Cell Therapy Core: GMP/Vector Labs

项目摘要 该计划项目补助金（PO 1）通过以下方式探索脐带血移植（CBT）的增强： 采用CB干细胞/祖细胞、自然杀伤（NK）细胞和T细胞的离体扩增， 在临床前研究和临床试验中表达嵌合抗原受体（汽车）和病毒特异性T细胞。所有 四个项目将在研究期间进行临床试验。这些都依赖于一个可用的 用于制备细胞治疗产品的GMP生产设施。项目1、3和4将使用 MD安德森癌症中心（MDACC）的药品生产质量管理规范（GMP）机构和项目2将 依靠儿童国家医疗中心（CNHS）的GMP设施-细胞增强和技术 免疫疗法（CETI）MDACC的GMP设施已运行超过15年， CNHS-CETI的GMP是一个新设施，于2013年开业。两个机构的细胞处理设施 在制备各种细胞产品方面具有相当丰富的经验，并且都收到了更多- 细胞疗法认证基金会（FACT）的最低限度细胞疗法认证。 两个工厂都配备了良好的GMP条件下运行，广泛的文件系统， 条形码、环境监测和质量保证、控制和改进方案。一个 在两个设施中提供独立且经验证的报警系统，以监测、记录和报警温度 所有培养箱、冰箱和冷冻机中的空气流量;每个生物安全柜中的空气流量;以及压差 ISO 7和ISO 8实验室之间的门。核心的其他组成部分是质量 CNHS-CETI和MDACC的控制实验室，对细胞产品进行内部测试， 负责GMP实验室和质量保证组的日常监测，以确保合规性 符合cGMP法规，并提供生产和放行所有方面的独立概述。的 两个机构的GMP人员都具有丰富的监管经验，这将有助于 实验室研究转化为临床试验。在该提案中，MDACC将生产五种细胞治疗产品。 对于项目1：已岩藻糖基化以增强植入的扩增CB细胞， 间充质基质细胞（MSC）治疗移植物抗宿主病。项目3：CB NK细胞遗传学 经修饰以表达靶向表达IL-1的CD 19+淋巴癌的嵌合抗原受体（CAR）， 15，和一个诱导型半胱天冬酶9自杀基因。项目4：表达靶向Pr 1+的CAR的CB T细胞 骨髓癌项目2：CNHS-CETI将生产针对CMV的CB多病毒特异性T细胞， EB病毒、腺病毒和BK病毒，以及将用于患者的新型HIV特异性T细胞产物 艾滋病病毒感染者。总之，GMP实验室核心是P01的重要组成部分， 为项目1、2、3和4中临床研究的实施提供必要服务。

PROJECT SUMMARY This Program Project Grant (PO1) explores the enhancement of cord blood transplantation (CBT) by employing ex-vivo expansion of CB stem/progenitors, natural killer (NK) cells and T cells engineered to express chimeric antigen receptors (CARs), and virus-specific T cells in preclinical studies and clinical trials. All four projects will undertake clinical trials during the course of the studies. These rely on the availability of a GMP manufacturing facility for the preparation of the cellular therapy products. Projects 1, 3 and 4 will use on the Good Manufacturing Practice (GMP) Facility at MD Anderson Cancer Center (MDACC) and Project 2 will rely on the GMP Facility at Children's National Medical Center (CNHS)-Cell Enhancement and Technologies for Immunotherapy (CETI). The GMP Facility at MDACC has been in operation for more than 15 years and the GMP at CNHS-CETI is a new facility, which opened in 2013. The Cell Processing Facilities at both institutions have considerable experience in the preparation of a wide variety of cellular products and both received more- than-minimal cell therapy accreditation from the Foundation for the Accreditation of Cellular Therapy (FACT). Both Facilities are well equipped to operate under GMP conditions, with extensive documentation systems, barcoding, environmental monitoring, and quality assurance, control and improvement programs. An independent and validated alarm system is provided in both facilities to monitor, log and alarm the temperature in all incubators, refrigerators and freezers; the airflow in each biosafety cabinet; and differential pressure across doors between the ISO 7 and ISO 8 laboratories. Additional components of the Core are the Quality Control Laboratories at CNHS-CETI and MDACC, which perform in-house testing of cellular products, and are responsible for routine monitoring of the GMP Laboratory and Quality Assurance Group to ensure compliance with cGMP regulations and provides independent overview of all aspects of manufacturing and release. The GMP personnel at both institutions have extensive regulatory experience that will facilitate the translational of laboratory studies into clinical trials. In this proposal, MDACC will manufacture five cellular therapy products. For Project 1: expanded CB cells that have been fucosylated to enhance engraftment, and fucosylated mesenchymal stromal cells (MSCs) to treat graft versus host disease. For Project 3: CB NK cells genetically modified to express a chimeric antigen receptor (CAR) targeting CD19+ lymphoid cancers which expresses IL- 15, and an inducible caspase 9 suicide gene. For Project 4: CB T cells expressing a CAR targeting Pr1+ myeloid cancers. For Project 2: CNHS-CETI will manufacture CB multi-virus-specific T cells targeting CMV, EBV, adenovirs and BK virus, as well as the novel HIV-specific T cell product which will be used for patients with HIV disease.. In summary, the GMP Laboratory Core is a vital component of the P01 that will provide essential services to the implementation of the clinical studies in Projects 1, 2, 3 and 4.