Stem Cell-Engineered Tumor Immunity in Man

干细胞工程改造人体肿瘤免疫

• 批准号: 8627561
• 负责人: DAVID BALTIMORE
• 金额: $ 279.52万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-03 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8627561
• 关键词: Affinity; Animals; Antitumor Response; Autoimmunity; Basic Science; Biological; Biology; Blood; CD4 Positive T Lymphocytes; Cancer Center; Cancer Patient; Cell Therapy; Clinical; Clinical Research; Clinical Sciences; Clinical Trials; Collaborations; Communicable Diseases; Development; Discipline; Engineering; Foundations; Frequencies; Genes; Genetic; Genetic Engineering; Goals; Hematopoietic; Hematopoietic stem cells; Human; Human Engineering; Image; Immune system; Immunologic Monitoring; Immunology; Immunotherapeutic agent; Institutes; Lentivirus Vector; Leukocytes; Malignant Neoplasms; Medicine; Metastatic Melanoma; Modification; Patient Care; Physicians; Positron-Emission Tomography; Program Research Project Grants; Property; Public Health; Reporter; Research; Research Personnel; Science; Scientist; Skin Cancer; Stem cells; T-Cell Receptor; T-Lymphocyte; Testing; Training; Translational Research; Transplantation; Tumor Antigens; Tumor Immunity; Universities; Work; base; cellular engineering; embryonic stem cell; gene therapy; human disease; induced pluripotent stem cell; killings; man; melanoma; neoplastic cell; pre-clinical; programs; receptor binding; stem; trafficking; tumor; virology

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.

描述（由申请人提供）：人类免疫系统是对抗癌症的潜在强大防线。癌症患者体内存在许多生物学障碍，阻碍肿瘤特异性 T 细胞的扩增、激活、肿瘤运输和杀伤。其中包括 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，高亲和力 TCR 转导干细胞的移植将在受体中创建具有有效抗肿瘤生物学功能的工程免疫系统。因此，该计划项目拨款 (PPG) 的唯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设。 该应用程序是该战略的关键部分，该战略是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）的二十名研究人员历时三年合作的成果，这些大学代表了 4 个癌症中心、2 个基因医学项目、13 个部门和多个研究所。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，设计肿瘤特异性的人类免疫系统。这将在具有 3 个核心支持的 5 个项目的 PPG 中完成。 PPG 将：(1) 开展两项首次人体临床研究，其中使用还表达 PET 报告基因的慢病毒载体将 MART-1 黑色素瘤抗原 TCR 引入 T 细胞和造血干细胞，从而对工程化免疫系统的发育进行连续无创成像，(2) TCR 工程化造血和胚胎干细胞的生物学基础研究， (3)TCR工程基础生物学。细胞和基因治疗、免疫监测和生物成像领域最先进的核心将为这门科学提供支持。 在这个 PPG 中，基础科学和临床科学将并行进行，相互告知；基础科学家和医师科学家将作为一个团队共同努力，开发基于发现的科学，从而改变患者的护理。

项目成果

Permissive secondary mutations enable the evolution of influenza oseltamivir resistance.

• DOI: 10.1126/science.1187816
• 发表时间: 2010-06-04
• 期刊: Science (New York, N.Y.)
• 作者: Bloom JD;Gong LI;Baltimore D
• 通讯作者: Baltimore D

Dendritic cell-directed vaccination with a lentivector encoding PSCA for prostate cancer in mice.

• DOI: 10.1371/journal.pone.0048866
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Xiao L;Joo KI;Lim M;Wang P
• 通讯作者: Wang P

Enhanced therapeutic efficacy of iRGD-conjugated crosslinked multilayer liposomes for drug delivery.

• DOI: 10.1155/2013/378380
• 发表时间: 2013
• 期刊: BioMed research international
• 作者: Liu Y;Ji M;Wong MK;Joo KI;Wang P
• 通讯作者: Wang P

Visualization of intracellular pathways of engineered baculovirus in mammalian cells.

• DOI: 10.1016/j.virusres.2014.01.006
• 发表时间: 2014-03-06
• 期刊: Virus research
• 影响因子: 5
• 作者: Liu Y;Joo KI;Lei Y;Wang P
• 通讯作者: Wang P

68Ga-DOTATATE PET/CT Interobserver Agreement for Neuroendocrine Tumor Assessment: Results of a Prospective Study on 50 Patients.

• DOI: 10.2967/jnumed.116.179192
• 发表时间: 2017-02
• 期刊: Journal of nuclear medicine : official publication, Society of Nuclear Medicine
• 作者: Fendler WP;Barrio M;Spick C;Allen-Auerbach M;Ambrosini V;Benz M;Bluemel C;Grewal RK;Lapa C;Miederer M;Nicolas G;Schuster T;Czernin J;Herrmann K
• 通讯作者: Herrmann K