OVARIAN CARCINOMA TIL TREATMENT AFTER IFN GAMMA/IL2

IFN GAMMA/IL2 治疗后的卵巢癌

• 批准号: 2107695
• 负责人: RALPH Stuart FREEDMAN
• 金额: $ 18.93万
• 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/2107695
• 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.

该交互式R01提案的长期目标是发展 上皮卵巢癌的新有效治疗方法 （EOC）基于肿瘤浸润淋巴细胞的体内激活 （TIL）特定于自体肿瘤。 尽管最近进展 EOC的化学疗法这些患者的存活情况很大 需要。 在本赠款申请中要检验的假设是 可以从腹膜渗出液开发出卵巢TIL衍生的T细胞系 腹膜内（IP）启动后EOC患者的细胞（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启动的问题 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； （b） 恢复大量CD3+ Tcralphabeta+淋巴细胞 表达CD8+或CD4+表型的腹膜腔（P.C.）； （C） 从PEC使用CD8+或CD4+ T细胞线的能力 T细胞纯化程序和（d）获得T细胞线 在IP启动后，用RIFN-LAMBDA以（i_ 自体肿瘤细胞溶解活性和/或（II）细胞因子的产生。 所有这些假设都集中在阐明作用机理， 在体内，这些tils，只能与 临床试验，其中EOC患者接受了一种策略 从（pec）开发的（pec）在体内获得的（pec） 用RIFN-LAMBDA和IL-2启动。 临床试验遵循基本 我们在EOC的IP收养免疫疗法试验中使用的设计 患者。 使用RIFN-LAMBDA的IP启动是我们试验的新功能 设计。 （e）我们还将在单独的协议中检验假设 那就是：卵巢底底的T细胞系集中在肿瘤部位 IP注入。 我们的具体目的是：确定IP启动是否 RIFN-LAMBDA的EOC患者随后是低剂量RIL-2相关的患者 （1）MHC I类或II类表面抗原的表达增加 在体内EOC细胞上，以及（2）产生卵巢TIL衍生的T细胞 （a）表达CD8+ tcralphabeta+或 CD4+ tcralphabeta+表型，（b）在 （i）自体肿瘤细胞细胞毒性和/或（ii）细胞因子的术语 生产。 其他具体目的是（3）确定频率和 有毒事件的强度和/或由 包括细胞因子和IP的IP启动的治疗策略 用RIFN-LAMBDA处理，然后是细胞因子启动的T细胞系和 低剂量RIL-2，（4）确定纯化的卵巢T细胞的能力 线以集中在肿瘤部位。