convertibleCARs: A chimeric antigen receptor system for flexible control of activity and antigen targeting

ABSTRACT We have developed a chimeric antigen receptor (CAR) platform that functions as a modular system to address limitations of current CAR therapies. An inert form of the NKG2D extracellular domain (iNKG2D) was used as the ectodomain of the CAR to generate convertible CAR™-T cells. These cells were activated only when an immunological synapse was formed with an antigenic target, mediated by a bispecific adaptor comprised of an iNKG2D-exclusive ULBP2-based ligand fused to an antigen-targeting antibody (MicAbody TM ). Efficacy against Raji tumors in NSG mice was dependent upon doses of both a rituximab-based MicAbody and convertible CAR-T cells. We have also demonstrated that the exclusive ligand-receptor partnering enabled the targeted delivery of a mutant form of IL-2 to exclusively promote the expansion of convertible CAR-T cells in vitro and in vivo . By altering the Fv domains of the MicAbody or the payload fused to the orthogonal ligand, convertible CAR-T cells can be readily targeted or regulated.