过降低NKG2D配体表达或裂解来逃避免疫监视。为了提高NKG2D CAR-T疗法的有效性，我们研究了将NKG2D CAR-T与可穿过血脑屏障并增强胶质瘤细胞中NKG2D配体表达的已批准药物联合使用的潜力。我们发现，丙戊酸钠（VPA），一种抗癫痫药物，在亚致死浓度下可显著增加胶质母细胞瘤细胞表面NKG2D配体的表达。在二维单层和三维肿瘤球体模型中，VPA处理均增强了胶质母细胞瘤细胞对NKG2D CAR-T介导的细胞毒性的敏感性。此外，VPA处理的胶质母细胞瘤细胞刺激CAR-T细胞产生更高水平的炎性细胞因子（IL-2、IFN-γ和IL-6）。机制上，VPA通过PI3K/Akt信号通路上调NKG2D配体的表达。此外，VPA处理增强了NKG2D CAR-T细胞在胶质母细胞瘤异种移植模型中的抗肿瘤活性。这些临床前结果表明，将VPA与NKG2D CAR-T疗法联合使用是改善胶质母细胞瘤治疗的一种有前景的策略，值得进一步的临床研究。
