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cd30 car的抗原识别域，并在体外将这些不同的scfv与car进行了比较。我们选择了最优的scFv，并在不同的CAR设计和小鼠肿瘤模型中进行了测试。我们已经确定了最佳的scFv和CAR设计，以供进一步开发。这项工作产生了两种对小鼠都非常有效的car。我们已经选择其中一种car进行I期临床试验。同时，已经完成了一种临床级慢病毒载体编码这种CAR的工作。我们已经完成了全人抗cd30 CAR临床试验的临床方案，该方案已获得NCI机构审查委员会的批准。我们继续进行临床前工作，以改进抗cd30 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CD28和4-1BB共刺激结构域。一项表达一种抗cd30 CAR的T细胞的临床试验已经开始，前两名接受治疗的患者获得了部分缓解，毒性较轻。我们将继续增加患者参加这个剂量递增的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.