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bioRxiv · 10.1101/696401

convertibleCAR-T cells provide a modular universal system for dose control of activity, flexible targeting, and versatile maintenance of CAR-cells

Landgraf, K.·Williams, S. R.·Steiger, D.·Gebhart, D.·Lok, S.·Martin, D. W.·Roybal, K. T.·Kim, K. C.
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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 (MicAbodyTM). Efficacy against Raji tumors in NSG mice was dependent upon doses of both a rituximab-based MicAbody and convertibleCAR-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 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.

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Landgraf, K., Williams, S. R., Steiger, D., Gebhart, D., Lok, S., Martin, D. W., Roybal, K. T., Kim, K. C.. 2019-07-09. convertibleCAR-T cells provide a modular universal system for dose control of activity, flexible targeting, and versatile maintenance of CAR-cells. https://doi.org/10.1101/696401

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