Stem Cell-Engineered Tumor Immunity in Man

描述（由申请人提供）：人体免疫系统是对抗癌症的潜在强大防线。癌症患者中存在许多生物学障碍，这些障碍阻碍肿瘤特异性T细胞扩增、活化、肿瘤运输和杀伤。其中之一是T细胞前体频率不足和T细胞受体（TCR）对肿瘤抗原的结合亲和力低。我们的假设是，移植高亲和力TCR转导的干细胞将在受体中产生具有有效抗肿瘤生物学的工程免疫系统。因此，该项目资助（PPG）的唯一目标是通过尝试控制或治愈转移性黑色素瘤来验证这一假设。 该申请是该战略的关键部分，该战略由来自四所研究型大学（加州理工学院，加州大学洛杉矶分校，南加州大学，康涅狄格大学）的数十名研究人员组成，代表4个癌症中心，2个基因医学项目，13个部门和几个研究所。我们的研究小组将融合免疫学、基因工程、干细胞生物学、病毒学、生物成像和人类基因医学等学科，设计肿瘤特异性人类免疫系统。这将在一个项目规划补助金中完成，其中5个项目由3个核心支助。PPG将：（1）进行两项首次人体临床研究，其中使用慢病毒载体将MART-1黑色素瘤抗原TCR引入T细胞和造血干细胞，所述慢病毒载体还表达PET报告子，允许对工程化免疫系统的发育进行连续非侵入性成像，（2）TCR工程化造血和胚胎干细胞的生物学的基础研究，TCR工程的基础生物学。细胞和基因治疗、免疫监测和生物成像的最新核心技术将支持这一科学。 在这个PPG中，基础科学和临床科学将并行进行，相互通报;基础科学家和医生科学家将作为一个团队共同努力，开发基于发现的科学，改变患者的护理。

DESCRIPTION (provided by applicant): The human immune system is a potentially powerful line of defense against cancer. Many biological obstacles exist in cancer patients that thwart tumor-specific T cell expansion, activation, tumor trafficking and killing. Among these is inadequate T cell precursor frequency and low T cell receptor (TCR) binding affinity for tumor antigen. Our hypothesis is that transplantation of high affinity TCR-transduced stem cells will create in the recipient an engineered immune system with potent antitumor biology. Thus, the single goal of this Program Project Grant (PPG) is to test this hypothesis by attempting to control or cure metastatic melanoma. This application is a key part of the strategy to arise from a 3-year collaboration among a score of investigators from four research universities (Caltech, UCLA, USC, UCONN) representing 4 cancer centers, 2 gene medicine programs, 13 departments and several institutes. Our research group will converge the disciplines of immunology, genetic engineering, stem ceil biology, virology, biological imaging and human gene medicine to engineer a tumor-specific human immune system. This will be accomplished in a PPG with 5 projects supported by 3 cores. The PPG will: (1) undertake two first-in-human clinical investigations in which a MART-1 melanoma antigen TCR will be introduced into T cells and hematopoietic stem cells using a lentiviral vector also expressing a PET reporter allowing serial noninvasive imaging of the development of an engineered immune system, (2) fundamental studies of the biology of TCR engineered hematopoietic and embryonic stem cells, and (3) basic biology of TCR engineering. State of the art cores in cell and gene therapy, immunological monitoring and biological imaging will support this science. In this PPG, basic and clinical science will be conducted in parallel, each informing the other; basic scientists and physician-scientists will work together as a team to develop discovery-based science that will change the care of patients.