Abstract
Abstract Background: IL-6 is a central myeloma growth factor and in vitro abnormal production of IL-1beta in the myeloma microenvironment stimulates the generation of paracrine IL-6. Mimicking in vitro observations, we have shown that responsive early stage myeloma patients at risk for progression to active myeloma who were treated with IL-1 inhibitors demonstrated decreases in the myeloma proliferative rate and C-reactive protein (IL-6 surrogate marker) leading to a chronic disease state with an improved progression free survival. In this study we investigated the effect of XOMA 052, a humanized anti-IL-1 antibody to inhibit stromal cell IL-6 production induced by either recombinant IL-1beta or supernatants generated from unsorted bone marrow cells from patients with smoldering multiple myeloma. Methods: Bone marrow stromal cells were incubated with varying concentrations of recombinant IL-1β (100, 10, 1, 0.1 pg/ml) in the absence or presence of anti-IL-1 antibody, anti-TNF antibody, or dexamethasone. In a similar fashion, supernatants from unsorted bone marrow cells from six patients with smoldering myeloma were co-cultured with bone marrow stromal cells and the effect of the humanized anti-IL-1β antibody was tested. Results: The anti-IL-1β antibody inhibited the IL-1 induced IL-6 production in vitro by > 85% at 100 pg/ml of IL-1 and > 90% at 10, 1, and 0.1 pg/ml of IL-1; specifically, using 10 pg/ml of IL-1, IL-6 production was inhibited from 149 down to 5.2 ng/ml in the presence of anti-IL-1 antibody. Anti-TNF antibody had minimal effect. At 10 pg/ml of IL-1 beta, a physiologically relevant amount of IL-1 in vitro in bone marrow samples from myeloma patients, the anti-IL-1 antibody was superior to dexamethasone at inhibition of IL-6 production. In in vitro testing of patient supernatants from unsorted bone marrow cells, three patients were high inducers and three patients low inducers of paracrine IL-6 production. The results demonstrate > 85% reduction of IL-6 production in all patients' samples tested. Importantly, the anti-IL-1β antibody was highly effective in samples from the three patients who were high inducers of paracrine IL-6 production (IL-6 production was inhibited from 191 down to 12 ng/ml; 157 to 13 ng/ml and 320 to 11 ng/ml). In comparison, the anti-TNF antibody had marginal effects. Conclusion: The humanized anti-IL-1beta antibody is highly effective in vitro at the inhibition of IL-6 generated by supernatant cultures from patients with early stage myeloma or by recombinant IL-1. Combination therapy with IL-1 inhibitors and apoptosis inducing agents may be useful in patients with active myeloma that have elevated IL-6 levels and a high growth rate at diagnosis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2449.
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