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

Communications Biology
Kyle LandgrafKaman Chan Kim

Abstract

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 generate convertibleCARTM-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 (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 selectively 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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Oct 4, 2020·International Journal of Molecular Sciences·Ashley R SutherlandC Ronald Geyer
Feb 20, 2021·Nature Reviews. Genetics·Gavin I EllisJames L Riley
May 1, 2021·International Journal of Molecular Sciences·Benjamin CaulierSébastien Wälchli
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Jan 12, 2022·Current Opinion in Hematology·Jan KoedamGerhard Ehninger

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Methods Mentioned

BETA
biolayer interferometry
ELISA
biosensor
ELISAs
flow cytometry
size-exclusion chromatography
transfection

Software Mentioned

GraphPad
Octet
GraphPad Prism

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