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

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

in 631/61/201 / 631/61/2297 / 631/61/51/1844 / 631/61/51/2318 / 692/699/67/1922 / Agriculture / Animal models / Animals / Antibodies, Bispecific - therapeutic use / Antigens / Antigens, Neoplasm - immunology / Antigens, Neoplasm - metabolism / Biocompatibility / Bioinformatics / Biomedical and Life Sciences / Biomedical Engineering/Biotechnology / Biomedicine / Biotechnology / Cell Differentiation / Cell therapy / Chimeric antigen receptors / Epidermal growth factor receptors / ErbB Receptors / Glioblastoma / Glioblastoma - immunology / Glioblastoma - metabolism / Glioblastoma - therapy / Grafts / Humans / Life Sciences / Lymphocytes / Lymphocytes T / Mice / Neoplasms, Experimental / Physiological aspects / Receptors, Chimeric Antigen / Skin / Skin grafts / Solid tumors / T cells / T-Lymphocytes - physiology / Toxicity / Tumors

2019

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2019

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2019

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Journal Article

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

Scarfò, Irene,

Carter, Bob S.,

Yu, Xiaoling,

Bouffard, Amanda A.,

Boroughs, Angela C.,

Cahill, Daniel P.,

Larson, Rebecca C.,

Wakimoto, Hiroaki,

Maus, Marcela V.,

Curry, William T.,

Bailey, Stefanie R.,

Castano, Ana P.,

Cetrulo, Curtis L.,

Choi, Bryan D.,

Nahed, Brian V.,

Schmidts, Andrea,

Demehri, Shadmehr,

Leick, Mark B.,

Frigault, Matthew J.

2019

Overview

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. BiTE-secreting CAR-T cells overcome antigen escape from EGFRvIII-targeted therapy for glioblastoma.

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Nature Publishing Group US,Nature Publishing Group

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