Cancer Immunol Res. 2026 Jan 8. doi: 10.1158/2326-6066.CIR-25-0880. Online ahead of print.

ABSTRACT

The ability of interleukin-12 (IL-12) to stimulate production of interferon gamma (IFN-γ) suggested it might improve the efficacy of low dose interferon alpha (IFN-α). In this phase II trial, patients with metastatic malignant melanoma were administered recombinant human (rh) IL-12 followed by IFN-α2b. Primary endpoints were clinical response and progression-free survival. Secondary objectives were to evaluate the effect of endogenous IFN-γ on JAK-STAT signaling and IFN-regulated genes in peripheral blood mononuclear cells (PBMCs). Patients with advanced melanoma received rhIL-12 on day 1 and IFN-α2b on days 2-6 of a 14-day cycle. rhIL-12 was given intravenously at 300 ng/kg. IFN α2b was dosed at 3×106 units subcutaneously. Plasma IFN-γ was assayed by ELISA; JAK-STAT signaling was measured in PBMCs by flow cytometry. The proportion of responders was assessed via Simon’s two-stage design. Thirty-eight patients were enrolled. The regimen was well-tolerated. Two patients achieved a partial response lasting 6 months or longer (5.3%). IL-12 administration led to an increase in mean plasma IFN-γ from 33.57 pg/mL at baseline to a maximum of 564.86 pg/mL and increased expression of STAT1 and STAT2 in PBMCs. Generation of phosphorylated STAT1 and interferon-simulated gene product 15 in response to IFN-α was enhanced following IL-12. rhIL-12 given prior to IFN-α2b stimulated production of IFN γ, which led to increased levels of JAK-STAT signaling intermediates in patient PBMCs. Combination therapy was reasonably well-tolerated but conferred marginal benefit in patients with metastatic melanoma. These results can inform future studies that employ recombinant IL-12 or novel IL-12 constructs.

PMID:41505731 | DOI:10.1158/2326-6066.CIR-25-0880