Tuning Sensitivity of CAR to EGFR Density Limits Recognition of Normal Tissue While Maintaining Potent Antitumor Activity.
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.
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.
Hillary G
HG
Caruso
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.
Lenka V
LV
Hurton
Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Amer
A
Najjar
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.
David
D
Rushworth
Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Sonny
S
Ang
Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Simon
S
Olivares
Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Tiejuan
T
Mi
Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Kirsten
K
Switzer
Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Harjeet
H
Singh
Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Helen
H
Huls
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.
Dean A
DA
Lee
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Amy B
AB
Heimberger
Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Richard E
RE
Champlin
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.
Laurence J N
LJ
Cooper
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000951:Antigens, Neoplasm / Q000276:immunology*; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000008:administration & dosage; D000939:Epitopes / Q000276:immunology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016219:Immunotherapy, Adoptive; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D011946:Receptors, Antigen / Q000276:immunology* / Q000627:therapeutic use; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; D000939:Epitopes; D011946:Receptors, Antigen; C501466:nimotuzumab; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab