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.

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。这项试验将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，以便在淋巴耗竭化疗后重新输注。这项研究设计将是一项具有扩展队列的I期细胞剂量递增研究，其中大约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细胞的产生过程。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。这项试验正在进行监管审查程序，预计将于2014年第四季度开始，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Catr结构，包括我们拥有专利的TSLPR目标汽车。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。有趣的是，利用这个体外系统和体内异种移植系统，我们正在研究CAR治疗后抗原丢失的机制。其次，我们正在开发新的急性髓系白血病CAR结构，该结构可能会降低与髓系抗原相关的靶向肿瘤外毒性。最后，我们正在为T细胞ALL(早期胸腺前体或ETP ALL)的一个非常高风险的子集开发额外的CAR结构。在这个项目的第三个目标下，我们利用从James Kochenderfer博士那里获得的小鼠CD19卡，结合我们实验室开发的可移植的全同基因模型(参见Zia BC 011295)来研究与CAR治疗相关的免疫生物学原理，包括优化CAR持续时间以及在接受CAR T细胞的患者中可以看到的严重细胞因子风暴的机制。该模型还提供了对CAR T细胞治疗后抗原丢失的见解。重要的是，所有这些问题都不能在需要高度免疫缺陷小鼠的异种移植系统中得到解决。在Zia BC 011295下进行的研究已经证明了ALL对T细胞的免疫抑制作用。该项目的目标3将测试使用CAR结构物重定向T细胞特异性是否可以克服这些免疫抑制效应，以及阻断免疫系统的负调控是否可以改善CAR T细胞的有效性。