SUSTAINED HIGH-LEVELS OF CIRCULATING CHAPERONED INTERLEUKIN-6 AFTER ACTIVE SPECIFIC CANCER-IMMUNOTHERAPY

In a phase 1 study of recombinant interleukin-6 (rIL-6) in patients wi th advanced solid tumors (n = 15), we discovered that the endogenous I L-6 levels, in pretreatment plasma or serum samples, were distributed into two groups. One set of patients (designated ''type 1''; n = 9) wa s characterized by low plasma IL-6 levels (48 to 1,700 pg/mL) as measu red using enzyme-linked immunosorbent assays (ELISA) for IL-6. In the second set of patients (designated ''type 2''; n = 6), IL-6 ELISAs sho wed high levels of plasma IL-6 (50 to 600 ng/mL). Neither group had de tectable B9 hybridoma cell growth factor activity associated with the IL-6 in their pretreatment plasma or serum. Plasma C-reactive protein (CRP) levels were markedly elevated in type II patients suggesting tha t the circulating IL-6 was biologically active in vivo. In both groups of patients there was a small but significant increase in B9 activity in the plasma within three hours after rIL-6 administration (9 = 5). Gel filtration profiles showed that circulating IL-6 in type 1 patient s, 15 to 120 minutes after rIL-6 administration was of approximate mas s 20 to 40 kD, whereas in type 2 patients, the IL-6 before and after e xogenous rIL-6 administration was indistinguishable and was of an appr oximate mass of 200 kD. IL-6 immunoaffinity purification of the 200 kD complexes showed these to contain multiple isoforms of IL-6 (14 to 31 kD) and the soluble IL-6 receptor (sIL-6R; 50 to 55 kD). A distinguis hing clinical history was that all of the type 2 patients had been act ively immunized with an anti-idiotypic monoclonal antibody (MoAb) (MK2 -23) 3 to 12 months before initiation of this study for advanced melan oma. An analysis of the plasma IL-6 content in other melanoma patients (n = 16) during antiidiotypic MoAb immunization indicated that marked (up to 600 ng/mL) and sustained (several months) elevations of circul ating ''chaperoned'' IL-6 were induced by active immunization regimens . (C) 1994 by The American Society of Hematology.