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

描述（由申请人提供）：临床癌症免疫治疗取得重大进展。然而，抗原反应性T细胞的前体频率仍然是实现更高临床应答率的重要限制因素。我们提出了一项转化研究，利用慢病毒载体将高亲和力的MART-1 T细胞受体（TCR）和HSVsr39tk PET报告/成像基因引入转移性黑色素瘤患者的CDS T细胞。该载体将在印第安纳大学国家基因载体实验室制造。这些TCR/tk工程T细胞将在淋巴细胞消耗后重新引入患者，但非清髓性调理方案。这些过继性转移的细胞将在体内得到全身白介素-2和MART26-35肽脉冲树突状细胞疫苗的支持。在这个剂量递增的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。提出了两个具体目标。在第一阶段，I期试验将以安全性、免疫学和临床反应终点进行。第二个目标将集中在生物成像：临床试验成像，利用工程人类T细胞进行定量动物建模和评估sr39tk特异性免疫反应。在这项首次人体临床研究中，我们将利用一种慢病毒载体编码三种转基因（a、p MART TCR链、HSV sr39tk），对人类抗肿瘤免疫反应进行非侵入性和序列成像。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研究人员持续合作的副产品。虽然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。总结。我们建议在转移性黑色素瘤患者中进行临床基因治疗试验。我们将使用一个残缺的病毒载体将三个基因导入从病人身上分离出来的白细胞中。其中两个基因会使这些白细胞在其表面产生一种受体，这种受体可以识别患者体内的黑色素瘤细胞，从而杀死它们。第三个基因将允许使用无创PET扫描在患者体内观察这些白细胞。

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.