New Chimeric Antigen Receptors for Treating Hematologic Malignancies

用于治疗血液恶性肿瘤的新型嵌合抗原受体

• 批准号: 8553170
• 负责人: James Kochenderfer
• 金额: $ 15.07万
• 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/8553170
• 关键词: Affect; Antigen Receptors; Antigens; B-Cell Lymphomas; CD28 gene; CD3 Antigens; Cells; Chronic Lymphocytic Leukemia; Clinical Trials; Future; Hematologic Neoplasms; Lead; Lentivirus Vector; Malignant Neoplasms; Modeling; Monoclonal Antibodies; Mus; Patients; Proliferating; Staging; T-Cell Activation; T-Lymphocyte; Testing; Work; cancer cell; cytokine; design; extracellular; improved; in vitro Assay; in vitro testing; in vivo; killings; receptor expression; receptor function; research clinical testing; vector

In the past year, this project has consisted of testing multiple factors that could affect the function of chimeric antigen receptors (CARs). First we compared lentiviral vector to the gammaretroviral vector that we have used in our current clinical trials. T cells transduced with the lentiviral vector had shorter duration of CAR expression; therefore, we have decided to perform future work with the gammaretroviral vector. Chimeric antigen receptors consis to several components, the antigen-recognition moiety that is usually derived from a monoclonal antibody, a hinge region that connects the antigen-recognition moiety to the transmembrane portion, costimulatory domains such as 4-1BB and CD28, and T cell activation domains such as CD3-zeta. We have constructed 10 new CARs over the past 6 months to test various components of CARs. T cells are transduced with the various CARs by using a gammaretroviral vector, and in vitro assays are carried out. The aim is to find CARs that impart T cells with the ability to kill cancer cells and proliferate without producing large amounts of potentially toxic inflamatory cytokines. We have found that changing the hinge region, costimulatory domains, or T cell activation domains all cause profound differences in CAR function. Following extensive in vitro testing, we will test promising CARs in a murine model within the next year. This work is all at early stages, but hopefully it will lead to improved CARs for clinical testing within the next 2-3 years.

在过去的一年中，该项目包括测试可能影响嵌合抗原受体（CARS）功能的多个因素。 首先，我们将慢病毒载体与我们在当前临床试验中使用的γ逆转录病毒载体进行了比较。 慢病毒载体转导的T细胞的CAR表达持续时间较短。因此，我们决定使用γ逆转录病毒载体进行未来的工作。 嵌合抗原受体cons cons cons cons cons cons，通常源自单克隆抗体的抗原识别部分，该抗体抗体是将抗原识别部分连接到跨膜部分的铰链区域，即跨膜部分，cotimulation tobion，例如4-1B和CD28和T细胞活化域，例如CD3-CD3-cd3-szeta。 在过去的6个月中，我们已经建造了10辆新车，以测试汽车的各种组件。 通过使用γ逆转录病毒载体将T细胞用各种汽车转导，并进行体外测定。 目的是找到能够杀死癌细胞和增殖的T细胞的汽车，而无需产生大量潜在的毒性炎性细胞因子。我们发现，改变铰链区域，共刺激域或T细胞活化域都会在CAR功能上产生深远的差异。 经过广泛的体外测试，我们将在明年的鼠模型中测试有希望的汽车。这项工作都处于早期阶段，但希望它将在未来2 - 3年内改善临床测试的汽车。