OVARIAN CARCINOMA TIL TREATMENT AFTER IFN GAMMA/IL2

IFN GAMMA/IL2 治疗后的卵巢癌

• 批准号: 2107694
• 负责人: RALPH Stuart FREEDMAN
• 金额: $ 18.2万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 1998-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2107694
• 关键词: MHC class I antigen; MHC class II antigen; T lymphocyte; clinical trials; clone cells; combination therapy; cytokine; cytotoxic T lymphocyte; epithelium; genetic transduction; human subject; human therapy evaluation; interferon gamma; interleukin 2; neoplasm /cancer immunotherapy; ovary neoplasms; passive immunization; recombinant DNA; surface antigens

The long-term objectives of this interactive R01 proposal are to develop new and effective treatment approaches for epithelial ovarian cancer (EOC) based upon the activation in vivo of tumor infiltrating lymphocytes (TIL) specific for autologous tumor. Notwithstanding recent advances in the chemotherapy of EOC the survival of these patients leaves much to be desired. The hypotheses to be tested in this grant application are that ovarian TIL-derived T-cell lines can be developed from peritoneal exudate cells (PEC) of EOC patients after intraperitoneal (IP) priming with interferon-lambda (rLFN-lambda) followed by low doses of IL-2. In particular, we will address the issues whether IP priming with these cytokines is correlated with (a) increased proportions of tumor cells that express MHC Class I and/or Class II surface antigens in vivo; (b) recovery of large numbers of CD3+TCRalphabeta+ lymphocytes from the peritoneal cavity (P.c.) that express either CD8+ or CD4+ phenotypes; (c) an ability to expand either CD8+ or CD4+ T-cell lines from PEC utilizing a T cell purification procedure and (d) that the T-cell lines obtained after IP priming with rIFN-lambda exhibit specificity in terms of (i_ autologous tumor cell cytolytic activity and/or (ii) cytokine production. All these hypotheses are focused on elucidating the mechanisms of action, in vivo, of these TILs and can be addressed only in conjunction with a clinical trial in which patients with EOC are treated with a strategy of adoptively transferred TIL developed from (PEC) obtained after in vivo priming with rIFN-lambda and IL-2. The clinical trial follows a basic design that we have used in IP adoptive immunotherapy trials of EOC patients. IP priming with rIFN-lambda is a novel feature of our trial design. (e) We will also test the hypothesis in a separate protocol that: ovarian TIL-derived T-cell lines concentrate at tumor sites after IP injection. Our specific aims are to: Determine whether IP priming of EOC patients with rIFN-lambda followed by low dose rIL-2 correlates with (1) Increased expression of MHC Class I or Class II surface antigens on EOC cells in vivo, and (2) Production of ovarian TIL-derived T-cell lines from PEC that (a) express either the CD8+TCRalphabeta+ or CD4+TCRalphabeta+ phenotype, and (b) exhibit tumor specific activity in terms of (i) Autologous tumor cell cytotoxicity and/or (ii) cytokine production. Other specific aims are to (3) Determine the frequency and intensity of toxic events and/or clinical responses that result from a treatment strategy that includes IP priming with cytokines and IP treatment with rIFN-lambda followed by cytokine primed T-cell lines and low dose rIL-2, and (4) Determine the ability of purified ovarian T-cell lines to concentrate at tumor sites.

此交互式 R01 提案的长期目标是开发 上皮性卵巢癌新的有效治疗方法 (EOC) 基于肿瘤浸润淋巴细胞的体内激活 (TIL) 特异性针对自体肿瘤。 尽管最近取得了进展 EOC 的化疗对这些患者的生存有很大影响 想要的。 本拨款申请中要测试的假设是 卵巢 TIL 衍生 T 细胞系可从腹膜渗出液中培养 EOC 患者腹膜内 (IP) 预充后的细胞 (PEC) 干扰素-lambda (rLFN-lambda)，然后是低剂量的 IL-2。 在 特别是，我们将解决 IP 启动是否与这些问题 细胞因子与 (a) 肿瘤细胞比例增加相关 在体内表达MHC I类和/或II类表面抗原； (二) 从细胞中回收大量 CD3+TCRαβ+ 淋巴细胞 表达 CD8+ 或 CD4+ 表型的腹膜腔 (P.c.)； (三) 利用 PEC 扩增 CD8+ 或 CD4+ T 细胞系的能力 T 细胞纯化程序和 (d) T 细胞系获得 用 rIFN-lambda 进行 IP 引发后，在 (i_ 自体肿瘤细胞的溶细胞活性和/或（ii）细胞因子的产生。 所有这些假设都集中在阐明作用机制， 在体内，这些 TIL 只能与 EOC 患者接受以下策略治疗的临床试验 过继转移的 TIL 是从体内获得的 (PEC) 开发的 用 rIFN-lambda 和 IL-2 引发。 临床试验遵循基本原则 我们在 EOC 的 IP 过继免疫治疗试验中使用的设计 患者。 rIFN-lambda 的 IP 启动是我们试验的一个新颖特点 设计。 (e) 我们还将在单独的协议中检验假设 认为：卵巢 TIL 衍生的 T 细胞系在肿瘤部位集中 IP注入。 我们的具体目标是： 确定 IP 启动是否有效 EOC 患者接受 rIFN-lambda 治疗后接受低剂量 rIL-2 治疗的比例相关 (1) MHC I 类或 II 类表面抗原表达增加 对体内 EOC 细胞的影响，以及 (2) 卵巢 TIL 衍生 T 细胞的产生 来自 PEC 的细胞系 (a) 表达 CD8+TCRalphabeta+ 或 CD4+TCRalphabeta+ 表型，并且 (b) 在以下方面表现出肿瘤特异性活性： (i) 自体肿瘤细胞细胞毒性和/或 (ii) 细胞因子术语 生产。 其他具体目标是 (3) 确定频率和 毒性事件和/或临床反应的强度 治疗策略，包括用细胞因子和 IP 启动 IP 用 rIFN-lambda 治疗，然后用细胞因子引发的 T 细胞系治疗， 低剂量 rIL-2，以及 (4) 测定纯化卵巢 T 细胞的能力 线集中在肿瘤部位。