Development of fully-human anti-CD30 chimeric antigen receptors

我们设计了4种不同的单链Fv分子作为抗CD 30汽车的抗原识别结构域，并在体外比较了具有这些不同scFv的汽车。我们选择了最佳的scFv，并在体外和小鼠肿瘤模型中在不同的CAR设计中对其进行了测试。我们已经确定了用于进一步开发的最佳scFv和CAR设计。这项工作产生了两种在小鼠中非常有效的汽车。我们已经选择了其中一种汽车进行I期临床试验。同时完成的工作已经导致编码这种CAR的临床级慢病毒载体的产生。我们已经完成了全人抗CD 30 CAR临床试验的临床方案工作，该方案已获得NCI机构审查委员会的批准。我们继续临床前工作，以改善抗CD 30 CAR设计和T细胞培养方法，重点是比较不同的铰链和跨膜结构域，以及比较CD 28与4-1BB共刺激结构域。一项表达抗CD 30 CAR的T细胞临床试验已经开始，前2名接受治疗的患者获得了部分缓解，毒性轻微。我们将继续招募患者参加这项剂量递增的I期临床试验。

We have designed 4 different single chain Fv molecules as antigen-recognition domains for anti-CD30 CARs and compared CARs with these different scFvs in vitro. We selected the optimal scFv, and tested it in different CAR designs in vitro and in mouse tumor models. We have identified an optimal scFv and CAR design for further development. This work led to 2 CARs that are both highly effective in mice. We have selected one of these CARs for a phase I clinical trial. Simultaneous work has been completed that has led to generation of a clinical-grade lentiviral vector encoding this CAR. We have completed work on a clinical protocol for a clinical trial of the fully-human anti-CD30 CAR, and this protocol has been approved by the NCI Institutional Review Board. We continue preclinical work to improve anti-CD30 CAR design and T-cell culture methods with an emphasis on comparing different hinge and transmembrane domains as well as comparing CD28 versus 4-1BB costimulatory domains . A clinical trial of T cells expressing an anti-CD30 CAR has opened, and the first 2 treated patients have obtained partial remissions with mild toxicity. We will continue to accrue patients to this dose-escalation phase I clinical trial.