LABORATORY STUDIES WITH INTRAPERITONEAL RHIL-12 THERAPY

腹腔内 RHIL-12 治疗的实验室研究

• 批准号: 2869812
• 负责人: RENATO LENZI
• 金额: $ 10万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-18 至 2000-09-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2869812
• 关键词: clinical research; clinical trial phase I; drug administration routes; human subject; human therapy evaluation; interferon gamma; interleukin 12; neoplasm /cancer immunotherapy; peritoneum neoplasm; recombinant proteins

The long-term goal of these studies is to develop effective immunotherapy with recombinant human interleukin-12 (rhIL-12) for the treatment of patients with peritoneal carcinomatosis. Peritoneal carcinomatosis due to either Mullerian or Gastrointestinal tract (GIT) malignancies is a major cause of morbidity and death. Despite recent advances, the results of presently available therapy leave much to be desired. There has been renewed interest in intraperitoneal (IP) therapies for malignancies that affect the peritoneal cavity. Recently rhIL-12 has been introduced into clinical trials. This cytokine is of particular interest since in animal studies it has been shown to be a powerful inducer of cytotoxic antitumor activity and of the differentiation of activation of T-helper 1 (TH1) lymphocytes, and because of its potential for synergy with other biotherapeutic agents. The hypothesis that rhIL-12 will enhance antitumor immunity in patients with peritoneal carcinomatosis caused by either Mullerian or GIT malignancies will be tested by elucidating mechanisms of action of rhIL-12 in patients participating in a phase I clinical study of IP rhIL-12. Therefore the specific aims are: (1) To determine, (a) whether interferon-g (IFN-gamma) levels are increased in the peritoneal cavity of patients treated with IP rHIL-12, (b) whether CD3+ (TH1) and CD3-(NK) lymphocytes are responsible for IFN-gamma production, and (c) whether MHC Class I and Class II expression on tumor calls is augmented by IP rhIL-12. (2) To determine whether IP rhIL-12 increases expression of activation markers on peritoneal NK and T-cells and expression of costimulatory and accessory molecules on antigen presenting cells. (3) To determine whether IP rhIL-12 treatment results in (a) the in vivo development of cytotoxic lymphocytes (CTL) and NK calls that exhibit augmented cytolytic activity against autologous tumor cells, and (b) to determine whether T-cell lines and clones with augmented cytotoxic activity against autologous tumor cells can be developed from peritoneal lymphocytes of patients treated with rhIL-12. (4) To determine whether IP rhIL-12 results in (a) increased production of tumor growth inhibitory molecules in the peritoneal cavity, specifically inducible nitric oxide synthetase (INOS), (b) decreased production of immunosuppressive molecules, specifically transforming growth factor beta and interleukin-10 and (c) increased levels of interferon inducible protein-10 (IP-10), a chemokine with antiangiogenesis activity.

这些研究的长期目标是开发有效的 重组人白细胞介素-12（rhIL-12）免疫治疗 腹膜癌病患者的治疗。腹膜 苗勒管或胃肠道（GIT）引起的癌病 恶性肿瘤是发病和死亡的主要原因。 尽管最近 进步，目前可用的治疗结果留下了很多东西， 需要的话 腹膜内（IP） 治疗影响腹膜腔的恶性肿瘤。 最近 rhIL-12已进入临床试验。 这种细胞因子是 特别感兴趣，因为在动物研究中，它已被证明是一种 细胞毒性抗肿瘤活性和抗肿瘤活性的强诱导剂， T辅助1（TH 1）淋巴细胞活化的分化，和 因为它与其它生物活性剂具有协同作用的潜力。 rhIL-12增强患者抗肿瘤免疫的假说 苗勒管或GIT引起的腹膜癌病 恶性肿瘤将通过阐明的作用机制进行测试， 参与IP I期临床研究的患者中的rhIL-12 rhIL-12。因此，具体目标是：（1）确定（a）是否 腹腔内干扰素-g（IFN-γ）水平升高 （B）在用IP rHIL-12治疗的患者中， 淋巴细胞负责IFN-γ的产生，以及（c）是否 IP增强了肿瘤细胞的MHC I类和II类表达 rhIL-12。(2)为了确定IP rhIL-12是否增加 腹膜NK和T细胞的活化标志物以及 抗原呈递细胞上的共刺激分子和辅助分子。（三） 确定IP rhIL-12治疗是否会导致（a）体内 细胞毒性淋巴细胞（CTL）和NK细胞的发展， 增强的对自体肿瘤细胞的细胞溶解活性，和（B） 确定具有增强的细胞毒性的T细胞系和克隆是否 抗自体肿瘤细胞的活性可以从腹膜 用rhIL-12治疗的患者的淋巴细胞。(4)以确定是否 IP rhIL-12导致（a）肿瘤生长的产生增加 腹膜腔中的抑制分子，特别是可诱导的 一氧化氮合成酶（INOS），（B）减少 免疫抑制分子，特别是转化生长因子 和（c）增加的干扰素诱导的β-干扰素和白细胞介素-10的水平 蛋白-10（IP-10），一种具有抗血管生成活性的趋化因子。