PHASE I-II STUDY OF DENILEUKIN DIFTITOX (ONTAK) IN PATIENTS WITH ADVANCED REFRR

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。子项目及 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。 晚期乳腺癌的联合化疗方案作为一线治疗通常导致35-75%的客观缓解，完全缓解发生在不到20%的患者中。 最近的研究表明IL-2 R在浸润性乳腺肿瘤中的表达增加，并且这种过度表达与肿瘤的恶性潜能相关。 Denileukin Diftitox（ONTAK）），细胞毒性融合蛋白靶向表达高亲和力形式的IL-2 R（CD 25）的恶性细胞，导致部分或完全疾病应答。 我们假设ONTAK可能在过表达IL-2 R的乳腺癌中具有抗肿瘤活性。 有证据表明，组成性表达IL-2 R链的CD 4+（CD 4 +/CD 25+）T细胞群体可作为“专职”抑制细胞（TCLs），其下调对自身抗原（例如肿瘤抗原）的免疫应答。 在乳腺癌患者的外周血中已经发现了增加的THBG数量。 从理论上讲，外周血中以及可能在肿瘤部位的T细胞活化素的消耗可以通过增加抗肿瘤效应细胞（包括CD 4+和CD 8 + T细胞）和增强内源性肿瘤特异性免疫来诱导抗肿瘤免疫。 我们假设ONTAK靶向肿瘤细胞上表达的IL-2 R可能导致恶性细胞的选择性细胞毒性。 此外，TcB的消耗可诱导抗肿瘤免疫，从而允许产生功能性免疫效应细胞。 本研究旨在评价ONTAK输注在晚期难治性乳腺癌患者中的安全性。 此外，我们还将评价ONTAK对治疗前后外周血T细胞百分比的影响。

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. Combination chemotherapy regimens for advanced breast cancer usually result in 35-75% objective responses as first line treatment, with complete remissions occurring in fewer than 20% of patients. Recent studies have shown increased expression of IL-2R in infiltrative breast tumors and this overexpression is associated with the malignant potential of the tumor. Denileukin Diftitox (ONTAK¿), a cytotoxic fusion protein targets malignant cells that express the high affinity form of IL-2R (CD25) resulting in partial or complete disease response. We hypothesize that ONTAK may have anti-tumor activity in breast cancers which overexpress IL-2R. Evidence suggests that a population of CD4+ (CD4+/CD25+) T cells that constitutively express the IL-2R chain may function as "professional" suppressor cells (Tregs) which down-regulates immune responses to self antigens, such as tumor antigens. Increased numbers of Tregs have been identified in the peripheral blood of patients with breast cancer. Theoretically, depletion of Tregs in the peripheral blood, and presumably at the tumor site, may induce anti-tumor immunity by augmenting anti-tumor effector cells including CD4+ and CD8+ T cells and enhancing endogenous tumor specific immunity. We hypothesize that targeting the IL-2R expressed on tumor cells with ONTAK could lead to selective cytotoxicity of malignant cells. Furthermore, depletion of Tregs may induce anti-tumor immunity allowing generation of functional immune effector cells. The purpose of this study is to evaluate the safety of ONTAK infusion in advanced refractory breast cancer patients. In addition, we will evaluate the effect of ONTAK on the percentage of peripheral blood Tregs pre- and post-treatment.