LABORATORY STUDIES WITH INTRAPERITONEAL RHIL-12 THERAPY

这些研究的长期目标是开发有效的 重组人白介素12免疫治疗急性淋巴细胞性白血病 腹膜癌病的治疗。腹膜 由苗勒氏或胃肠道(GIT)引起的癌症 恶性肿瘤是发病率和死亡率的主要原因。尽管最近 尽管取得了进展，但目前可用的治疗结果还有待于 想要。人们对腹膜腔内注射(IP)重新产生了兴趣。 影响腹膜腔的恶性肿瘤的治疗。最近 重组人白介素12已被引入临床试验。这种细胞因子是一种 特别感兴趣，因为在动物研究中，它被证明是一种 强大的细胞毒抗肿瘤活性诱导剂和 T辅助细胞1(TH1)活化的分化，以及 因为它与其他生物治疗剂有协同作用的潜力。 重组人白介素12可增强患者抗肿瘤免疫的假说 由苗勒氏菌或胃肠炎引起的腹膜癌病 恶性肿瘤将通过阐明其作用机制进行测试。 参与IP I期临床研究患者的重组人IL-12水平 重组人白介素12。因此，具体目标是：(1)确定，(A)是否 腹膜腔内的干扰素-g(干扰素-γ)水平升高 接受IP rHIL-12治疗的患者中，(B)CD3+(TH1)和CD3-(NK) 淋巴细胞负责产生干扰素-伽马，以及(C) IP增强肿瘤呼叫上MHC Class I和Class II的表达 重组人白介素12。(2)确定ip rh IL-12是否增加了hIL-12的表达 腹膜NK、T细胞活化标志物及其表达 抗原提呈细胞上的共刺激分子和辅助分子。(3) 确定ip rh IL-12治疗是否导致(A)体内 细胞毒性淋巴细胞(CTL)和NK细胞的发育 增强对自体肿瘤细胞的杀伤活性，以及(B) 确定T细胞系和克隆是否具有增强的细胞毒性 从腹膜中可以获得抗自体肿瘤细胞的活性 重组人白细胞介素12治疗后患者的淋巴细胞。(4)确定是否 Ip rhIL-12导致(A)增加肿瘤生长的产生 腹膜腔内的抑制分子，特别是可诱导的 一氧化氮合酶(INOS)，(B)减少 免疫抑制分子，特别是转化生长因子 β和白介素10和(C)可诱导的干扰素水平增加 蛋白-10(IP-10)，具有抗血管生成活性的趋化因子。

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.