Phase ii intraperitoneal rhIL 12

简介(申请人提供)：我们的长远目标是发展一个 有效的生物免疫治疗方法提高慢性粒细胞白血病患者的存活率 上皮性卵巢癌(EOC)。卵巢癌累及腹盆腔腹膜 和浆膜表面，并为腹膜内注射提供了合适的靶点 (IP)治疗试验。重组人白细胞介素12(rhIL-12)刺激 自然杀伤细胞活性和通过激活增强获得性免疫 体外培养的TH1淋巴细胞。重组人白介素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 机械装置。IL-12分子的大分子及其免疫生物学效应 临床前研究表明，重组人白细胞介素12可能具有有用的临床应用价值， 作为免疫生物制剂的药理和药效学作用 卵巢癌患者的IP治疗。我们已经确定了剂量限制 I期临床试验中IPrhIL-12(遗传学研究所)的毒性(DLT) 在每周一次的IP注入计划中。该药时相药动学研究 I期临床试验证实腹腔液中IL-12持续存在 在IP注入之后。在某些情况下，增加了Pf的干扰素-γ水平 在注射重组人IL-12后，检测到肿瘤坏死因子-α，并进一步降低 促血管生成分子FGF2和血管内皮生长因子在腹膜腔中的表达 在较高剂量水平的ip rh IL-12可检测到肿瘤。 这项回应PA00-047的建议是：(1)进行第二阶段临床 在经过一次化疗后有微小残留病变的患者中进行试验， 以每周300 ng/kg的剂量ip重组人白介素12，并确定(A)应答率， (B)无进展生存；(C)临床毒性；(D)生活质量 简介，(E)对腹膜肿瘤细胞的治疗效果(DNA流动和细胞凋亡)， &(F)药物动力学。(2)测定ip rh IL-12的药效学和 它是否促进体内的适应性免疫或先天免疫，如(A)所示 治疗后指示TH1型应答的细胞因子谱的变化(TIL2， (向上箭头)干扰素-g(向上箭头)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((上箭头)干扰素-g)&患者 反应与特定的细胞因子谱相关；(B)确定IP 重组人白介素12导致外周血产生干扰素-g的增加 细胞水平的淋巴细胞或腹膜渗出液T细胞或NK细胞； (3)确定IL-12是否促进血清对肿瘤的抗体反应 应用免疫印迹分析EOC细胞上的相关抗原。(4) 检测促血管生成因子VEGF、FGF2和IL-8的表达 Rh IL-12治疗后下降。

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.