Flt-3 ligand and sequential FL/interleukin-2 in patients with metastatic renal carcinoma: clinical and biologic activity.
Flt3 (fms-like tyrosine kinase 3) ligand, a cytokine that stimulates increases in the number of dendritic cells (DC) in vivo, has been shown to have antitumor activity in murine models via an immune-mediated mechanism. Therefore, we examined the clinical activity of this cytokine in patients with an immunologic-responsive cancer, metastatic renal cell carcinoma. Flt3 ligand (25 microg/kg subcutaneous) was administered daily for the first 14 days of a 28-day cycle. Although the treatment was well tolerated and was confirmed to induce expansion of lineage (Lin)-/HLA-DR+/CD11c+ myeloid DC and Lin-/HLA-DR+/CD123+ plasmacytoid DC, no clinical activity was observed. Reasoning that DC expanded by Flt3 ligand might potentiate the clinical activity of low-dose interleukin-2, a second study was conducted of sequential administration of 25 microg/kg of Flt3 ligand daily for 7 days was followed by 11 x 10(6) IU of subcutaneous interleukin-2 for 4 consecutive days x 4 weeks. In this study, increased numbers of circulating DC were again observed, which was followed by increased numbers of activated T cells, confirming a biologic effect of each cytokine. However, toxicity and clinical efficacy were similar to what has been seen with low-dose interleukin-2 alone, with two minor responses observed. These results demonstrate that Flt3 ligand, although capable of inducing expansion of circulating myeloid and plasmacytoid DC in patients with metastatic renal cell carcinoma, lacks significant clinical activity at the doses and schedules examined.
Rini
Brian I
BI
Department of Medicine, Section of Hematology/Oncology, The University of Chicago, 5841 S Maryland Avenue, Chicago, IL 60637, U.S.A.
Paintal
Ajit
A
Vogelzang
Nicholas J
NJ
Gajewski
Thomas F
TF
Stadler
Walter M
WM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology; D003713:Dendritic Cells / Q000502:physiology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use; D006801:Humans; D016130:Immunophenotyping; D016167:Integrin alphaXbeta2 / Q000032:analysis; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000009:adverse effects; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000008:administration & dosage* / Q000009:adverse effects; D008875:Middle Aged; D009362:Neoplasm Metastasis
D016167:Integrin alphaXbeta2; D007376:Interleukin-2; D008565:Membrane Proteins; C084881:flt3 ligand protein; D016178:Granulocyte-Macrophage Colony-Stimulating Factor