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

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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.