HEMATOLOGIC AND IMMUNOLOGICAL EVALUATION OF RECOMBINANT HUMAN INTERLEUKIN-6 IN PATIENTS WITH ADVANCED MALIGNANT DISEASE - EVIDENCE FOR MONOCYTE ACTIVATION

Eighteen advanced cancer patients received weekday subcutaneous inject ions of recombinant interleukin-6 (rIL-6) for 4 weeks at escalating do ses. Patients were evaluated for hematologic and immune system effects . Hematologic monitoring included WBC, differential, Hgb and Hct, plat elet counts, and assessment of marrow and peripheral blood progenitors . Immunologic monitoring included evaluation of acute-phase reactants (APRs), immunophenotyping, serum cytokine levels, cytokine-induced pro teins, and cytokine messenger RNA (mRNA). The maximal tolerated dose ( MTD) was 8.0 mu g/kg/day, with neurocortical toxicity as the major lim iting factor. All patients became anemic, and most had fever and chill s. APRs were increased throughout treatment. WBCs increased transientl y on day 2; granulocytes and monocytes increased again through day 26, whereas lymphocytes decreased to baseline or lower levels. Platelets responded by day 12 and increased through day 26 at the MTD with no ef fect on colony-forming unit-megakaryocyte (CFU-Mk). Peripheral WBC and RBC progenitors were not affected but decreased in the marrow. T-cell percentages declined with little effect on absolute numbers; T-cell a ctivation was seen. CD45RO(+) T cells decreased, but there was no sign ificant effect on CD8(+) CD28(+) T cells. Neither B cells nor natural killer (NK) cells were affected. However, evidence of monocyte effects included upregulation of CD71, induction of the cytokine-induced prot eins 2-5A synthetase and neopterin, and increases in tumor necrosis fa ctor-alpha (TNF-alpha) mRNA. Serum cytokines were undetected, and mRNA for IL-1 beta, IL-2, and interferon-gamma (IFN-gamma) was not induced ; however, mRNA for IL-4 and IL-10 did increase suggesting activation of Th2-like T cells. One mixed tumor response was seen. We conclude th at IL-6 alone has systemic activity on the immune system, as well as t he hematopoietic system, which at the MTD, primarily involves inductio n of APR, activation and expansion of monocytes, and activation of Th2 -like T cells.