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Chimeric antigen receptor (CAR)-T-cell therapy for solid tumors is limited due to heterogeneous target antigen expression and outgrowth of tumors lacking the antigen targeted by CAR-T cells directed against single antigens. Here, we developed a bicistronic construct to drive expression of a CAR specific for EGFRvIII, a glioblastoma-specific tumor antigen, and a bispecific T-cell engager (BiTE) against EGFR, an antigen frequently overexpressed in glioblastoma but also expressed in normal tissues. CART.BiTE cells secreted EGFR-specific BiTEs that redirect CAR-T cells and recruit untransduced bystander T cells against wild-type EGFR. EGFRvIII-specific CAR-T cells were unable to completely treat tumors with heterogenous EGFRvIII expression, leading to outgrowth of EGFRvIII-negative, EGFR-positive glioblastoma. However, CART.BiTE cells eliminated heterogenous tumors in mouse models of glioblastoma. BiTE-EGFR was locally effective but was not detected systemically after intracranial delivery of CART.BiTE cells. Unlike EGFR-specific CAR-T cells, CART.BiTE cells did not result in toxicity against human skin grafts in vivo.

Citation

Bryan D Choi, Xiaoling Yu, Ana P Castano, Amanda A Bouffard, Andrea Schmidts, Rebecca C Larson, Stefanie R Bailey, Angela C Boroughs, Matthew J Frigault, Mark B Leick, Irene Scarfò, Curtis L Cetrulo, Shadmehr Demehri, Brian V Nahed, Daniel P Cahill, Hiroaki Wakimoto, William T Curry, Bob S Carter, Marcela V Maus. CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity. Nature biotechnology. 2019 Sep;37(9):1049-1058

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PMID: 31332324

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