Cell Production Core Facility

电池生产核心设施

• 批准号: 10703064
• 负责人: Hyunmi Halas
• 金额: $ 150.12万
• 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/10703064
• 关键词: Activated Lymphocyte; Address; Adoptive Cell Transfers; Antigens; Area; Autologous; B-Lymphocytes; Back; Biological Response Modifiers; Biopsy; Blood; Blood specimen; Candidate Disease Gene; Carcinoma; Cell Therapy; Cell physiology; Cells; Characteristics; Cholangiocarcinoma; Clinical; Clinical Trials; Colorectal Cancer; Competence; Computer software; Core Facility; Cryopreservation; Cyclic GMP; Data; Dendritic Cell Vaccine; Development; Disseminated Malignant Neoplasm; Documentation; Effectiveness; Enrollment; Ensure; Environmental Monitoring; Equipment; Excision; Extramural Activities; Future; Gene-Modified; Genes; Goals; Human; Human Papillomavirus; Human Resources; Immunologics; Immunotherapy; Industrialization; Infusion procedures; Institution; Laboratories; Lymphocyte; Malignant Neoplasms; Mission; Mutation; National Cancer Institute; Neoplasms; Operative Surgical Procedures; Patients; Peptides; Peripheral Blood Lymphocyte; Physiologic pulse; Procedures; Process; Production; Protocols documentation; Research; Research Personnel; Research Project Grants; Research Support; Resected; Sampling; Sleeping Beauty; Somatic Mutation; Source; Specialist; Supporting Cell; System; T cell therapy; T-Lymphocyte; Testing; Time; Training Programs; Translating; Tumor Antigens; Tumor Tissue; Tumor-Infiltrating Lymphocytes; United States National Institutes of Health; Vendor; Viral Vector; anti-cancer; cancer cell; cancer therapy; clinical translation; design and construction; gene delivery system; improved; interest; lymphoid neoplasm; malignant breast neoplasm; manufacturing facility; melanoma; neoantigens; novel; novel therapeutics; operation; programs; square foot; success; synovial sarcoma; therapy development; tool; transfusion medicine; tumor; tumor immunology

The mission of this core laboratory is to provide support to the immunotherapy program established by the Surgery Branch of the National Cancer Institute. The laboratory is overseen by Dr. Hyunmi Halas. The main effort of the laboratory involves the production of large numbers of human anti-cancer T lymphocytes ex vivo, to treat patients with advanced metastatic cancer enrolled on Surgery Branch clinical trials. Cancer targeting lymphocytes are either isolated directly from biopsied material or are generated by genetically modifying T lymphocytes from a patient's blood. 32 patients each underwent a resection between 01-Aug-2021, 01-July, 2022. Of the 32 total resections processed by CPF, 16 resections were processed in the new Cell Production Facility (T30), which began clinical GMP manufacturing and processing on 24 Feb 2022. The 16 resections processed in T30 provided potential source of tumor-infiltrating lymphocytes (TIL) and 16 were research resection from which initial fragments as potential source of tumor-infiltrating lymphocytes (TIL) were not performed. 70% of the 16 resections processed for fragments and subsequent TIL cells during this time provided sufficient tumor tissue to provide 10+ fragments, which were cryopreserved. 3 patient resections yielded reactive fragments with tumor specific reactivity to generate TIL cell which can be expanded in culture cultures for potential treatments. 2 of these patients were resected in mid 2022 and most of the resections with expanded fragments are currently being screened for reactivity as potential future therapies. 4 patient resections were identified reactive fragments as well as candidates for gene modified T lymphocyte therapies. 5 patients were found to not have reactive fragments but were found to have reactive neoantigens for gene modified T lymphocyte therapies identified from the tumor resection and gene modified therapies to provide TCR known to recognize the cancer cells were identified. Nine(9) cell products, delivered to patients enrolled on 2 clinical trials, were used to treat patients with autologous cell therapies generated by this core laboratory since opening the new facility in Feb 2022 to July 2022. A second critical function of this core lab is to collect, process, and curate samples from patients enrolled in Surgery Branch protocols. These samples are used to generate the cancer therapies described above and are also used by investigators in the Surgery Branch cell therapy program to evaluate the progress of each clinical trial, as well as to address research questions that identify changes that can be implemented to improve these trials. In addition, the samples from these trials facilitate research that generates new patient therapies. These research projects include 1) Transducing patients' T cells with genes whose products will better target tumors or enhance endogenous tumor activity, 2) Evaluating the ability of infused anticancer lymphocytes to function and survive in patients, 3) Identifying new cancer-associated antigens that can be targeted by anticancer cells, 4) Identifying novel patient-specific antigens that are created by somatic mutations and selecting cultures that recognize these mutations for use in personalized T cell therapies 5) Identifying characteristics of infused anticancer cells that are associated with objective tumor regression, 6) Identifying characteristics of patients who are most likely to respond to anticancer T cell therapies, 7) Evaluating selected biological response modifiers tested in Surgery Branch clinical trials, 8) Evaluating new gene delivery systems such as the sleeping beauty transposon, 9) Producing dendritic cell vaccines that are pulsed with peptides representing a patient's own unique mutanome. Finally, the core laboratory maintains and curates all source documents, data, protocols, and expertise associated with cGMP manufacturing and the clinical translation of anticancer cell therapies. Due to the success of these therapies developed by the Surgery Branch, investigators within the Surgery Branch, intramural NCI laboratories, extramural regulatory agencies, industrial and academic partners, and other interested parties increasingly want access to these data, protocols, and advice. There is a need to develop new tools for curating data from older trials. There is a need to convert existing data into a format that can be read by newer software packages, it is essential that existing is not lost as older file types become obsolete. The Surgery Branch Cell Production Facility has implemented several programs since the development of a Quality Management Systems (QMS) in 2016 and oversight from the Office of Research Support and Compliance (ORSC). These programs include 1. Independent QA - Established through a memorandum of understanding with the Department of Transfusion Medicine who oversees the program. The program has a total of 7 QA specialists to manage the program. 2. Quality Management System (QMS) that governs all operations. 3. A materials management program to ensure that all products/materials that are used in the manufacture or come in to contact with patient therapies are of highest quality and free from adulteration. 4. An environmental monitoring program that ensures the facility is maintained in the highest possible state of cleanliness. 5. Equipment management program that ensures that all equipment used in manufacturing operations is functioning and is maintained appropriately. 6. A document management program that ensures all personnel are working from vetted and approved procedures. 7. A personnel training program that ensures competency and emphasizes the responsibilities and duties of all personnel involved in manufacturing cell therapies in the Surgery Branch. The facilities and QMS is audited annually by third party vendors through ORSC. 3 The former primary cell production facility 3W/TIL lab is no longer used for manufacturing as of Dec 2020. New facilities have been qualified and validated for cGMP cellular manufacturing on the NIH campus. These include Trailer 10B, which will provide clinical cell supporting capabilities; 1B42 in building 10, which will support viral vector manufacturing; and T30, a 5000 square foot modular building that will serve as the main manufacturing facility for Surgery Branch Cell Therapies, which was completed in March 2021. Cell Processing Facility staff were actively involved in the review of all design and construction documents as well as in drafting and reviewing the commissioning documentation that is being generated for these facilities and are responsible for the cGMP operations of these facilities.

该核心实验室的任务是为国家癌症研究所手术部门建立的免疫疗法计划提供支持。该实验室由Hyunmi Halas博士监督。实验室的主要工作涉及生产大量人类抗癌淋巴细胞，以治疗参加手术分支机构临床试验的晚期转移性癌症患者。靶向淋巴细胞的癌症直接从活检材料中分离出来，或者是通过从患者血液中遗传改性的T淋巴细胞而产生的。 32例患者在2021年8月1日至7月，2022年之间进行切除。是研究切除术，最初的片段是肿瘤浸润淋巴细胞（TIL）的潜在片段。在此期间，在处理片段和随后的til细胞的16个切除术中，有70％提供了足够的肿瘤组织，以提供10多个片段，这些片段被冷冻保存。 3患者切除产生具有肿瘤特异性反应性的反应性片段，从而产生了TIL细胞，该细胞可以在培养物中扩展以进行潜在治疗。这些患者中有2例在2022年中期切除，并且大多数随着片段扩展的切除率目前正在筛选以作为潜在的未来疗法的反应性。 4个患者切除术被确定为反应性片段以及基因改性T淋巴细胞疗法的候选物。发现5例患者没有反应性片段，但发现从肿瘤切除和基因改性疗法中鉴定出的基因改性T淋巴细胞疗法具有反应性新抗原，以提供已知的TCR，以识别鉴定出癌细胞的已知TCR。自2022年2月至2022年7月开放新设施以来，该核心实验室产生的自体细胞疗法的患者使用了9（9）个细胞产品，用于治疗该核心实验室生成的自体细胞疗法的患者。该核心实验室的第二个关键功能是收集，过程和策展人的样品，这些样品来自手术室中的患者。这些样品用于产生上述癌症疗法，并被研究人员在手术分支细胞疗法计划中使用，以评估每个临床试验的进度，并解决鉴定可以实施改善这些试验的变化的研究问题。此外，这些试验的样本有助于产生新的患者疗法的研究。这些研究项目包括1）用基因转导患者的T细胞，其产物将更好地靶向肿瘤或增强内源性肿瘤活性，2）评估注入抗癌淋巴细胞在患者中起作用和生存的能力，3）识别新的癌症相关抗原，可通过抗抗菌细胞靶向的新型抗原群体，4）鉴定出抗性抗菌细胞，4）4）4）4） in personalized T cell therapies 5) Identifying characteristics of infused anticancer cells that are associated with objective tumor regression, 6) Identifying characteristics of patients who are most likely to respond to anticancer T cell therapies, 7) Evaluating selected biological response modifiers tested in Surgery Branch clinical trials, 8) Evaluating new gene delivery systems such as the sleeping beauty transposon, 9) Producing dendritic cell vaccines that are pulsed with代表患者自己独特的诱变症的肽。最后，核心实验室维护并策划了与CGMP制造和抗癌细胞疗法相关的所有来源文档，数据，协议和专业知识。由于手术部门开发的这些疗法的成功，手术部门内的研究人员，壁内NCI实验室，壁外监管机构，工业和学术伙伴以及其他有关方面越来越希望越来越希望获得这些数据，协议和建议。 有必要开发新工具来策划较旧试验的数据。有必要将现有数据转换为可以通过较新的软件包读取的格式，因为旧文件类型已过时，因此必须不会丢失现有数据。自2016年开发质量管理系统（QMS）和研究支持与合规办公室（ORSC）以来，手术分支机构生产设施已实施了多个计划。这些计划包括1。独立质量检查 - 通过与监督该计划的输血医学系的理解备忘录建立。该计划共有7位质量保证专家来管理该计划。 2。管理所有操作的质量管理系统（QMS）。 3。材料管理计划，以确保制造中使用或与患者疗法接触的所有产品/材料均具有最高质量，并且没有掺假。 4。一项环境监测计划，以确保设施保持最高的清洁状态。 5。设备管理计划，以确保制造运营中使用的所有设备都起作用并得到适当维护。 6。一项文档管理计划，可确保所有人员都在审查和批准的程序中工作。 7.一项人员培训计划，可确保能力并强调手术分支机构制造细胞疗法的所有人员的责任和职责。第三方供应商每年通过ORSC对设施和QM进行审核。 3截至2020年12月，以前的主要细胞生产设施3W/TIL实验室不再用于制造。新设施已获得资格和验证用于NIH校园的CGMP蜂窝制造。其中包括预告片10B，它将提供临床细胞支撑功能； 1B42在10号建筑物中，将支持病毒矢量制造； T30是一座5000平方英尺的模块化建筑，它将作为2021年3月完成的手术分支机构疗法的主要制造设施。细胞处理设施的工作人员积极参与所有设计和施工文档的审查，以及为这些设施而生成的调试文档，并负责这些设施，并负责这些设施，并负责这些设施。