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. 2019 Sep;37(9):1049-1058.
doi: 10.1038/s41587-019-0192-1. Epub 2019 Jul 22.

CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity

Bryan D Choi  1   2 , Xiaoling Yu  1 , Ana P Castano  1 , Amanda A Bouffard  1 , Andrea Schmidts  1 , Rebecca C Larson  1 , Stefanie R Bailey  1 , Angela C Boroughs  1 , Matthew J Frigault  1   3 , Mark B Leick  1 , Irene Scarfò  1 , Curtis L Cetrulo  4 , Shadmehr Demehri  5 , Brian V Nahed  2 , Daniel P Cahill  2 , Hiroaki Wakimoto  2 , William T Curry  2 , Bob S Carter  2 , Marcela V Maus  6   7
Affiliations

CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity

Bryan D Choi et al. Nat Biotechnol. 2019 Sep.

Abstract

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.

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Comment in

  • Steering CARs in the right direction.
    Dart A. Dart A. Nat Rev Cancer. 2019 Sep;19(9):487. doi: 10.1038/s41568-019-0189-6. Nat Rev Cancer. 2019. PMID: 31371792 No abstract available.
  • CAR Ts BiTE in brain.
    Flemming A. Flemming A. Nat Rev Immunol. 2019 Sep;19(9):535. doi: 10.1038/s41577-019-0211-y. Nat Rev Immunol. 2019. PMID: 31384014 No abstract available.

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