Journal for immunotherapy of cancer
Local T-cell engager secretion reprograms endogenous antitumor immunity and enhances CAR-T cell persistence in solid tumors
By Arroyo-Ródenas J, Chen A, Tonne J and 15 others.
Abstract
Background
Adoptive T-cell therapies can mediate potent antitumor activity, yet their efficacy against solid tumors remains limited by antigen heterogeneity, tumor escape, and insufficient induction of endogenous antitumor immunity. Whether distinct T cell-redirecting strategies differentially engage host immune responses that contribute to durable tumor control remains poorly understood.
Methods
Here, we compared conventional chimeric antigen receptor (CAR)-T cells, systemic T-cell engagers (TCEs), TCE-secreting (STAb)-T cells, and dual-targeting CAR–STAb-T cells in immunocompetent mouse models of high-grade glioma. CAR–STAb-T cells combined an EGFRvIII-specific CAR with local secretion of a B7-H3-targeted TCE, enabling simultaneous direct tumor targeting and recruitment of endogenous bystander T cells. Using heterogeneous tumor models, together with functional immune profiling and T-cell receptor repertoire sequencing, we investigated the mechanisms underlying durable antitumor responses.