Strain-dependent Lethal Toxicity in NKG2D Ligand-targeted CAR T-cell Therapy

Abstract

Ligands for NKG2D, the NK cell–activating receptor, have been explored as targets for chimeric antigen receptor T-cell (CART) therapy of cancer in preclinical mouse models for over a decade, and a phase I clinical trial is currently recruiting patients to test this platform. In this issue of Molecular Therapy, VanSeggelen and colleagues report on the observation of lethal toxicity in mice following administration of chimeric NKG2D (chNKG2D) CART therapy for targeting NKG2D ligands.1 CART-mediated toxicities were mouse strain-dependent, highlighting the influence of intraspecies differences that are often overlooked when using genetically inbred mice for preclinical studies. These findings warrant careful consideration as chNKG2D CART therapeutic regimens move into the clinic and raise broader questions regarding the variability in, and prognostic value of, syngeneic mouse models for preclinical validation of CART therapy.