In vivo cytokine responses to interleukin-2 immunotherapy after autologous stem cell transplantation in children with solid tumors.
The potent immunostimulatory cytokine interleukin-2 (IL-2) has been extensively investigated for its potential to induce anti-tumor immunity in a number of tumor models. Only recently the complex interplay of mutually suppressive or supportive cytokines of the IL-2-induced network of cytokines has been better characterized. The aim of this study was to assess which of these in vitro findings are reproducible in vivo in recipients of stem cell transplants (SCT), since in these patients long- lasting impairments in cytokine inducibility have been described. We have therefore studied the kinetics of putative modulators and mediators of IL-2-induced immune activation, namely IL-1beta, IL-4, IL-5, IL-10, IL-12, soluble Fas ligand (sFasL), and GM-CSF during IL-2 therapy. All patients were children or adolescents suffering from solid tumors with poor prognosis who received three 5-day courses of high-dose intravenous IL-2 as an adjuvant to their radio-chemotherapy and autologous SCT. While IL-1beta, IL-4 and IL-12 were not, and sFasL was only mildly affected by the IL-2 therapy, we observed a consistent and early rise of IL-10, IL-5, and GM-CSF. These increases were rapidly reversible after discontinuation of IL-2 therapy. The inducibility of IL-10, IL-5 and GM-CSF was more pronounced with increasing time from the SCT, and in the third cycle reached an order of magnitude as in high-dose IL-2 patients without SCT. Together with the abundant in vitro data, these findings may help devise a combination immunotherapy permitting stronger anti-tumor effects, but lesser adverse effects.
Department of Pediatric Hematology and Oncology, Center of Child Health, Heinrich-Heine University Medical Center, Düsseldorf, Germany.
H
H
Bönig
H J
HJ
Laws
A
A
Wundes
J
J
Verheyen
M
M
Hannen
Y M
YM
Kim
U
U
Banning
W
W
Nürnberger
D
D
Körholz
D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000276:immunology / Q000628:therapy*; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000097:blood; D006133:Growth Substances / Q000627:therapeutic use; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007376:Interleukin-2 / Q000627:therapeutic use*; D008213:Lymphocyte Activation; D009447:Neuroblastoma / Q000276:immunology / Q000628:therapy*; D012516:Osteosarcoma / Q000276:immunology / Q000628:therapy*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012208:Rhabdomyosarcoma / Q000276:immunology / Q000628:therapy*; D012512:Sarcoma, Ewing / Q000276:immunology / Q000628:therapy*; D014182:Transplantation, Autologous; D014916:Whole-Body Irradiation
D016207:Cytokines; D006133:Growth Substances; D007376:Interleukin-2; D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor