ACTIVATION OF T-CELLS FOR TUMOR SPECIFIC IMMUNOTHERAPY

激活 T 细胞进行肿瘤特异性免疫治疗

• 批准号: 2099543
• 负责人: SUYU SHU
• 金额: $ 20.51万
• 依托单位: CLEVELAND CLINIC FOUNDATION
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-03-01 至 1997-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2099543
• 关键词: CD3 molecule; T lymphocyte; active immunization; antigen receptors; antineoplastics; cytotoxicity; immunofluorescence technique; interleukin 2; laboratory mouse; lymphokines; monoclonal antibody; neoplasm /cancer immunotherapy; passive immunization; phenotype; tissue /cell culture

Several lines of evidence indicate that progressively growing tumor triggers a T cell immune response in the autochthonous host and this immunity can be exploited for therapeutic benefits. Using syngeneic murine tumors, we have previously demonstrated the existence of immunologically sensitized but functionally deficient T lymphocytes in the tumor-draining lymph nodes. These cells, designated as "pre-effector" cells, could be stimulated in vitro by the tumor cells and IL-2 to differentiate into immune effector cells with demonstrable in vivo antitumor effects. However, the requirement of viable tumor cells for stimulating the pre-effector cells represents a severe deterrence to the clinical application of this procedure. Since specific antigenic recognition by T lymphocytes involves the T cell antigen receptor (TCR)/CD3 complex, we recently developed an alternative procedure for pre-effector cell activation. In the absence of tumor cells, pre-effector cells can differentiate into effector cells upon stimulation with anti-CD3 followed by culture in IL-2. Although the mode of anti-CD3/IL-2 activation is not immunologically specific, cells generated mediate tumor-specific reactivity which is apparently determined during the pre-effector cell sensitized in vivo. The ability to elicit a pre-effector cell response is a general phenomenon and demonstrated in many immunogenic as well as poorly immunogenic tumors. However, eliciting the pre-effector cell response to poorly immunogenic tumors requires the use of the bacterial adjuvant Corynebacterium parvum. In addition, the generation of pre-effector cells in vivo is subjected to down-regulation by the progressive tumor growth and by the presence of visceral metastases. Such suppression is mediated by the tumor-induced suppressor cells and is also immunologically specific. Because the mode of activation by the anti-CD3/IL-2 involves the TCR/CD complex and because both the pre-effector and suppressor cell responses are immunologically specific, the goal of the proposed studies is to elucidate the mechanisms of T cell immune recognition of tumor-associated antigens and to develop methodologies for enhancing the pre-effector cell response for generating and utilizing specific T cell immunity in cancer therapy. The specific aims are: (1) to identify and selectively activate pre-effector cells according to their usage of TCR V-beta segments; (2) to analyze lymphokine profiles of antitumor effector cells that correlate with in vivo antitumor functions at the clonal level; (3) to determine the heterogeneity of tumor-associated antigens recognized by the anti- CD3/IL-2 activated immune cells; (4) to characterize tumor-specific suppressor cells and their regulatory effects on the pre-effector cell sensitization; and (5) to develop therapeutic manipulations that could result in augmentation of the pre-effector cell sensitization.

多条证据表明，进行性生长的肿瘤 在原生宿主中触发T细胞免疫反应，这 免疫力可以被利用来获得治疗益处。使用同源基因 小鼠肿瘤，我们之前已经证明了存在 免疫致敏但功能缺陷的T淋巴细胞 肿瘤引流的淋巴结。这些细胞，指定为 “前效应”细胞，可在体外被肿瘤细胞和 IL-2诱导分化为免疫效应细胞 体内抗肿瘤作用。然而，对活的肿瘤细胞的要求 因为刺激前效应器细胞代表着对 该手术的临床应用。由于特定的抗原性 T淋巴细胞的识别涉及T细胞抗原受体 (TCR)/CD3复合体，我们最近开发了一种替代程序来治疗 前效应子细胞激活。在没有肿瘤细胞的情况下， 前效应细胞在刺激下可分化为效应细胞 先用抗CD3抗体，再用IL-2培养。虽然这一模式 抗CD3/IL-2的激活不是免疫特异性的，细胞产生 介导肿瘤特异性反应性，这显然是在 前效应子细胞在体内致敏。能够引出一种 前效应细胞反应是一种普遍现象，在 许多免疫原性肿瘤以及免疫原性差的肿瘤。然而， 激发免疫原性低的肿瘤的前效应细胞反应 需要使用细菌佐剂短小棒状杆菌。在……里面 此外，体内前效应细胞的产生受到 肿瘤的进行性生长和存在下调调控 内脏转移。这种抑制是由肿瘤诱导的 抑制细胞，也是免疫专一性的。 因为抗CD3/IL-2的激活方式涉及TCR/CD 复杂，因为前效应器和抑制器细胞的反应 都是免疫特异性的，拟议研究的目标是 阐明肿瘤相关T细胞免疫识别的机制 抗原，并开发增强前效应细胞的方法 肿瘤中产生和利用特异性T细胞免疫的反应 心理治疗。具体目标是：(1)识别并有选择地激活 根据前效应细胞对TCR V-β片段的使用情况；(2) 分析相关的抗肿瘤效应细胞的淋巴因子谱 具有体内抗肿瘤功能的克隆水平；(3)确定 抗肿瘤相关抗原的异质性 CD3/IL-2激活的免疫细胞；(4)肿瘤特异性 抑制细胞及其对前效应细胞的调节作用 敏化；以及(5)开发能够 导致前效应细胞增敏作用增强。