Persistent augmentation of natural-killer- and T-cell-mediated cytotoxicity in peripheral blood mononuclear cells pulsed in vitro with high-dose recombinant interleukin-2 prior to culturing with a low maintenance dose.
The toxicity of high-dose recombinant interleukin-2 (rIL-2) treatment limits its use in tumour therapies. This paper describes in vitro studies of whether a single, peak rIL-2 dose, followed by low maintenance doses, could enhance the cytotoxic potential of peripheral blood mononuclear cells (PBMC) without inducing a significant sustained release of secondary cytokines, known to contribute to undesirable side-effects of therapy. Pre-pulsing of PBMC with high-dose rIL-2 (16,000 IU/ml for 30 min), followed by low-dose (5 IU/ml) maintenance culturing, was found to induce persistent augmentation of cytotoxic activity towards natural-killer(NK)-sensitive and -insensitive tumour targets, as well as increased T-cell-mediated target cell killing. Under these conditions the level of killing was as high as that achieved by higher maintenance doses (20-100 IU/ml). Although not reflected by overexpression of cell surface markers, enhanced activation of cytotoxic capacities by high-dose pre-pulsing remained clearly apparent for at least 12 days of culture. Increased secondary cytokine production (tumour necrosis factor, interleukin-6 and interferon gamma) was only evident during the first 24-72 h after pulsing, and not at later stages of culturing at the low maintenance dose of 5 IU rIL-2/ml. These results may warrant a human phase-1 B study to investigate the in vivo effect of high-dose prepulsing, followed by low-dose maintenance.
Palmer
P A
PA
EuroCetus BV, Amsterdam, The Netherlands.
Scharenberg
J G
JG
von Blomberg
B M
BM
Stam
A G
AG
Meijer
C J
CJ
Roest
G J
GJ
Franks
C R
CR
Scheper
R J
RJ
D000818:Animals; D002478:Cells, Cultured; D003470:Culture Media; D016207:Cytokines / Q000032:analysis; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D010641:Phenotype; D011994:Recombinant Proteins / Q000494:pharmacology; D012680:Sensitivity and Specificity; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D003470:Culture Media; D016207:Cytokines; D007376:Interleukin-2; D011994:Recombinant Proteins