Novel chimeric antigen receptor (CAR) T-cell engineering concepts. Multi-specific CAR T-cells have been designed to target multiple antigens using either “AND” or “OR” gates. Tandem CAR T-cells are composed of a single CAR structure that targets 2 tumor antigens with a distinct antigen recognition domain (scFv) linked consecutively with a single intracellular domain. Furthermore, CARs integrated with synthetic Notch Receptor (synNotch) receptors^23,24 or Synthetic Intramembrane Proteolysis Receptors (SNIPRs)²⁴ allow central nervous system (CNS) tumor- or CNS tissue-specific induction of CAR. Another on-off CAR design approach is represented by split CARs characterized by their capacity to target 2 independent antigens with the co-stimulatory domains split by 2 CARs. In split CARs, CAR T-cell activation requires the presence of both antigens to assemble the functional co-stimulatory domain. Furthermore, split CAR constructs integrating drug-responsible domains (degrons) allow the on/off switch CAR signals to be controlled by small molecule drugs.²⁵ Alternatively, drug-induced dimerization can serve as an ON-switch for split CAR circuit design.²⁶ To provide more versatility of antigen-specificity, Universal CARs (Uni-CARs) have been developed whose antigen-binding domains bind to exogenous antigen-specific molecules, such as scFV, monoclonal antibodies, or tumor-specific ligands.²⁷ Recent genomic engineering approaches have reported further improved CAR functionality. For example, CRISPR/Cas9 gene screening and editing have been used to disrupt inhibitory genes or endogenous T-cell receptor expression (TRAC-CAR).