Improved Chimeric Antigen Receptor Therapies B-cell Malignancies

在过去的一年里，我们设计并选择了一个最佳的双顺反子CAR构建体， 同时针对CD 19和CD 20的抗体双顺反子构建体编码2个汽车，其中一个汽车是 先前描述的Hu 19-CD 828 Z CAR。第二CAR是抗CD 20 CAR，命名为 Hu20-CD8BBZ。整个双顺反子构建体被命名为Hu 19-CD 828-Hu 20 BB，并且 构建体由γ逆转录病毒载体编码。我们计划开始一项临床试验， 在2022年底，靶向CD 19和CD 20的双顺反子CAR设计。我们花了大量时间 优化所述双顺反子载体的DNA序列以消除由 同源DNA序列。我们有一个优化的基因治疗载体， 在GMP条件下。IND将很快提交给FDA。我们还准备了一个 生产细胞克隆，其产生编码Hu 19-CD 828 Z抗CD 19 CAR的γ-逆转录病毒。 已从该主细胞库生产GMP级载体。我们计划在一个 临床试验将招募CLL患者。已经花费了大量的时间和精力， 在过去的一年里，我们为即将进行的两项临床试验准备了所需的监管文件。 我们还进行了实验以检查细胞因子对CAR毒性的影响 包括用于治疗CAR T细胞毒性的皮质类固醇的作用 细胞

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.