Surgery Branch Cell Prep Core

手术分支细胞制备核心

• 批准号: 10703023
• 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/10703023
• 关键词: Activated Lymphocyte; Address; Adoptive Cell Transfers; Air; Antigens; Area; Autologous; B lymphoid malignancy; Back; Biological Response Modifiers; Biopsy; Blood; Blood specimen; Candidate Disease Gene; Carcinoma; Cell Therapy; Cell physiology; Cells; Characteristics; Cholangiocarcinoma; Clinical; Clinical Treatment; Clinical Trials; Colorectal Cancer; Computer software; Contracts; Cryopreservation; Cyclic GMP; Data; Dendritic Cell Vaccine; Development; Disseminated Malignant Neoplasm; Documentation; Effectiveness; Employee; Enrollment; Ensure; Environmental Monitoring; Excision; Extramural Activities; Gene-Modified; Genes; Goals; Human; Immunologics; Immunotherapy; Industrialization; Industry; Infusion procedures; Institution; Laboratories; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Manufactured Materials; Manufacturer; Mission; Mutation; National Cancer Institute; Neoplasm Metastasis; Operative Surgical Procedures; Patients; Peptides; Peripheral Blood Lymphocyte; Physiologic pulse; Procedures; Process; Production; Program Effectiveness; Protocols documentation; Quality Control; Quarantine; Regulation; Research; Research Personnel; Research Project Grants; Research Support; Resected; Sampling; Sanitation; Services; Sleeping Beauty; Somatic Mutation; Source; Surface; System; T cell therapy; T-Lymphocyte; Testing; Time; Tissues; Training; Translating; Tumor Antigens; Tumor Tissue; Tumor-Infiltrating Lymphocytes; United States National Institutes of Health; Update; adverse event monitoring; anti-cancer; authority; base; cancer cell; clinical translation; expiration; gene delivery system; gene therapy; improved; interest; malignant breast neoplasm; melanoma; microbial; neoantigens; novel; novel therapeutics; operation; patient safety; prevent; programs; quality assurance; response; success; synovial sarcoma; therapy development; tool; trend; 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 has been managed 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 in Surgery Branch clinical trials. Cancer-targeting lymphocytes are either isolated directly from biopsied cancer metastases or are generated by genetically modifying T lymphocytes from a patient's blood. 26 patients each underwent a resection between 01-July-2021 and 01-Aug-2021, with 1 patient undergoing 3 independent resections. Of the 28 total resections processed by CPF, 15 resections provided potential source of tumor-infiltrating lymphocytes (TIL) and 13 were research resection from which initial fragments as potential source of tumor-infiltrating lymphocytes (TIL) were not performed. 70% of the 15 resections processed for fragments and subsequent TIL cells during this time provided sufficient tumor tissue to provide 11+ fragments, which were cryopreserved. 5 patient resections yielded reactive fragments with tumor specific reactivity to generate TIL cell which can be expanded in culture for potential treatments. 2 patient resections were identified reactive fragments as well as candidates for gene modified T lymphocyte therapies. 3 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 to provide TCR known to recognize the cancer cells. Sixteen (16) cell products, delivered to patients enrolled on 5 clinical trials, were used to treat patients with autologous cell therapies generated by this core laboratory during FY20 through December 2020. A second critical function of this core lab is to distribute resected cancer tissue, leftover after the clinical treatment needs have been fulfilled. These samples are 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 portion of the clinical translation of anticancer cell therapies carried out in the core lab. 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 data generated in the core lab is not lost as older file types become obsolete. In response to two independent audits of the Surgery Branch cell production facility in early 2016, several programs and systems have been developed to comply with NIH, FDA and industry guidance/best practices. We have established an independent Quality Assurance (QA) program. This QA program functions independently of the cell processing facility and has the authority to stop production or prevent the release of cell-based therapies manufactured by the Surgery Branch cell processing facility when deemed necessary. Additionally, the QA program performs internal audits to ensure compliance with SOPs and procedures and approves the new employee and annual training of the facility staff. These programs ensure that patient safety, along with generating clinically effective anti-cancer cells, is a primary concern of all employees involved in the manufacture of cell-based therapies. A crucial component of the QA program is document control. The document management system used by NCI SB Operations and Quality Assurance group, MediaLab, is employed to ensure that all staff has access to the most update version of SOPs, forms, and regulations used by the cell processing facility. MediaLab allows full tracking of all document versions and changes to ensure better compliance and training for all cell processing facility SOPs and regulations. A cleaning service that specializes in cleanroom sanitation has been contracted by the Office of Research Support and Compliance (ORSC) to clean all NIH aseptic facilities, including NCI SB manufacturing and support facilities, Trailer 10B and T30. The effectiveness of this program is tracked with a newly implemented environmental monitoring program that tracks and trends air and surface quality/cleanliness within the manufacturing areas of the facility. This program identifies potential sources of microbial contamination before they can impact the overall manufacturing operation. The final component of efforts to develop a robust QA system is the development of a materials management program. Materials management controls the acquisition, quarantine, acceptance, and release of all manufacturing materials. The goal of this program is to increase patient safety by improving documentation of source, lot number and expiration date and quality control of all materials used to manufacture cell products within the Surgery Branch cell processing facility. This program is crucial in identifying patient's whose past or pending treatments are associated with a manufacturer recall. The materials management program allows all patients impacted by a recall to be identified and monitored for adverse events. Dr. Xu Zhao is currently the facility manager of the Cell Production Facility at the Surgery Branch of the National Cancer Institute in Bethesda, USA, where the main interest is to establish successful gene therapies and cell-based treatments for patients with advanced metastatic cancer.

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博士管理。实验室的主要努力是生产大量的人类抗癌淋巴细胞，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。靶向癌症的淋巴细胞要么直接从活检的癌症转移酶中分离出来，要么是通过从患者血液中基因修饰T淋巴细胞而产生的。 26例患者在2021年7月至7月1日至01年8月1日进行切除，其中1名患者接受了3个独立切除术。在通过CPF处理的28个总切除术中，有15个切除术提供了潜在的肿瘤浸润淋巴细胞（TIL）和13个研究切除术，是研究切除术，最初的片段作为肿瘤浸润淋巴细胞（TIL）的潜在片段。在此期间，在处理碎片和随后的蒂尔细胞的15个切除术中，有70％提供了足够的肿瘤组织，以提供11+片段，这些片段被冷冻保存。 5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，该细胞可以在培养中扩展以进行潜在治疗。 2个患者切除术被鉴定出反应性片段以及基因改性T淋巴细胞疗法的候选物。 发现3例患者没有反应性片段，但被发现具有反应性新抗原，用于从肿瘤切除中鉴定出的基因修饰的T淋巴细胞疗法，并修饰了基因，以提供已知识别癌细胞的TCR。送给参加5项临床试验的患者的16（16）个细胞产物用于治疗该核心实验室在20财年至2020年12月期间该核心实验室产生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分布切除的癌症组织，满足临床治疗后剩余的剩余。研究人员在手术分支细胞治疗计划中使用这些样本来评估每个临床试验的进展，并解决研究问题，这些问题可以确定可以实施的变化以改善这些试验。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功能和生存的能力，在患者中发挥作用和生存，3）识别新的癌症相关的抗原，可以通过抑制抗原的抗原细胞靶向的新型抗原，4）在抗原抗原中识别抗药性，4）4）抗原因素，4） 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代表患者自己独特的杂种。最后，核心实验室维护并策划了与CGMP制造业相关的所有来源文档，数据，协议和专业知识以及在核心实验室中进行的抗癌细胞疗法的临床翻译部分。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，因为核心实验室中生成的现有数据至关重要，因为旧文件类型已过时。为了响应2016年初对手术分支细胞生产设施的两项独立审核，已经开发了几种计划和系统，以遵守NIH，FDA和行业指导/最佳实践。我们已经建立了一个独立的质量保证（QA）计划。该质量保证程序独立于细胞处理设施的功能，并有权停止生产或防止在认为必要的情况下由手术分支分支机构处理设施制造的基于细胞的疗法。此外，质量保证计划还进行内部审核，以确保遵守SOP和程序，并批准新员工和设施人员的年度培训。 这些程序确保患者的安全以及产生临床有效的抗癌细胞，是所有参与基于细胞疗法的员工的主要关注点。 QA程序的关键组成部分是文档控制。使用NCI SB操作和质量保证小组使用的文档管理系统，用于确保所有员工都可以访问细胞处理设施使用的SOP，表格和法规的最新版本。 Medialab允许对所有文档版本和更改进行全面跟踪，以确保所有细胞处理设施SOP和法规的更好合规性和培训。研究支持与合规办公室（ORSC）签约了一项专门从事洁净室卫生设施的清洁服务，以清洁所有NIH无菌设施，包括NCI SB制造和支持设施，预告片10B和T30。通过新实施的环境监测计划跟踪该计划的有效性，该计划在设施的制造区域跟踪和趋势的空气和表面质量/清洁度。该程序在影响整体制造运营之前确定了微生物污染的潜在来源。开发强大质量检查系统的努力的最终组成部分是制定材料管理计划。材料管理控制所有制造材料的采集，隔离，接受和释放。该计划的目的是通过改善对手术分支机构处理设施中生产细胞产品的所有材料的资源，批号和到期日期的文档，到期日期和质量控制来提高患者安全。该计划对于确定患者的过去或待处理治疗与制造商召回有关的患者至关重要。材料管理计划允许所有受召回影响的患者被识别和监控，以实现不良事件。 Xu Zhao博士目前是美国贝塞斯达国家癌症研究所手术分支的细胞生产设施的设施经理，在那里，主要兴趣是为晚期转移性癌症患者建立成功的基因疗法和基于细胞的疗法。