Enhancement of the anti-tumor activity of a peripheral blood progenitor cell graft by mobilization with interleukin 2 plus granulocyte colony-stimulating factor in patients with advanced breast cancer

Abstract

Objective. Autologous interleukin 2 (IL-2)-activated natural killer (NK) cells kill a broad spectrum of tumor targets, including breast cancer. We hypothesized that mobilization with IL-2 and granulocyte colony-stimulating factor (G-CSF) for collection of peripheral blood progenitor cells (PBPC) may enhance the anti-tumor activity of the graft in autograft recipients. We determined the dose-limiting toxicity and maximum tolerated dose of subcutaneous IL-2 given with G-CSF for PBPC mobilization, the ability of IL-2 + G-CSF mobilized stem cells to reconstitute hematopoiesis, and the in vitro immunologic function of the graft in patients with advanced breast cancer. Materials and Methods. Forty-three women with stage IIIA/B or metastatic breast cancer underwent mobilization of PBPC with IL-2 administered subcutaneously for 14 days along with G-CSF for the latter 7 days. IL-2 was given in a dose-escalated manner, with the maximum tolerated dose determined to be 1.75 × 10 6 IU/m 2/day. Fifteen women with stage IIIA/B or metastatic breast cancer underwent G-CSF mobilization alone and served as a control group. Fifty-two percent of the patients mobilized with IL-2 at the maximum tolerated dose reached the target number of CD34 + cells for transplantation with three aphereses compared to 93% of control patients who were mobilized with G-CSF alone. Results. There was no significant impact on time to engraftment of neutrophils or platelets using either mobilization regimen. The addition of subcutaneous IL-2 to mobilization increased the cytotoxicity of IL-2–activated mononuclear cells from the PBPC product against the breast cancer cell target, MCF-7, and increased the percentage of NK cells and activated T cells in the PBPC product. The enhanced NK cell number was sustained in the early posttransplant period. IL-2 + G-CSF mobilization is safe, may lead to a more immunologically functional graft without impairing hematologic recovery, and thus merits further exploration to evaluate the clinical anti-tumor efficacy of these immunocompetent grafts. Conclusions. Limitations of this combined approach to stem cell mobilization include a decrease in the number of CD34 + cells mobilized with the combined cytokines and the short duration of the increased number of anti-tumor effector cells after transplant.