Cancer Immunity 3:7 (2003)

Two phase I studies of low dose recombinant human IL-12 with Melan-A and influenza peptides in subjects with advanced malignant melanoma

Jonathan Cebon¹, Elke Jäger², Mark J. Shackleton¹, Peter Gibbs¹, Ian D. Davis¹, Wendie Hopkins¹, Sharen Gibbs¹, Qiyuan Chen¹, Julia Karbach², Heather Jackson¹, Duncan P. MacGregor¹, Sue Sturrock¹, Hilary Vaughan¹, Eugene Maraskovsky¹, Antje Neumann², Eric Hoffman³, Mathew L. Sherman⁴, and Alexander Knuth^2*

¹Ludwig Institute for Cancer Research, Melbourne, Australia
²Krankenhaus Nordwest, Frankfurt, Germany
³Ludwig Institute for Cancer Research, New York, NY, USA
⁴Genetics Institute/Wyeth Ayerst, Cambridge, MA, USA
^*Present address: Department of Medical Oncology, University Hospital Zurich, Zurich, Switzerland

Keywords: clinical trial, melanoma, IL-12, vaccination, Melan-A peptide, immunological monitoring

Abstract

Preclinical studies have shown that low dose IL-12 can potentiate cytotoxic lymphocyte responses. Since previous trials have demonstrated significant toxicity from high dose recombinant human IL-12 (rhIL-12), we sought to determine an optimal biological dose for rhIL-12 at lower doses when combined with peptide antigens. Two studies were undertaken. The rhIL-12 was administered at doses of 0 (placebo), 10, 30 and 100 ng/kg, subcutaneously in one study and intravenously in the other. Apart from IL-12 dosing, the studies were identical. Subjects had evaluable stage III or IV melanoma which expressed Melan-A by RT-PCR or immunohistochemistry. Melan-A_26-35 (EAAGIGILTV) and influenza matrix_58-66 (GILGFVFTL) peptides were administered intradermally on weeks 1, 2, 3, 4 and 9. Twenty-eight subjects were enrolled, of whom 24 were evaluable for clinical and immunological responses. Therapy was well tolerated, the main adverse event being influenza-like symptoms. Immunological monitoring included the evaluation of cutaneous reactions and assays for antigen-specific T-cells. Clinical responses included a complete response in a subject with small volume subcutaneous disease, a partial response in a subject with hepatic metastases, and mixed responses in pulmonary, pleural and nodal disease. Biopsies of accessible tumors showed infiltration with CD4+ and CD8+ lymphocytes capable of lysing Melan-A peptide-pulsed targets in vitro. No clear dose-dependent effect of rhIL-12 could be determined. The rhIL-12 given either s.c. or i.v. was well tolerated at doses of 10-100 ng/kg. Clinical and immunological activity has been observed in this study where peptides were administered either with or without low dose rhIL-12.