T CELL COSTIMULATION IN ANTITUMOR RESPONSES

T 细胞共刺激在抗肿瘤反应中的作用

• 批准号: 2098691
• 负责人: JAMES P ALLISON
• 金额: $ 18.41万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-08-20 至 1997-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2098691
• 关键词: T cell receptor; antireceptor antibody; athymic mouse; biological signal transduction; cell mediated cytotoxicity; cytotoxic T lymphocyte; gene therapy; helper T lymphocyte; laboratory mouse; leukocyte activation /transformation; melanoma; monoclonal antibody; natural killer cells; neoplasm /cancer immunotherapy; passive immunization; tissue /cell culture; transfection; tumor antigens

A number of recent studies suggest that one of the reasons that tumors do not provoke protective immune responses in the host is that tumors do not induce effective "help" for the generation of cytotoxic T lymphocytes (CTL). The basis for this failure may be that tumors lack the signals necessary for activation of T cells. It has been demonstrated that T cells require two signals for activation, an antigen-specific signal generated via the antigen receptor, and a second costimulatory signal. Without the second signal, Tcells not only fail to respond, but enter a long-lived stated of antigen-specific anergy. Recent studies have strongly implicated the T cell surface molecule CD28 as the costimulatory receptor, and the B7 molecule as its ligand on the antigen presenting cell. Expression of the costimulatory ligand is largely restricted to B cells, macrophages, and dendritic cells. Many solid tumors appear to lack B7 expression and thus may have a poor capacity to directly activate T cell responses and may even induce specific non-responsiveness. We propose a novel approach to immunotherapy which will exploit the costimulatory receptor and its ligand to enhance the immunogenicity of tumors in a mouse model. A monoclonal antibody to the costimulatory receptor CD28 will be used to provide costimulation systemically, and the gene for the costimulatory ligand B7 will be used to provide costimulation specifically by the tumor. The effectiveness of the antibody and gene therapy approaches in preventing the growth of primary tumors, established tumors, and in eliciting immunity to subsequent tumor challenge will be assessed in vivo. The mechanism of protection will be determined by analyzing helper and killer T cells in treated mice. We will also determine whether the costimulatory approach can be used in the long term propagation of tumor specific T cells in vitro for use in adoptive immunotherapy and the identification of tumor-specific antigens. Since reagents are currently available for the human costimulatory receptor and ligand, the results of this study can be rapidly transferred to treatment of human cancer.

最近的一些研究表明，肿瘤发生的原因之一是， 不会在宿主中引起保护性免疫反应的原因是肿瘤不会 诱导有效的“帮助”细胞毒性T淋巴细胞的产生 （CTL）。 这种失败的基础可能是肿瘤缺乏信号 这是激活T细胞所必需的。 结果表明，T 细胞需要两种信号来激活，一种是抗原特异性信号， 通过抗原受体产生的第一共刺激信号和第二共刺激信号。 如果没有第二个信号，T细胞不仅不能做出反应，而且会进入一个 抗原特异性无反应性的长期状态。 最近的研究 强烈暗示T细胞表面分子CD28作为共刺激分子， 受体，B7分子作为其抗原呈递上的配体 cell. 共刺激配体的表达主要限于B 细胞、巨噬细胞和树突细胞。 许多实体瘤似乎 缺乏B7表达，因此可能具有较差的直接激活 T细胞反应，甚至可能诱导特异性无反应性。 我们 提出了一种新的免疫治疗方法， 共刺激受体及其配体，以增强 小鼠模型中的肿瘤。 抗共刺激因子的单克隆抗体 受体CD28将用于提供系统性共刺激， 共刺激配体B7的基因将用于提供 肿瘤特异性的共刺激。 的有效性 抗体和基因治疗方法在预防原发性 肿瘤，已建立的肿瘤，以及引发对随后的肿瘤的免疫 将在体内评估攻击。 保护机制将是 通过分析治疗小鼠中的辅助和杀伤T细胞来确定。 我们 还将确定共刺激方法是否可以用于 肿瘤特异性T细胞在体外的长期增殖， 过继免疫治疗和肿瘤特异性抗原的鉴定。 由于目前可获得用于人共刺激因子的试剂， 受体和配体，这项研究的结果可以迅速转移 人类癌症的治疗。