Stem Cell-Engineered Tumor Immunity in Man

描述(申请人提供)：人体免疫系统是抵御癌症的一条潜在的强大防线。癌症患者存在许多生物学障碍，这些障碍阻碍了肿瘤特异性T细胞的扩增、激活、肿瘤转移和杀伤。其中之一是T细胞前体频率不足和T细胞受体(TCR)与肿瘤抗原的低亲和力。我们的假设是，移植高亲和力TCR转导的干细胞将在受者体内创建具有强大抗肿瘤生物学活性的工程化免疫系统。因此，该计划项目赠款(PPG)的单一目标是通过尝试控制或治愈转移性黑色素瘤来检验这一假说。 这项申请是该战略的关键部分，来自四所研究型大学(加州理工大学、加州大学洛杉矶分校、南加州大学、康涅狄格州大学)的数十名研究人员经过3年的合作，代表了4个癌症中心、2个基因医学项目、13个系和几个研究所。我们的研究小组将融合免疫学、遗传工程、干细胞生物学、病毒学、生物成像和人类基因医学等学科，设计出肿瘤特异性的人类免疫系统。这将在一个由3个核心支持的5个项目的PPG中完成。PPG将：(1)进行两项首次人类临床研究，将MART-1黑色素瘤抗原TCR导入T细胞和造血干细胞，使用同时表达PET报告基因的慢病毒载体，从而对工程免疫系统的发展进行一系列无创成像；(2)对TCR工程造血和胚胎干细胞的生物学进行基础研究；以及(3)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方面的最新核心将支持这一科学。 在这个PPG中，基础科学和临床科学将并行进行，相互告知；基础科学家和内科科学家将作为一个团队合作，开发基于发现的科学，这将改变患者的护理。

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.