期刊
CANCER RESEARCH
卷 75, 期 17, 页码 3505-3518出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-15-0139
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资金
- Cancer Center Core Grant [CA16672, CA124782, CA120956, CA141303, CA148600]
- Center for Clinical and Translational Sciences
- National Center for Advancing Translational Sciences of the NIH [TL1TR000369]
- SPORE [P50 CA136411]
- Albert J Ward Foundation
- Alex Lemonade Stand Foundation
- American Legion Auxiliary
- Burroughs Wellcome Fund
- Cancer Answers
- Cancer Prevention and Research Institute of Texas
- Charles B. Goddard Foundation of Texas
- CLL Global Research Foundation
- DARPA (Defense Sciences Office)
- Department of Defense
- Estate of Noelan L. Bibler
- Gillson Longenbaugh Foundation
- Harry T. Mangurian, Jr, Fund for Leukemia Immunotherapy
- Khalifa Bin Zayed Al Nahyan Foundation
- Leukemia and Lymphoma Society
- Lymphoma Research Foundation
- Miller Foundation
- Moon Shot program at MDACC
- Mr. Herb Simons
- Mr. and Mrs. Joe H. Scales
- Mr. Thomas Scott
- National Foundation for Cancer Research
- Pediatric Cancer Research Foundation
- Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy
- R.W. Butcher Foundation
- MDACC Sister Institution Network Fund
- Moon Shot Fund
- William Lawrence and Blanche Hughes Children's Foundation
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. (C)2015 AACR.
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