Tuning sensitivity of CAR to EGFR density limits recognition of normal tissue while maintaining potent antitumor activity

HG Caruso, LV Hurton, A Najjar, D Rushworth, S Ang… - Cancer research, 2015 - AACR
HG Caruso, LV Hurton, A Najjar, D Rushworth, S Ang, S Olivares, T Mi, K Switzer, H Singh
Cancer research, 2015AACR
Many tumors overexpress tumor-associated antigens relative to normal tissue, such as
EGFR. This limits targeting by human T cells modified to express chimeric antigen receptors
(CAR) due to potential for deleterious recognition of normal cells. We sought to generate
CAR+ T cells capable of distinguishing malignant from normal cells based on the disparate
density of EGFR expression by generating two CARs from monoclonal antibodies that differ
in affinity. T cells with low-affinity nimotuzumab-CAR selectively targeted cells …
Abstract
Many tumors overexpress tumor-associated antigens relative to normal tissue, such as EGFR. This limits targeting by human T cells modified to express chimeric antigen receptors (CAR) due to potential for deleterious recognition of normal cells. We sought to generate CAR+ T cells capable of distinguishing malignant from normal cells based on the disparate density of EGFR expression by generating two CARs from monoclonal antibodies that differ in affinity. T cells with low-affinity nimotuzumab-CAR selectively targeted cells overexpressing EGFR, but exhibited diminished effector function as the density of EGFR decreased. In contrast, the activation of T cells bearing high-affinity cetuximab-CAR was not affected by the density of EGFR. In summary, we describe the generation of CARs able to tune T-cell activity to the level of EGFR expression in which a CAR with reduced affinity enabled T cells to distinguish malignant from nonmalignant cells. Cancer Res; 75(17); 3505–18. ©2015 AACR.
AACR