Cytotoxic effectors activated by low-dose IL-2 plus IL-12 lyse IL-2-resistant autologous acute myeloid leukaemia blasts.
We have investigated the susceptibility of primary acute myeloid leukaemia (AML) samples to the lytic action of normal peripheral blood mononuclear cells (PBMC), as well as of the patients' autologous and allogeneic PBMC collected at the time of remission following stimulation with different concentrations of interleukin (IL)-2 and IL-12, both alone and in variable combinations. Primary AML blasts were resistant to IL-2-activated PBMC effectors generated from normal individuals, allogeneic and autologous patients in five, six and eight of the 10 AML samples tested, respectively, IL-12 alone proved ineffective in generating anti-leukaemic activity, whereas, in combination, the two cytokines induced anti-leukaemic killing in all five cases resistant to normal PBMC, in 4/6 samples resistant to allogeneic AML effectors and in 5/8 cases resistant to autologous effectors. In each case the lytic effect was maintained at the lowest cytokine combination (10 + 10 IU/ml) utilized. The suggestion of a synergistic effect was further strengthened by the evidence that at the lowest doses of IL-2 and IL-12 the degree of killing was greater than that promoted by each cytokine independently. The results of this study suggest that two major limitations associated with the administration of IL-2 to AML patients, the resistance of the blasts to IL-2-generated killing and the toxicity associated with high-dose IL-2, may be overcome by the combined use of very low doses of IL-2 and IL-12. As IL-2-resistant blasts may be lysed by a low-dose combination of IL-2/IL-12, feasibility studies with this cytokine combination are worthy of exploration in vivo.
Vitale
A
A
Dipartimento di Biotecnologie Cellulari ed Ematologia, University La Sapienza, Rome, Italy.
Guarini
A
A
Latagliata
R
R
Cignetti
A
A
Foa
R
R
D000328:Adult; D004306:Dose-Response Relationship, Immunologic; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D018664:Interleukin-12 / Q000008:administration & dosage*; D007376:Interleukin-2 / Q000008:administration & dosage*; D007694:Killer Cells, Natural / Q000502:physiology*; D007951:Leukemia, Myeloid / Q000276:immunology / Q000628:therapy*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged
D004338:Drug Combinations; D007376:Interleukin-2; D018664:Interleukin-12