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.
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 AID 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 x 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.


RESULTS
[corrected] Fifty-two percent of the patients mobilized with 1L-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. [corrected] 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.


CONCLUSIONS
[corrected] 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. [corrected] 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.
Burns
L J
LJ
Department of Medicine, University of Minnesota, Minneapolis 55455, USA. burns019@tc.umn.edu
Weisdorf
D J
DJ
DeFor
T E
TE
Repka
T L
TL
Ogle
K M
KM
Hummer
C
C
Miller
J S
JS
D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000096:biosynthesis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000276:immunology* / Q000556:secondary / Q000628:therapy; D016516:CD4-CD8 Ratio; D017024:Chemotherapy, Adjuvant; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006085:Graft Survival / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage* / Q000009:adverse effects; D006684:HLA-DR Antigens / Q000096:biosynthesis; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive; D007279:Injections, Subcutaneous; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000009:adverse effects; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D014407:Tumor Cells, Cultured
D018952:Antigens, CD34; D006684:HLA-DR Antigens; D007376:Interleukin-2; D016179:Granulocyte Colony-Stimulating Factor