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

DENILEUKIN DIFTITOX (ONTAK) 在高级 RefRR 患者中的 I-II 期研究

• 批准号: 7603486
• 负责人: LUPE G SALAZAR
• 金额: $ 0.21万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2007-09-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7603486
• 关键词: Affinity; Autoantigens; CD8B1 gene; Cancer Patient; Chemotherapy-Oncologic Procedure; Chimeric Proteins; Computer Retrieval of Information on Scientific Projects Database; Denileukin Diftitox; Disease; Disease remission; Effector Cell; Funding; Generations; Grant; IL2RA gene; Immune; Immune response; Immunity; Infusion procedures; Institution; Lead; Malignant - descriptor; Mammary Neoplasms; Numbers; Patients; Phase; Population; Protein Overexpression; Purpose; Refractory; Research; Research Personnel; Resources; Safety; Site; Source; Suppressor-Effector T-Lymphocytes; T-Lymphocyte; Tumor Antigens; Tumor Immunity; United States National Institutes of Health; cancer cell; cytotoxic; cytotoxicity; malignant breast neoplasm; neoplastic cell; peripheral blood; response; tumor

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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 作为一线治疗，联合化疗方案治疗晚期乳腺癌的目标缓解率通常为35-75%，完全缓解率不到20%。最近的研究表明，IL-2R在浸润性乳腺肿瘤中的表达增加，这种过度表达与肿瘤的恶性潜能有关。Denileukin Diftitox(Ontak？)是一种细胞毒融合蛋白，针对表达高亲和力形式的IL-2R(CD25)的恶性细胞，导致部分或完全疾病反应。我们推测，在过度表达IL-2R的乳腺癌中，Ontak可能具有抗肿瘤活性。 有证据表明，一群表达IL-2R链的CD_4~+(CD_4~+/CD_(25+))T细胞可能作为“专职”抑制细胞(Tregs)，下调对自身抗原(如肿瘤抗原)的免疫反应。在乳腺癌患者的外周血中发现了数量增加的Tregs。从理论上讲，外周血中Tregs的耗尽可能通过增强包括CD4+和CD8+T细胞在内的抗肿瘤效应细胞和增强内源性肿瘤特异性免疫来诱导抗肿瘤免疫。我们推测，用Ontak靶向肿瘤细胞上表达的IL-2R可以导致对肿瘤细胞的选择性细胞毒作用。此外，Tregs的耗尽可能诱导抗肿瘤免疫，从而产生功能性免疫效应细胞。本研究的目的是评价安达克输注治疗晚期难治性乳腺癌患者的安全性。此外，我们还将评估安达克对治疗前后外周血Tregs百分比的影响。