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.

根据该项目的目标1，我们已经开展了必要的临床前工作，以启动一项临床试验，测试CD22靶向的CAR T细胞作为治疗复发或耐药的前B-ALL的方法。CD22在95%的前B细胞ALL上表达，儿科肿瘤科在CD22靶向治疗ALL方面拥有广泛的专业知识，使用免疫毒素结合抗体。这项试验目前是公开的，并利用慢病毒为基础的病毒载体对患者来源的扩增T细胞进行基因改造，以便在淋巴清除化疗后重新输注。这项研究设计是一项I期细胞剂量递增研究，有一个扩展队列，大约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，一些重要的发现来自临床前的工作，这些工作大大简化了CAR T细胞的生成过程。其次，这项试验对于确定CD19 CAR T细胞疗法的成功是否可以推广到ALL的其他靶点至关重要。第三，由于在CD19 CAR疗法后观察到CD19阴性复发，第二个靶点可能会增加CAR疗法对所有人的总体疗效潜力。这项试验是开放的，已经治疗了6名患者，预计在1.5年内完成。我们还在进行必要的临床前工作，以纳入替代的半自动T细胞扩增和转导，这将进一步简化生产过程。在这个项目的目标2下，我们已经开发了一些新的汽车结构，包括我们拥有专利的TSLPR目标汽车。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，我们还获得了具有良好体内活性的CD19/CD22双特异性CAR。这种结构可以防止在体外系统中出现ALL的靶标缺失变体。其次，我们正在开发新的急性髓系白血病CAR结构，可能会降低与髓系抗原(如Flt3)相关的靶向肿瘤外毒性。