Locally secreted BiTEs complement CAR T cells by enhancing killing of antigen heterogeneous solid tumors

作者：Yin, Yibo; Rodriguez, Jesse L.; Li, Nannan; Thokala, Radhika; Nasrallah, MacLean P.; Hu, Li; Zhang, Logan; Zhang, Jiasi Vicky; Logun, Meghan T.; Kainth, Devneet; Haddad, Leila; Zhao, Yang; Wu, Tong; Johns, Emily X.; Long, Yu; Liang, Hongsheng; Qi, Jiping; Zhang, Xiangtong; Binder, Zev A.; Lin, Zhiguo^*; O'Rourke, Donald M.^*

来源：Molecular Therapy, 2022, 30(7): 2537-2553.

DOI：10.1016/j.ymthe.2022.05.011

• CHAIN ANTIBODY CONSTRUCTS
• GROWTH-FACTOR RECEPTOR
• MALIGNANT GLIOMAS
• BLINATUMOMAB
• GLIOBLASTOMA
• EGFR
• STRATEGIES
• EPITOPE

Bispecific T cell engagers (BiTEs) are bispecific antibodies that redirect T cells to target antigen-expressing tumors. We hy-pothesized that BiTE-secreting T cells could be a valuable ther-apy in solid tumors, with distinct properties in mono-or multi -valent strategies incorporating chimeric antigen receptor (CAR) T cells. Glioblastomas represent a good model for solid tumor heterogeneity, representing a significant therapeu-tic challenge. We detected expression of tumor-associated epidermal growth factor receptor (EGFR), EGFR variant III, and interleukin-13 receptor alpha 2 (IL13R alpha 2) on glioma tissues and cancer stem cells. These antigens formed the basis of a multivalent approach, using a conformation-specific tu-mor-related EGFR targeting antibody (806) and Hu08, an IL13R alpha 2-targeting antibody, as the single chain variable frag-ments to generate new BiTE molecules. Compared with CAR T cells, BiTE T cells demonstrated prominent activation, cyto-kine production, and cytotoxicity in response to target-positive gliomas. Superior response activity was also demonstrated in BiTE-secreting bivalent T cells compared with bivalent CAR T cells in a glioma mouse model at early phase, but not in the long term. In summary, BiTEs secreted by mono-or multi-val-ent T cells have potent anti-tumor activity in vitro and in vivo with significant sensitivity and specificity, demonstrating a promising strategy in solid tumor therapy.

• 单位
  1; 哈尔滨医科大学