Abstract
Abstract Glioblastoma is a devastating disease with poor responses to all current therapies. Chimeric antigen receptor (CAR) T cell therapy has achieved impressive success against hematological malignancies but produces responses in only a limited number of glioblastoma patients. Here, we developed a novel platform for CAR constructs using de novo designed protein binders to target tumor antigens. We firstly designed a binder CAR targeting epidermal growth factor receptor (EGFR), which is highly expressed in glioblastoma, to validate the feasibility of our platform. Our EGFR binder CAR design promoted CAR T cell proliferation, cytotoxic cytokine secretion and exhaustion resistance, leading to better antitumor performance both in vitro and in vivo. Bulk and single-cell transcriptional profiling of binder CAR T cells revealed an underlying mechanism involving enhanced effector activity and reduced exhaustion responses. Mechanismly, the binder CARs exhibited higher surface expression and greater resistance to degradation triggered by tumor antigens. Moreover, we designed and engineered a novel CD276 binder CAR T cell product and verified its antitumor function, further demonstrating the general applicability of our binder-based CAR platform. Overall, our study provides an alternative avenue for the design of a CAR antigen-binding domain to potentiate CAR T cell antitumor efficacy.
Published Version
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