Probing the balance of sensitivity and selectivity, Park et al. created CAR T cells with a range of affinities for ICAM-1, a cell-surface molecule basally expressed on several normal tissues and multiple solid tumors and upregulated by inflammation. Reduced (micromolar) affinity resulted in enhanced antitumor effect, longer survival, and lower on-target, off-tumor toxicity compared with higher (nanomolar) affinity in a thyroid carcinoma xenograft mouse model, suggesting that more is not always better, and that optimization could yield safer and more effective CAR T cell therapies.
Adoptive transfer of high-affinity chimeric antigen receptor (CAR) T cells targeting hematological cancers has yielded impressive clinical results. However, safety concerns regarding target expression on healthy tissue and poor efficacy have hampered application to solid tumors. Here, a panel of affinity-variant CARs were constructed targeting overexpressed ICAM-1, a broad tumor biomarker, using its physiological ligand, LFA-1. Anti-tumor T cell potency in vitro was directly proportional to CAR affinity and ICAM-1 density. In a solid tumor mouse model allowing simultaneous monitoring of anti-tumor potency and systemic off-tumor toxicity, micromolar affinity CAR T cells demonstrated superior anti-tumor efficacy and safety compared to their nanomolar counterparts. Longitudinal T cell tracking by PET/CT and concurrent cytokine measurement revealed superior expansion and contraction kinetics of micromolar affinity CAR T cells. Therefore, we developed an ICAM-1 specific CAR with broad anti-tumor applicability that utilized a reduced affinity targeting strategy to significantly boost efficacy and safety.
Author Info: (1) Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA. Department of Biomedical Engineering, Cornell University, It
Author Info: (1) Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA. Department of Biomedical Engineering, Cornell University, Ithaca, NY, 14850, USA. (2) Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA. (3) Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA. Department of Biomedical Engineering, Cornell University, Ithaca, NY, 14850, USA. (4) Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA. (5) Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA. (6) Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA. (7) Department of Surgery, Weill Cornell Medicine, New York, NY, 10065, USA. (8) Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA. moj2005@med.cornell.edu. Department of Surgery, Weill Cornell Medicine, New York, NY, 10065, USA. moj2005@med.cornell.edu. Department of Biomedical Engineering, Cornell University, Ithaca, NY, 14850, USA. moj2005@med.cornell.edu.
