Salzer Benjamin, Schueller Christina M, Zajc Charlotte U, Peters Timo, Schoeber Michael A, Kovacic Boris, Buri Michelle C, Lobner Elisabeth, Dushek Omer, Huppa Johannes B, Obinger Christian, Putz Eva M, Holter Wolfgang, Traxlmayr Michael W, Lehner Manfred
St. Anna Children's Cancer Research Institute (CCRI), 1090, Vienna, Austria.
Christian Doppler Laboratory for Next Generation CAR T Cells, 1090, Vienna, Austria.
Nat Commun. 2020 Aug 20;11(1):4166. doi: 10.1038/s41467-020-17970-3.
T cells engineered to express chimeric antigen receptors (CAR-T cells) have shown impressive clinical efficacy in the treatment of B cell malignancies. However, the development of CAR-T cell therapies for solid tumors is hampered by the lack of truly tumor-specific antigens and poor control over T cell activity. Here we present an avidity-controlled CAR (AvidCAR) platform with inducible and logic control functions. The key is the combination of (i) an improved CAR design which enables controlled CAR dimerization and (ii) a significant reduction of antigen-binding affinities to introduce dependence on bivalent interaction, i.e. avidity. The potential and versatility of the AvidCAR platform is exemplified by designing ON-switch CARs, which can be regulated with a clinically applied drug, and AND-gate CARs specifically recognizing combinations of two antigens. Thus, we expect that AvidCARs will be a highly valuable platform for the development of controllable CAR therapies with improved tumor specificity.
经过基因工程改造以表达嵌合抗原受体的T细胞（CAR-T细胞）在治疗B细胞恶性肿瘤方面已显示出令人瞩目的临床疗效。然而，由于缺乏真正的肿瘤特异性抗原以及对T细胞活性的控制不佳，用于实体瘤的CAR-T细胞疗法的发展受到阻碍。在此，我们展示了一个具有诱导和逻辑控制功能的亲和力控制CAR（AvidCAR）平台。关键在于（i）改进的CAR设计相结合，该设计能够实现可控的CAR二聚化，以及（ii）显著降低抗原结合亲和力以引入对二价相互作用（即亲和力）的依赖性。通过设计可由临床应用药物调节的开启开关CAR和特异性识别两种抗原组合的与门CAR，例证了AvidCAR平台的潜力和多功能性。因此，我们预计AvidCAR将成为开发具有更高肿瘤特异性的可控CAR疗法的极有价值的平台。
