Improved Chimeric Antigen Receptor Therapies B-cell Malignancies

在过去的一年里，我们设计并选择了一款针对CD19和CD20的最佳双顺反子汽车结构。双顺反子结构编码2辆车，其中一辆车是前面描述的Hu19-CD828Z车。第二辆车是一辆名为Hu20-CD8BBZ的反CD20车。整个双顺反子构建体命名为Hu19-CD828-Hu20BB，该构建体由伽玛逆转录病毒载体编码。我们计划在2022年底开始一项针对CD19和CD20的双顺反子汽车设计的临床试验。我们花了大量的时间来优化双顺反子载体的DNA序列，以消除由同源DNA序列驱动的缺失事件。我们有一种在GMP条件下生产的优化的基因治疗载体。IND将很快提交给FDA。我们还准备了一个生产型细胞克隆，它可以产生编码Hu19-CD828Z抗CD19 CAR的伽马逆转录病毒。GMP级载体已从该主细胞库中产生。我们计划在一项临床试验中使用这种载体，该试验将招募CLL患者。在过去的一年里，已经花费了大量的时间和精力来为即将到来的两项临床试验准备所需的管理文件。我们还进行了实验，以检查细胞因子对CAR毒性的影响，包括皮质类固醇的作用，皮质类固醇被用于治疗CAR T细胞对CAR T细胞的毒性。

In the past year, we have designed and selected an optimal bicistronic CAR construct that targets both CD19 and CD20. The bicistronic construct encodes 2 CARs, one of the CARs is the previously -described Hu19-CD828Z CAR. The second CAR is an anti-CD20 CAR designated Hu20-CD8BBZ. The entire bicistronic construct is designated Hu19-CD828-Hu20BB, and the construct is encoded by a gammaretroviral vector. We plan to start a clinical trial with bicistronic CAR designs targeting CD19 and CD20 in late 2022. We have spent extensive time optimizing the DNA sequence of the bicistronic vector to eliminate deletion events driven by homologous DNA sequences. We have an optimized gene therapy vector that has been produced under GMP conditions. An IND will be submitted to the FDA very soon. We have also prepared a producer cell clone that generates a gamma-retrovirus encoding the Hu19-CD828Z anti-CD19 CAR. GMP-grade vector has been produced from this master cell bank. We plan to use this vector in a clinical trial that will enroll CLL patients. Substantial time and effort has been expended in the past year to prepare required regulatory documents for the two upcoming clinical trials. We have also carried out experiments to examine the impact of cytokines on CAR toxicity including the role of corticosteroids, which are used to treat CAR T-cell toxicity on CAR T cells.