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Cancer Res. 2015 Sep 1;75(17):3505-18. doi: 10.1158/0008-5472.CAN-15-0139.

Tuning Sensitivity of CAR to EGFR Density Limits Recognition of Normal Tissue While Maintaining Potent Antitumor Activity.

Author information

1
Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas. The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas.
2
Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
3
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
4
Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
5
Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas. The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas. ljncooper@mdanderson.org ljncooper@ziopharm.com.

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.

PMID:
26330164
PMCID:
PMC4624228
DOI:
10.1158/0008-5472.CAN-15-0139
[Indexed for MEDLINE]
Free PMC Article

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