car-t免疫治疗好文分享

文章来源: http://cancerres.aacrjournals.org/content/75/17/3505.full.pdf



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 CARt 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


在正常组织中转变密度限制性识别表皮生长因子受体的CAR的敏感性，同时保持强有力的抗肿瘤活性

很多肿瘤与正常组织相比，会过度表达肿瘤相关的抗原，如EGFR。这会限制表达CAR的人类T细胞的靶向治疗，因为有可能对正常细胞进行有害的识别。我们通过具有不同亲和性的单克隆抗体，试图生产一种CAR-T细胞，能够根据细胞表达的EGFR的不同密度，从正常组织中区分恶性肿瘤。与尼妥珠单抗具有低亲和力的T细胞选择性靶向过度表达EGFR的细胞，但是随着EGFR密度的减少，靶向能力减弱。相比之下，与西妥昔单抗具有高亲和性的T 细胞的活性不会受到EGFR密度的影响。总之，我们描述了一种CARs能够根据EGFR表达的水平来调整T细胞的活性，这样，亲和性降低的CAR能够使得T细胞从正常组织中区分出恶性细胞。