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

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

238 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3505-3518
Number of pages14
JournalCancer Research
Volume75
Issue number17
DOIs
StatePublished - Sep 1 2015
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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