PET IMAGING OF MART TCR-ENGINEERED CD8 T CELL IMMUNOTHERAPY IN MAN

MART TCR 工程 CD8 T 细胞免疫疗法在人体中的 PET 成像

• 批准号: 7892594
• 负责人: James S. Economou
• 金额: $ 29.26万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-13 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7892594
• 关键词: Acquired Immunodeficiency Syndrome; Advisory Committees; Affinity; Animal Model; Antigens; Biological; CD8B1 gene; Cancer Center; Cells; Clinical; Clinical Trials; Collaborations; Dendritic Cell Vaccine; Dose; Engineering; Frequencies; Genes; Herpesvirus 1; Human; Human Engineering; Image; Immune response; Immunotherapy; Indiana; Institutes; Interleukin-2; Investigation; Laboratories; Language; Lentivirus Vector; Leukocytes; Los Angeles; Medicine; Melanoma Cell; Metastatic Melanoma; Molecular Medicine; Patients; Pediatric Hospitals; Peptides; Phase I Clinical Trials; Physiologic pulse; Positron-Emission Tomography; Recombinant DNA; Recombinants; Regimen; Reporter; Research; Research Infrastructure; Research Personnel; Safety; Science; Simplexvirus; Stem cells; Surface; T-Cell Receptor; T-Lymphocyte; Transgenes; Transgenic Organisms; United States National Institutes of Health; Universities; Viral Vector; cancer immunotherapy; conditioning; gene therapy clinical trial; in vivo; killings; man; molecular imaging; programs; receptor; response; vector

DESCRIPTION (provided by applicant): Significant advances have been made in clinical cancer immunotherapy. Nevertheless, precursor frequency of antigen-reactive T cells remains an important limiting factor in achieving higher clinical response rates. We propose a translational investigation in which a high affinity MART-1 T cell receptor (TCR) and the HSVsr39tk PET reporter/imaging gene are introduced into CDS T cells from metastatic melanoma patients using a lentiviral vector. This vector will be manufactured at the Indiana University National Gene Vector Laboratory. These TCR/tk-engineered T cells will be reintroduced to the patient after a lymphodepleting, but nonmyeloablative conditioning regimen. These adoptively transferred cells will be supported in vivo by systemic interleukin-2 and MART26-35 peptide pulsed dendritic cell vaccines. In this dose-escalation phase I clinical trial, already approved by the NIH Recombinant DNA Advisory Committee, safety and feasibility will be primary end-points, transgenic T cell persistence and in vivo PET imaging will be secondary end-points and clinical response the tertiary end-point. Two specific aims are proposed. In the first, the phase I trial will be conducted with safety, immunological and clinical response end-points. The second aim will focus on biological imaging: clinical trial imaging, quantitative animal modeling using engineered human T cells and assessment of sr39tk-specific immune responses. In this first-in-human clinical investigation, we will utilize a lentiviral vector encoding three transgenes (a, p MART TCR chains, HSV sr39tk) to noninvasively and serially image antitumor immune responses in man. This application is the byproduct of an ongoing collaboration between investigators from UCLA, Caltech, Children's Hospital of Los Angeles and USC. Although the trial will be conducted at UCLA, it takes advantage of the science and infrastructure of 3 research universities, 8 academic departments, 2 gene medicine programs, 3 cancer centers and 4 institutes (Molecular Imaging, Stem Cell, Molecular Medicine, AIDS). Lay summary. We propose to conduct a clinical gene therapy trial in patients with metastatic melanoma. We will use a crippled viral vector to introduce three genes into white blood cells isolated from the patients. Two of these genes will cause these white blood cells to produce a receptor on their surface that will recognize melanoma cells in patients, allowing them to be killed. The third gene will allow these white blood cells to be visualized in patients using a noninvasive PET scan.

描述（由申请人提供）：临床癌症免疫治疗已取得重大进展。然而，抗原反应性 T 细胞的前体频率仍然是实现更高临床反应率的重要限制因素。我们提出了一项转化研究，其中使用慢病毒载体将高亲和力 MART-1 T 细胞受体 (TCR) 和 HSVsr39tk PET 报告基因/成像基因引入转移性黑色素瘤患者的 CDS T 细胞中。该载体将在印第安纳大学国家基因载体实验室生产。这些 TCR/tk 工程 T 细胞将在进行淋巴细胞清除但非清髓性预处理方案后重新引入患者体内。这些过继转移的细胞将在体内得到全身性白细胞介素 2 和 MART26-35 肽脉冲树突状细胞疫苗的支持。在这项已获得 NIH 重组 DNA 咨询委员会批准的剂量递增 I 期临床试验中，安全性和可行性将是主要终点，转基因 T 细胞持久性和体内 PET 成像将是次要终点，临床反应是第三终点终点。提出了两个具体目标。首先，第一阶段试验将针对安全性、免疫学和临床反应终点进行。第二个目标将侧重于生物成像：临床试验成像、使用工程化人类 T 细胞的定量动物模型以及 sr39tk 特异性免疫反应的评估。在这项首次人体临床研究中，我们将利用编码三种转基因（a、p MART TCR 链、HSV sr39tk）的慢病毒载体对人体抗肿瘤免疫反应进行无创连续成像。该应用程序是加州大学洛杉矶分校、加州理工学院、洛杉矶儿童医院和南加州大学的研究人员持续合作的副产品。尽管该试验将在加州大学洛杉矶分校进行，但它利用了 3 所研究型大学、8 个学术部门、2 个基因医学项目、3 个癌症中心和 4 个研究所（分子成像、干细胞、分子医学、艾滋病）的科学和基础设施。平铺总结。我们建议对转移性黑色素瘤患者进行临床基因治疗试验。我们将使用受损的病毒载体将三个基因引入从患者身上分离的白细胞中。其中两个基因将导致这些白细胞在其表面产生一种受体，该受体将识别患者体内的黑色素瘤细胞，从而将其杀死。第三个基因将允许使用无创 PET 扫描在患者体内观察到这些白细胞。