PILOT/FEASIBILITY STUDY TO EVALUATE THE SAFETY OF CELLULAR

评估蜂窝安全性的试点/可行性研究

• 批准号: 7603866
• 负责人: Michael C Jensen
• 金额: $ 3.7万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7603866
• 关键词: B-Cell Lymphomas; B-Lymphocytes; Back; Blood; Blood Cells; CD19 Antigens; CD19 gene; Cells; Computer Retrieval of Information on Scientific Projects Database; Cytotoxic T-Lymphocytes; DNA; Daily; Feasibility Studies; Follicular Lymphoma; Funding; Grant; Hormones; Human; Immune System Part; Immune response; Immune system; Immunoglobulins; Immunotherapy; Infection; Infusion procedures; Injection of therapeutic agent; Institution; Interleukin-2; Intravenous infusion procedures; Laboratories; Lymphoma; Mus; Numbers; Pharmaceutical Preparations; Preparation; Proteins; Purpose; Recombinant DNA; Recombinants; Research; Research Personnel; Resources; Risk; Safety; Skin; Source; Stream; Study Subject; T-Lymphocyte; Testing; Time; United States National Institutes of Health; Veins; Work; cell type; chemotherapy; day; experience; fighting; fludarabine; killings; neoplastic cell; quality assurance; receptor; response; rituximab; subcutaneous

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The purpose of this study is to assess the safety and feasibility of collecting T cells (blood cells that help fight infection) from subjects with a type of follicular lymphoma of B-cell origin, genetically modifying them in the laboratory to recognize this type of lymphoma cell, and infusing them (giving them back by vein) to the same subjects. In addition to assessing the safety of delivering lymphoma-specific T cells, the safety of using the hormone IL-2 to support the survival of the infused T cells will also be studied. This study will also try to determine how long these cells stay in the blood stream after re-infusion and if they attack lymphoma cells once they are inside the body. In this study, cells that are part of the immune system, called cytotoxic T lymphocytes (CTL) or T cells, will be collected from study subjects with follicular lymphoma of B cell origin. These T cells will then be genetically modified in the laboratory to kill follicular lymphoma cells of B cell origin. To do this, a piece of recombinant (artificial) DNA will be made in the laboratory and inserted into the T cells. This piece of recombinant DNA will allow the T cell to make a "receptor" that recognizes CD19, a substance expressed by lymphoma cells of B cell origin. The number of genetically modified T cells will be expanded in the laboratory. The cells will undergo safety and quality assurance testing. The cells will also be tested to make sure they recognize CD19. After all of these steps have been completed, the genetically modified T cells will be infused intravenously (IV, by vein) into the subject from whom the T cells were orignally collected. While these genetically modified T cells have been shown to kill tumor cells in the laboratory and in mice, it is not known whether they will work in a similar manner in humans. Normal B cells also express the CD19 molecule. B cells make a protein called immunoglobulin (Ig) that is important in fighting off infections. The genetically modified T cells are not capable of distinguishing a normal B cell from a lymphoma cell derived from a B cell. Therefore, the genetically modified T cells would be likely to target both types of cells. To lower the risk that the genetically modified T cells will attack normal B cells, subjects are given a single IV infusion of the commercially available drug rituximab before the first T cell infusion. Rituximab will lower the amount of both lymphoma cells derived from B cells and normal B cells (that would otherwise serve as targets for the genetically modified T cells). During the period of time that the number of B cells is lower, subjects who experience an infection may be given IVIg, a purified protein preparation of Ig obtained from healthy donors that can be given IV. In previous immunotherapy studies, subjects' immune systems generated a response against the genetically modified T cells that caused them to be destroyed early. Another reason for giving rituximab before the first T cell infusion is that it will lower the risk of such an immune response. In addition, beginning the fourth day after the first T cell infusion, subjects will also be given up to five daily infusions of fludarabine. Fludarabine is a commerically available chemotherapy agent that will also help lower the risk of an immune response. The hormone IL-2 will also be given by subcutaneous (under the skin) injection to help the genetically modified T cells survive for a longer period of time inside the subject's body.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 这项研究的目的是评估从具有B细胞起源的类型的受试者中收集T细胞（有助于抵抗感染的血细胞）的安全性和可行性，从而在实验室中遗传修饰它们以识别这种类型的淋巴瘤细胞，并将其吸入（将其融入静脉）给同一受试者。 除了评估输送淋巴瘤特异性T细胞的安全性外，还将研究使用激素IL-2支持注入T细胞的存活的安全性。 这项研究还将试图确定这些细胞在重新灌注后留在血流中多长时间，以及它们一旦体内的淋巴瘤细胞攻击淋巴瘤细胞。 在这项研究中，将是免疫系统一部分的细胞，称为细胞毒性T淋巴细胞（CTL）或T细胞，将从B细胞起源的卵泡淋巴瘤的研究受试者中收集。 然后，这些T细胞将在实验室中进行基因修饰，以杀死B细胞起源的卵泡淋巴瘤细胞。 为此，将在实验室中制作一块重组（人造）DNA并插入T细胞。 这种重组DNA将使T细胞成为识别CD19的“受体”，CD19是由B细胞起源的淋巴瘤细胞表达的物质。 遗传修饰的T细胞的数量将在实验室中扩大。 细胞将经过安全和质量保证测试。 这些细胞还将进行测试以确保它们识别CD19。 所有这些步骤都完成后，将遗传修饰的T细胞静脉注射（IV，静脉）将其注入口径收集T细胞的受试者中。 尽管这些遗传修饰的T细胞已被证明可以杀死实验室和小鼠中的肿瘤细胞，但尚不清楚它们是否会在人类中以类似的方式工作。 正常B细胞​​还表达CD19分子。 B细胞形成一种称为免疫球蛋白（IG）的蛋白质，对于抗击感染很重要。 转基因的T细胞无法将正常B细胞​​与源自B细胞衍生的淋巴瘤细胞区分开。 因此，转基因T细胞可能靶向两种细胞。 为了降低转基因T细胞会攻击正常B细胞​​的风险，受试者在第一次T细胞输注之前将单次IV输注市售药​​物利妥昔单抗。 利妥昔单抗将降低源自B细胞和正常B细胞​​的两个淋巴瘤细胞的量（否则这将作为转基因T细胞的靶标）。 在B细胞数量较低的一段时间内，可能会给予感染的受试者IVIG，这是从健康供体获得的Ig的纯化蛋白质制备，可以给予IV。 在先前的免疫疗法研究中，受试者的免疫系统对转基因T细胞产生了反应，导致它们早期被破坏。 在第一次T细胞输注之前给予利妥昔单抗的另一个原因是，它将降低这种免疫反应的风险。 此外，从第一次T细胞输注后的第四天开始，受试者也将每天赋予氟达拉滨的五次输注。 氟达拉滨是一种商业上可用的化学疗法剂，还将有助于降低免疫反应的风险。 皮下（在皮肤下）注射中也将给予激素IL-2，以帮助遗传改性的T细胞在受试者体内长期存活。