Caruso Hillary G, Hurton Lenka V, Najjar Amer, Rushworth David, Ang Sonny, Olivares Simon, Mi Tiejuan, Switzer Kirsten, Singh Harjeet, Huls Helen, Lee Dean A, Heimberger Amy B, Champlin Richard E, Cooper Laurence J N
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.
Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer Res. 2015 Sep 1;75(17):3505-18. doi: 10.1158/0008-5472.CAN-15-0139.
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.
相对于正常组织，许多肿瘤会过度表达肿瘤相关抗原，如表皮生长因子受体（EGFR）。这限制了经改造表达嵌合抗原受体（CAR）的人类T细胞的靶向作用，因为存在对正常细胞进行有害识别的可能性。我们试图通过从亲和力不同的单克隆抗体生成两种CAR，来产生能够基于EGFR表达密度差异区分恶性细胞与正常细胞的CAR(+) T细胞。具有低亲和力尼妥珠单抗-CAR的T细胞选择性地靶向过度表达EGFR的细胞，但随着EGFR密度降低，其效应器功能减弱。相比之下，携带高亲和力西妥昔单抗-CAR的T细胞的激活不受EGFR密度的影响。总之，我们描述了能够将T细胞活性调节至EGFR表达水平的CAR的产生，其中亲和力降低的CAR使T细胞能够区分恶性细胞与非恶性细胞。
