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

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.

• Authors: Jonathan Cebon, Elke Jäger, Mark J Shackleton, Peter Gibbs, Ian D Davis, Wendie Hopkins, Sharen Gibbs, Qiyuan Chen, Julia Karbach, Heather Jackson, Duncan P MacGregor, Sue Sturrock, Hilary Vaughan, Eugene Maraskovsky, Antje Neumann, Eric Hoffman, Mathew L Sherman, Alexander Knuth
• Journal: Cancer immunity (Cancer Immun) Vol. 3 Pg. 7 (Jul 16 2003) ISSN: 1424-9634 [Electronic] United States
• PMID: 12862418 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article)

Chemical References

• Adjuvants, Immunologic
• Antigens, Neoplasm
• Cancer Vaccines
• MART-1 Antigen
• MLANA protein, human
• Neoplasm Proteins
• Peptide Fragments
• Recombinant Proteins
• Viral Matrix Proteins
• influenza virus membrane protein (58-66)
• Interleukin-12

Topics

• Adjuvants, Immunologic (therapeutic use)
• Adolescent
• Adult
• Aged
• Antigens, Neoplasm (adverse effects, therapeutic use)
• Cancer Vaccines (adverse effects, therapeutic use)
• Drug Administration Schedule
• Drug Hypersensitivity
• Drug Therapy, Combination
• Female
• Humans
• Influenza A virus (chemistry)
• Injections, Intravenous
• Injections, Subcutaneous
• Interleukin-12 (administration & dosage, adverse effects, therapeutic use)
• MART-1 Antigen
• Male
• Melanoma (drug therapy, immunology)
• Middle Aged
• Neoplasm Proteins (adverse effects, therapeutic use)
• Peptide Fragments (therapeutic use)
• Recombinant Proteins (administration & dosage, adverse effects, therapeutic use)
• Viral Matrix Proteins (therapeutic use)