Adoptive T cell Therapy for Pediatric Leukemia

小儿白血病的过继 T 细胞疗法

• 批准号: 8938198
• 负责人: Terry Fry
• 金额: $ 87.97万
• 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/8938198
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Acute leukemia; Address; Antibodies; Antigens; B-Lymphocytes; Biological; CD19 gene; CD22 gene; Cells; Cessation of life; Child; Childhood Acute Lymphocytic Leukemia; Childhood Leukemia; Clinical; Clinical Trials; Development; Disease remission; Dose; Genetic; Goals; Homologous Transplantation; Hybrids; Immune system; Immunodeficient Mouse; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Immunotoxins; In Vitro; Laboratories; Legal patent; Malignant Childhood Neoplasm; Modeling; Modification; Mus; Myelogenous; Non-Malignant; Outcome; Patients; Pediatric Oncology; Phase; Process; Production; Proteins; 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; T-Lymphocyte Subsets; Testing; Toxic effect; Variant; Viral Vector; Work; Xenograft procedure; antibody conjugate; base; chemotherapy; chimeric antigen receptor; cohort; cytokine; high risk; improved; in vivo; insight; leukemia; novel; pre-clinical; prevent; receptor; success; 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 will utilize lentiviral-based viral vectors for genetic modification of patient-derived expanded T cells to be reinfused after lymphodepleting chemotherapy. The study design will be 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 finding resulted from the pre-clinical work that have substantially streamlined the process of generated 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 undergoing the regulatory review process and is anticipated to open by the fourth quarter of 2014 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 CATR constructs including a TSLPR-targeted CAR for which we hold a patent. 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. Interestingly, using this in vitro system as well as in vivo xenograft system we are studying the mechanisms of antigen loss following CAR therapy. Second, we are developing novel acute myelogenous leukemia CAR constructs that may reduce the on-target off-tumor toxicity associated with myeloid antigens. Finally, we are developing additional CAR constructs for a very high-risk subset of T cell ALL (Early Thymic Precursor or ETP ALL). Under the third Aim of this project we are utilizing a murine CD19 CAR obtained form Dr. James Kochenderfer in conjunction with a transplantable ALL syngeneic model developed in our laboratory (see Project ZIA BC 011295) to study immunobiological principles associated with CAR therapy including the optimization CAR persistence and the mechanism for severe cytokine storm that can be seen in patients receiving CAR T cells. This model is also providing insights into antigen loss following CAR T cell therapy. Importantly, all of these questions cannot be addressed in the xenograft systems that require highly immunodeficient mice. Work conducted under ZIA BC 011295 has demonstrated the immunosuppressive effects of ALL on T cells. Aim 3 of this project will test whether redirection of T cell specificity using CAR constructs will overcome these immunosuppressive effects and whether blockade of negative regulators of the immune system can improve on the efficacy of CAR T cells.

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。该试验将利用基于慢病毒的病毒载体来修饰患者衍生的扩张型T细胞，以在淋巴结化的化学疗法后恢复。研究设计将是I期细胞剂量升级研究，其扩展队列将使用约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的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。该试验正在进行监管审查过程，预计将于2014年第四季度开放，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CATR结构，包括符合TSLPR的汽车，我们为其拥有专利。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。有趣的是，使用此体外系统以及体内异种移植系统，我们正在研究汽车治疗后抗原损失的机制。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相关的靶向外毒性毒性。最后，我们正在为T细胞的非常高风险的子集开发其他汽车构建体（早期的胸腺前体或ETP全部）。在该项目的第三个目标下，我们使用的是詹姆斯·科钦德弗（James Kochenderfer）博士获得的鼠CD19汽车以及在我们的实验室中开发的所有合成模型（请参阅Zia Zia BC 011295）来研究与汽车治疗相关的免疫生物学原理，包括优化汽车的持久性和严重的celtivity cartiviving cartive cartive cartive cartive cartive cartive cartive cartive cartive cartive cartive cartive cartive cartive cartiviant cartiviation the Imploybiologological Promication。该模型还提供了对CAR T细胞治疗后抗原损失的见解。重要的是，所有这些问题都无法在需要高度免疫缺陷小鼠的异种移植系统中解决。在BC 011295下进行的工作证明了所有T细胞的免疫抑制作用。该项目的目标3将测试使用CAR构建体对T细胞特异性的重定向是否会克服这些免疫抑制作用，以及免疫系统负调节剂的阻断是否可以提高CAR T细胞的功效。