-edited) While high dose chemotherapy with hematopoietic stem cell rescue has improved response rates in patients with metastatic breast cancer, chemotherapy-resistant relapse still occurs in most patients. Use of CSF-mobilized peripheral blood progenitor cells (PBPC) as a source of stem cells can shorten the duration of cytopenia and decrease morbidity of high dose chemotherapy. However, this approach is unlikely to improve disease outcome and other strategies acting through different anti- tumor mechanisms (immunologic/biologic) are needed. Preclinical data supports a strategy based upon the immune activation of the stem cell source with interleukin-2 (IL-2) in order to mediate an antitumor effect, in addition to hematologic recovery. The proposed project is a phase I trial of IL-2 in combination with G-CSF for the mobilization of PBPC and immune effector cells in patients who will undergo high dose chemotherapy with stem cell rescue. In cancer patients, IL-2 administration can activate and expand CD56+, NK/LAK calls, induce multiple hematopoietic cytokines (IL-6, G-CSF, GM-CSF), and expand CFU-GM in the peripheral blood. As part of the trial, cells induced and mobilized by IL-2 plus G-CSF will be harvested and used as a source of stem cells and adoptive immunotherapy following high dose combination chemotherapy (STAMP-V) in patients with advanced breast cancer. If tolerated, additional patients will receive a fixed, low dose of IL-2 immediately following stem cell infusion. The trial seeks to accomplish the following specific clinical and laboratory objectives. Toxicities will be characterized and used to define a phase II dose of IL-2 to combine with G-CSF for stem cell mobilization. This IL-2 dose must allow for prompt hematopoietic engraftment following STAMP-V chemotherapy with stem cells alone or with post-stem cell- IL-2. The immune effects of IL-2 plus G-CSF will be quantified for NK/LAK and T cell phenotype (CD56+, CD3+, CD25+) and function (NK/LAK cytoxicity, T cell proliferation-specific, and tumor- specific response directed at HER-2/neu protein, and cytokine release- TNF, IL-6) immediately after their administration and following hematologic recovery after stem cell infusion. The biologic effects of IL-2 plus G-CSF will be quantified for hematopoietic progenitors (CD34+, CFU-GM, BFU-E) in peripheral blood. The effects of therapy on the presence of minimal residual disease will be characterized based on polymerase chain reaction (PCR) for cytokeratin as a marker for breast cancer within bone marrow and blood. These changes will be correlated with disease outcome. Ultimately, this study may form a basis for phase II/III trials assessing the impact of this immunotherapeutic approach on disease progression and survival in breast cancer. Also, the trial may form a basis for future, more innovative trials utilizing active specific immunotherapy or transfer of specific tumor-directed T cells.
