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

Landgraf et al. developed a chimeric antigen receptor (CAR) platform that functions as a modular system.convertible(TM)-T cells are designed to kill antigen-expressing target cells only in the presence of ligands fused to antigen-targeting antibodies (MicAbody(TM)). This method provides a wide dosing window while minimizing toxicity. We have developed a chimeric antigen receptor (CAR) platform that functions as a modular system to address limitations of traditional CAR therapies. An inert form of the human NKG2D extracellular domain (iNKG2D) was engineered as the ectodomain of the CAR to generateconvertibleCAR(TM)-T cells. These cells were specifically directed to kill antigen-expressing target cells only in the presence of an activating bispecific adapter 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 andconvertibleCAR-T cells. We have also demonstrated that the exclusive ligand-receptor partnering enabled the targeted delivery of a mutant form of IL-2 to selectively promote the expansion ofconvertibleCAR-T cells in vitro and in vivo. By altering the Fv domains of the MicAbody or the payload fused to the orthogonal ligand,convertibleCAR-T cells can be readily targeted or regulated.