Phase ii intraperitoneal rhIL 12

II期腹腔注射rhIL 12

• 批准号: 6340132
• 负责人: RALPH Stuart FREEDMAN
• 金额: $ 30.75万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6340132
• 关键词: apoptosis; drug adverse effect; enzyme linked immunosorbent assay; fibroblast growth factor; human subject; human therapy evaluation; interferon gamma; interleukin 10; interleukin 12; interleukin 2; interleukin 5; interleukin 8; intraperitoneal injections; minimal residual disease; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; ovary neoplasms; patient oriented research; pharmacokinetics; quality of life; recombinant proteins; tumor antigens; tumor necrosis factor alpha; vascular endothelial growth factors

DESCRIPTION (Provided by applicant): Our long-term goal is to develop an effective bioimmunotherapy approach to improve the survival of patients with epithelial ovarian carcinoma (EOC). EOC involves the abdominopelvic peritoneum and serosal surfaces, and provide an appropriate target for intraperitoneal (IP) therapy trials. Recombinant human interleukin- 12 (rhIL- 12) stimulates natural killer cell activity and enhances adaptive immunity through activation of TH1 lymphocytes in vitro. rhIL-12 mediated antitumor effects in preclinical animal models primarily involve tumor specific T cells and antiangiogenic mechanisms. The large size of the IL-12 molecule and its immunobiologic potency in preclinical studies suggest that rhIL-12 could have useful clinical, pharmacologic and pharmacodynamic effects as an immunobiological agent in the IP treatment of patients with EOC. We have determined the dose limiting toxicity (DLT) of IP rhIL-12 (Genetics Institute) in a phase I clinical trial in a once weekly IP injection schedule. Pharmacokinetic studies from the phase I clinical trial demonstrated persistence of IL-12 in peritoneal fluid (pf) after IP injection. Increased pf levels of IFN-gamma and in some instances TNF-a, were detected after IP injection of rhIL- 12. Furthermore, decreased expression of the proangiogenic molecules FGF2 and VEGF on peritoneal cavity tumor was detected at higher dosing levels of IP rhIL- 12. The specific aims of this proposal in response to PA00-047 are: (1) To conduct a phase II clinical trial in patients with minimal residual disease after one prior chemotherapy, with IP rhIL-12 at a weekly dose of 300 ng/kg, and determine (a) response rate, (b) progression-free survival, (c) clinical toxicity, (d) quality of life profiles, (e) therapy effects on peritoneal tumor cells (DNA flow & apoptosis), & (f) pharmacokinetics. (2) Determine pharmacodynamics of IP rhIL-12 and whether it facilitates adaptive or innate immunity in vivo evidenced by (a) change in posttreatment cytokine profiles indicating a TH1 type response (tIL2, (up arrow) IFN-g (up arrow) TNF-a) or TH2 type response ((up arrow) IL-5,(up arrow) IL-10) or NK cell response ((up arrow) IFN-g) & whether patient responses correlate with a specific cytokine profile; (b) Determine whether IP rhIL- 12 results in increased production of IFN-g by peripheral blood lymphocytes or peritoneal exudate T cells or NK cells at the cellular level; (3) Determine whether IL-12 facilitates serum antibody responses to tumor associated antigens on EOC cells utilizing immunoblotting analysis. (4) Determine whether expression of proangiogenic factors VEGF, FGF2 and IL-8 are decreased following IF rhIL- 12.

描述（由申请人提供）：我们的长期目标是开发 有效的生物免疫治疗方法可提高患者的生存率 上皮性卵巢癌（EOC）。 EOC 累及腹盆腔腹膜 和浆膜表面，并为腹膜内注射提供适当的目标 (IP) 治疗试验。重组人白细胞介素 12 (rhIL- 12) 刺激 自然杀伤细胞活性并通过激活增强适应性免疫 体外TH1淋巴细胞。 rhIL-12介导的临床前抗肿瘤作用 动物模型主要涉及肿瘤特异性T细胞和抗血管生成 机制。 IL-12 分子的大尺寸及其免疫生物学效力 临床前研究表明 rhIL-12 可能具有有用的临床、 作为免疫生物学制剂的药理和药效学作用 EOC 患者的 IP 治疗。我们已经确定了剂量限制 IP rhIL-12（遗传学研究所）在 I 期临床试验中的毒性 (DLT) 每周一次的 IP 注射计划。该阶段的药代动力学研究 I 临床试验证明 IL-12 在腹膜液中持续存在 (pf) IP注入后。 IFN-γ 的 pf 水平增加，在某些情况下 腹腔注射 rhIL-12 后检测到 TNF-a。此外，TNF-a 减少 腹膜腔促血管生成分子 FGF2 和 VEGF 的表达 在更高剂量水平的 IP rhIL-12 中检测到肿瘤。 该提案针对 PA00-047 的建议是： (1) 进行 II 期临床 在一次先前化疗后有微小残留病的患者中进行的试验， 每周剂量为 300 ng/kg 的腹腔注射 rhIL-12，并确定 (a) 反应率， (b) 无进展生存期，(c) 临床毒性，(d) 生活质量 概况，(e) 对腹膜肿瘤细胞的治疗效果（DNA 流和细胞凋亡）， & (f) 药代动力学。 (2) 确定IP rhIL-12和的药效学 它是否促进体内适应性或先天免疫，由 (a) 证明 治疗后细胞因子谱的变化表明 TH1 型反应（tIL2、 (向上箭头) IFN-g (向上箭头) TNF-a) 或 TH2 型反应 ((向上箭头) IL-5,(向上箭头) 箭头）IL-10）或 NK 细胞反应（（向上箭头）IFN-g）以及患者是否 反应与特定的细胞因子谱相关； (b) 判断是否有IP rhIL-12 导致外周血 IFN-g 的产生增加 细胞水平的淋巴细胞或腹膜渗出物T细胞或NK细胞； (3) 确定IL-12是否促进血清抗体对肿瘤的反应 利用免疫印迹分析确定 EOC 细胞上的相关抗原。 (4) 确定促血管生成因子 VEGF、FGF2 和 IL-8 的表达是否 IF rhIL-12 后下降。