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

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.

Automated summary

Bispecific T cell engagers (BiTEs), which redirect T cells to target antigen-expressing tumors, have potential therapeutic effects in solid tumors. In our study using glioblastomas as a model, we found that BiTE-secreting T cells showed prominent activation, cytokine production, and cytotoxicity against the tumor antigens compared to CAR T cells. Bivalent BiTE-secreting T cells also demonstrated superior response activity in the early phase of a glioma mouse model. This suggests that BiTEs secreted by mono- or multi-valent T cells have potent anti-tumor activity, making them a promising strategy in solid tumor therapy.