Author:
Hotblack Alastair,Kokalaki Evangelia K.,Palton Morgan J.,Cheung Gordon Weng-Kit,Williams Iwan P.,Manzoor Somayya,Grothier Thomas I.,Piapi Alice,Fiaccadori Valeria,Wawrzyniecka Patrycja,Roddy Harriet A.,Agliardi Giulia,Roddie Claire,Onuoha Shimobi,Thomas Simon,Cordoba Shaun,Pule Martin
Abstract
AbstractChimeric antigen receptor (CAR) T cells are a promising form of cancer immunotherapy, although they are often associated with severe toxicities. Here, we present a split-CAR design incorporating separate antigen recognition and intracellular signaling domains. These exploit the binding between the tetracycline repressor protein and a small peptide sequence (TIP) to spontaneously assemble as a functional CAR. Addition of the FDA-approved, small molecule antibiotic minocycline, acts as an “off-switch” by displacing the signaling domain and down-tuning CAR T activity. Here we describe the optimization of this split-CAR approach to generate a CAR in which cytotoxicity, cytokine secretion and proliferation can be inhibited in a dose-dependent and reversible manner. Inhibition is effective during on-going CAR T cell activation and inhibits activation and tumor control in vivo. This work shows how optimization of split-CAR structure affects function and adds a novel design allowing easy CAR inhibition through an FDA-approved small molecule.
Publisher
Springer Science and Business Media LLC
Cited by
11 articles.
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