American Association for Cancer Research
00085472can150139-sup-143964_1_supp_2948012_nn6v1d.pdf (1.09 MB)

Supplementary Figure 4 from Tuning Sensitivity of CAR to EGFR Density Limits Recognition of Normal Tissue While Maintaining Potent Antitumor Activity

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journal contribution
posted on 2023-03-30, 23:07 authored by Hillary G. Caruso, Lenka V. Hurton, Amer Najjar, David Rushworth, Sonny Ang, Simon Olivares, Tiejuan Mi, Kirsten Switzer, Harjeet Singh, Helen Huls, Dean A. Lee, Amy B. Heimberger, Richard E. Champlin, Laurence J.N. Cooper

Surface expression of CAR during co-culture with tEGFR+ EL4 or CAR-L+ EL4



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.