Adoptive T cell Therapy for Pediatric Leukemia

在这个项目的Aim 1下，我们已经进行了必要的临床前工作，以启动一项临床试验，测试cd22靶向CAR - T细胞作为复发或耐药前b ALL的治疗方法。CD22在95%的前b细胞ALL中表达，儿科肿瘤科在使用免疫毒素结合抗体的CD22靶向治疗ALL方面有广泛的专业知识。该试验目前处于开放状态，利用基于慢病毒的病毒载体对患者来源的扩增T细胞进行遗传修饰，以便在淋巴细胞耗尽化疗后重新输注。该研究设计是一项I期细胞剂量递增研究，扩大队列，其中约30%的完全缓解率将用于确定该结构是否将进一步发展。首先，临床前工作的一些重要发现大大简化了生成CAR - T细胞的过程。其次，该试验对于确定CD19 CAR - T细胞疗法的成功是否可以扩展到ALL的其他靶点至关重要。第三，由于CD19 CAR治疗后已经观察到CD19阴性复发，第二个靶点将潜在地增加CAR治疗ALL的整体治疗潜力。该试验是开放的，已经治疗了6名患者，预计将在1.5年内完成。我们还在进行必要的临床前工作，以结合一种替代的、半自动的T细胞扩增和转导，这将进一步简化生产过程。在该项目的目标2下，我们开发了许多新颖的CAR结构，包括我们拥有专利的tslpr靶向CAR。这项研究已经发表在《血液》杂志上，我们正在准备进行临床试验。此外，我们还生成了一种具有出色体内活性的CD19/CD22双特异性CAR。这种结构可以防止体外系统中ALL靶缺失变体的出现。其次，我们正在开发新的急性髓系白血病CAR构建物，它可能会降低与髓系抗原（如Flt3）相关的靶外肿瘤毒性。

Under Aim 1 of this project we have conducted necessary preclinical work for the initiation of a clinical trial testing CD22-targeted CAR T cells as a therapy for relapsed or resistant pre-B ALL. CD22 is expressed on 95 % of pre-B cell ALL and there is extensive expertise in the Pediatric Oncology Branch in CD22-targeted therapy for ALL using immunotoxin conjugated antibodies. This trial is currently open and utilizes lentiviral-based viral vectors for genetic modification of patient-derived expanded T cells to be reinfused after lymphodepleting chemotherapy. The study design is a phase I cell dose escalation study with an expansion cohort where an approximately 30% complete remission rate will used to determine whether this construct will be developed further. First, a number of important findings resulted from the pre-clinical work that have substantially streamlined the process of generating CAR T cells. Second, this trial will be critical in establishing whether the success of CD19 CAR T cell therapy can be extended to other targets on ALL. Third, since CD19 negative relapse has been observed following CD19 CAR therapy, a second target will potentially increase the overall curative potential of CAR therapy for ALL. This trial is open, has treated 6 patients and is expected to be completed in 1.5 years. We are also performing necessary pre-clinical work for the incorporation of an alternative, semi-automated T cell expansion and transduction that will further streamline the production process. Under Aim 2 of this project we have developed a number of novel CAR constructs including a TSLPR-targeted CAR for which we hold a patent. This work has been published in Blood and we are preparing for a clinical trial. In addition, we have generated a CD19/CD22 bispecific CAR with excellent in vivo activity. This construct can prevent the emergence of target-loss variants of ALL in an in vitro system. Second, we are developing novel acute myelogenous leukemia CAR constructs that may reduce the on-target off-tumor toxicity associated with myeloid antigens such as Flt3.