Chimeric antigen receptor (CAR) signalling system

A nucleic acid comprising a nucleotide sequence encoding a chimeric antigen receptor (CAR) signalling system, said signalling system comprising;

• (i) a receptor component comprising an extracellular antigen-binding domain, a transmembrane domain and an intracellular first chemical inducer of dimerization (CID) binding domain (CBD1);
• and
• (ii) a plurality of soluble intracellular signalling components that localise to the cytoplasm when expressed in a cell, each intracellular signalling component comprising a T cell receptor signalling domain and a second CID binding domain (CBD2), wherein the CBD2 of each intracellular signalling component recognises the same CID but the T cell receptor signalling domains comprise different endodomains;
• wherein the nucleic acid sequence encodes a polypeptide that comprises the receptor component and the intracellular signalling components, joined by cleavage sites;
• wherein CBD1 and CBD2 are capable of simultaneously binding to a CID;
• wherein, in the absence of CID, binding of the antigen-binding domain to antigen does not result in signalling through the T cell receptor signalling domain;
• whereas, in the presence of CID, the receptor component and the intracellular signalling component heterodimerize and binding of the antigen-binding domain to antigen results in T cell receptor signalling through the T cell receptor signalling domain.