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 convertibleCAR™-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 rituximabbased MicAbody and convertibleCAR-T cells. We have also demonstrated that the exclusive ligandreceptor partnering enabled the targeted delivery of a mutant form of IL-2 to exclusively promote the expansion of convertibleCAR-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.

Exploiting the CRISPR‐Cas9 gene‐editing system for human cancers and immunotherapy

“…Interestingly, most current CAR‐T cell clinical trials utilise autologous T cells from the patient’s own peripheral blood mononuclear cells. Although this is ineffective, attempts have been made to create a universal CAR‐T cell 56,57 . The CRISPR‐Cas9 system offers many alternatives to enhance the current CAR‐T and facilitates efficient and straightforward multiplex genomic modification of T cells to enhance its activation, tumor specificity and infiltration to improve the overall efficacy and safety of CAR‐T cells (Figure 2).…”