PHASE I DOSE ESCALATION STUDY OF INTRAPERITONEAL ONTAK IN ADVANCED OVARIAN CANCE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 卵巢癌具有免疫原性，并与多种肿瘤诱导的免疫抑制机制相关。 最近的研究已经确定了一个独特的CD 4 + CD 25 + T调节细胞（T细胞）群体，其功能是“专业”抑制细胞，可能在防止卵巢肿瘤被免疫系统识别中发挥作用。 在卵巢癌患者中的研究已经证明腹膜腹水中的TcR增加。 因此，TdR可能抑制诱导腹膜主动免疫的尝试。 最近的研究表明，肿瘤内T细胞与卵巢癌患者改善的结果以及改善的化疗反应有关。 假设通过腹膜内给予ONTAK（一种靶向白喉毒素的CD 25+恶性肿瘤配体融合蛋白）消耗肿瘤部位（腹膜）的TcR，可通过增强抗肿瘤效应物（包括CD 4 + T细胞、CD 8 + T细胞和功能性瘤内T细胞）诱导抗肿瘤免疫。 在这项I期研究中，我们将（1）评价ONTAK腹腔内给药的安全性，（2）确定腹腔内最大耐受剂量，（3）收集ONTAK腹腔内给药对外周血和腹膜中TdR影响的数据。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Ovarian cancer is immunogenic and associated with multiple mechanisms of tumor induced immunosuppression. Recent studies have identified a unique population of CD4+CD25+ T regulatory cells (Tregs) which function as "professional" suppressor cells and may play a role in preventing ovarian tumors from being recognized by the immune system. Studies in ovarian cancer patients have demonstrated increased Tregs in peritoneal ascites. Thus, Tregs may inhibit attempts to induce active immunity in the peritoneum. Recent investigations have demonstrated that intratumoral T cells are associated with both improved outcome as well as improved response to chemotherapy in ovarian cancer patients. It is hypothesized that depletion of Tregs at the tumor site (peritoneum) by I.P. administration of ONTAK, a ligand fusion protein targeting diptheria toxin to CD25+ malignancies, may induce anti-tumor immunity by augmenting anti-tumor effectors including CD4+ T cells, CD8+ T cells, and functional intratumoral T cells. In this phase I study we will (1) evaluate the safety of I.P. administration of ONTAK, (2) establish the I.P. maximum tolerated dose, and (3) gather data on the effect of I.P. ONTAK on Tregs in peripheral blood and peritoneum.