Adoptive T cell Therapy for Pediatric Leukemia

小儿白血病的过继 T 细胞疗法

• 批准号: 9153986
• 负责人: Terry Fry
• 金额: $ 98.52万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9153986
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Acute leukemia; Antibodies; Antigens; B-Lymphocytes; Blood; CD19 gene; CD22 gene; Cells; Cessation of life; Child; Childhood Acute Lymphocytic Leukemia; Childhood Leukemia; Clinical; Clinical Trials; Development; Disease remission; Dose; Genetic; Goals; Hybrids; Immunotherapeutic agent; Immunotherapy; Immunotoxins; In Vitro; Legal patent; Malignant Childhood Neoplasm; Modification; Myelogenous; Non-Malignant; Outcome; Patients; Pediatric Oncology; Phase; Process; Production; Proteins; Publishing; Quality of life; Receptor Signaling; Recurrent disease; Refractory Disease; Relapse; Research Design; Resistance; Specificity; Surface; System; T cell therapy; T-Cell Immunologic Specificity; T-Cell Receptor; T-Lymphocyte; Testing; Toxic effect; Variant; Viral Vector; Work; antibody conjugate; base; chemotherapy; chimeric antigen receptor; cohort; in vivo; leukemia; novel; pre-clinical; prevent; receptor; success; targeted treatment; tumor; young adult

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.

在该项目的AIM 1下，我们进行了必要的临床前工作，用于启动临床试验测试CD22靶向的CAR T细胞，作为用于复发或抗性的PER-B ALL的疗法。 CD22以95％的BER-B细胞全部表达，并且在CD22靶向的疗法中，使用免疫毒素共轭抗体具有广泛的专业知识。该试验目前是开放的，并利用基于慢病毒的病毒载体来修饰患者衍生的膨胀T细胞，以在淋巴结化的化学疗法后恢复。研究设计是一项I期细胞剂量升级研究，其膨胀队列将使用约30％的完整缓解率来确定该构建体是否会进一步开发。首先，许多重要的发现是由临床前的工作实质上简化了产生CAR T细胞的过程的。其次，该试验对于确定CD19 CAR T细胞疗法的成功至关重要。第三，由于在CD19 CAR治疗后已经观察到CD19阴性复发，因此第二个靶标可能会增加所有人汽车治疗的总体治疗潜力。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。我们还正在进行必要的临床前工作，以纳入一种替代性，半自动化的T细胞扩展和转导，以进一步简化生产过程。在该项目的AIM 2下，我们开发了许多新型的汽车构造，包括针对TSLPR的汽车，我们为其拥有专利。这项工作已发表在血液中，我们正在为临床试验做准备。此外，我们已经生成了具有出色体内活性的CD19/CD22双特异性汽车。该结构可以防止在体外系统中所有人的目标损害变体的出现。其次，我们正在开发新型的急性髓质白血病汽车构建体，这些构建可能会降低与髓样抗原（如FLT3）相关的靶向外肿瘤毒性。