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获得较高临床应答率的重要限制因素。我们提出了一项翻译研究，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/成像基因导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设计的T细胞将在淋巴耗竭但非清髓性调节方案后重新注入患者体内。这些过继转移的细胞将在体内得到系统白介素2和MART26-35多肽冲击的树突状细胞疫苗的支持。在这项已经得到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，临床反应将是第三终点。提出了两个具体目标。在第一阶段，第一阶段试验将在安全性、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方面：临床试验成像，使用工程化人类T细胞进行定量动物建模，以及评估sr39tk特异性免疫反应。在这项首次人类临床研究中，我们将利用编码三个转基因(a，p-Mart TCR链，HSV sr39tk)的慢病毒载体来无创和连续地成像人类的抗肿瘤免疫反应。这款应用程序是加州大学洛杉矶分校、加州理工大学、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。虽然这项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。版面总结。我们建议在转移性黑色素瘤患者中进行一项临床基因治疗试验。我们将使用残缺的病毒载体将三个基因导入从患者身上分离出来的白细胞。其中两个基因将导致这些白细胞在其表面产生一种受体，该受体将识别患者的黑色素瘤细胞，从而使它们被杀死。第三个基因将允许使用非侵入性PET扫描在患者身上显示这些白细胞。

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.