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Design of Switchable Chimeric Antigen Receptor T Cells Targeting Breast Cancer
Author(s) -
Cao Yu,
Rodgers David T.,
Du Juanjuan,
Ahmad Insha,
Hampton Eric N.,
Ma Jennifer S. Y.,
Mazagova Magdalena,
Choi Seihyun,
Yun Hwa Young,
Xiao Han,
Yang Pengyu,
Luo Xiaozhou,
Lim Reyna K. V.,
Pugh Holly M.,
Wang Feng,
Kazane Stephanie A.,
Wright Timothy M.,
Kim Chan Hyuk,
Schultz Peter G.,
Young Travis S.
Publication year - 2016
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201601902
Subject(s) - chimeric antigen receptor , trastuzumab , cancer research , epitope , antigen , immunotherapy , cancer immunotherapy , t cell , antibody , chemistry , breast cancer , cancer , immunology , biology , medicine , immune system
Abstract Chimeric antigen receptor T (CAR‐T) cells have demonstrated promising results against hematological malignancies, but have encountered significant challenges in translation to solid tumors. To overcome these hurdles, we have developed a switchable CAR‐T cell platform in which the activity of the engineered cell is controlled by dosage of an antibody‐based switch. Herein, we apply this approach to Her2‐expressing breast cancers by engineering switch molecules through site‐specific incorporation of FITC or grafting of a peptide neo‐epitope (PNE) into the anti‐Her2 antibody trastuzumab (clone 4D5). We demonstrate that both switch formats can be readily optimized to redirect CAR‐T cells (specific for the corresponding FITC or PNE) to Her2‐expressing tumor cells, and afford dose‐titratable activation of CAR‐T cells ex vivo and complete clearance of the tumor in rodent xenograft models. This strategy may facilitate the application of immunotherapy to solid tumors by affording comparable efficacy with improved safety owing to switch‐based control of the CAR‐T response.