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的抗原识别结构域，并在体外将这些不同的单链Fv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。我们已经完成了临床前工作，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。一项表达抗cd30 CAR的T细胞的临床试验已经开始，我们已经在这项试验中治疗了20名患者。不幸的是，这些患者的最长客观反应持续时间只有3个月。由于反应持续时间短，我们已经开发出一种基因结构，允许一个T细胞同时靶向CD30和CD19，目标是能够消除霍奇金里德斯滕伯格细胞和B细胞，后者是里德斯滕伯格细胞的起源。

We 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 have completed 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 we have treated 20 patients on this trial. Unfortunately, the longest objective duration of response in these patients has been only 3 months. Because of these short durations of response, we have developed genetic constructs that allow one T cell to simultaneously target both CD30 and CD19 with a goal of being able to eliminate both the Hodgkin Reed Sternberg cells and the B cells that are the origin of Reed Sternberg cells.