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 上表达，儿科肿瘤科在使用免疫毒素偶联抗体针对 ALL 进行 CD22 靶向治疗方面拥有广泛的专业知识。该试验将利用基于慢病毒的病毒载体对患者来源的扩增 T 细胞进行基因改造，以便在淋巴细胞清除化疗后回输。该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是否进一步开发该构建体。首先，临床前工作产生了许多重要发现，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扩展到 ALL 的其他靶点至关重要。第三，由于在 CD19 CAR 治疗后观察到 CD19 阴性复发，第二个目标将有可能增加 CAR 治疗 ALL 的整体治疗潜力。该试验正在进行监管审查程序，预计于 2014 年第四季度启动，预计 1.5 年内完成。我们还正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。根据该项目的目标 2，我们开发了许多新颖的 CATR 构建体，包括我们拥有专利的 TSLPR 靶向 CAR。此外，我们还生成了具有优异体内活性的CD19/CD22双特异性CAR。该构建体可以防止体外系统中出现 ALL 靶标丢失变体。有趣的是，利用这种体外系统以及体内异种移植系统，我们正在研究 CAR 治疗后抗原丢失的机制。其次，我们正在开发新型急性髓性白血病 CAR 结构，可以减少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）的极高风险子集开发额外的 CAR 构建体。根据该项目的第三个目标，我们正在利用从 James Kochenderfer 博士获得的小鼠 CD19 CAR 与我们实验室开发的可移植 ALL 同基因模型（参见项目 ZIA BC 011295）相结合，研究与 CAR 治疗相关的免疫生物学原理，包括优化 CAR 持久性以及在接受 CAR T 细胞的患者中可以看到的严重细胞因子风暴的机制。该模型还提供了有关 CAR T 细胞治疗后抗原丢失的见解。重要的是，所有这些问题都无法在需要高度免疫缺陷小鼠的异种移植系统中得到解决。 ZIA BC 011295 下进行的工作已经证明了 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 构建体对 T 细胞特异性进行重定向是否会克服这些免疫抑制效应，以及阻断免疫系统负调节因子是否可以提高 CAR T 细胞的功效。