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Effects of Interleukin-12 on the Immune Response to a Multipeptide Vaccine for Resected Metastatic Melanoma

From the Departments of Medicine, Division of Medical Oncology, and Department of Preventive Medicine, Keck/University of Southern California School of Medicine, Los Angeles; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford; and Department of Experimental Therapeutics, City of Hope National Medical Center, Duarte, CA.

Address reprint requests to Jeffrey Weber, MD, PhD, University of Southern California Norris Comprehensive Cancer Center, Rm 6428, 1441 Eastlake Ave, Los Angeles, CA 90089; email: jweber{at}hsc.usc.edu

PURPOSE: Forty-eight patients with high-risk re-sected stage III or IV melanoma were immunized with two tumor antigen epitope peptides derived from gp100_209-217(210M) (IMDQVPSFV) and tyrosin-ase_368-376(370D) (YMDGTMSQV) emulsified with incomplete Freund’s adjuvant (IFA). Patients received peptides/IFA with or without interleukin (IL)-12 30 ng/kg to evaluate the toxicities and immune responses in either arm with time to relapse and survival as secondary end points.

PATIENTS AND METHODS: Immunizations were administered every 2 weeks for 8 weeks, then every 4 weeks for 12 weeks, and then once 8 weeks later. A leukapheresis to obtain peripheral-blood mononuclear cells for immune analyses was done before and after vaccination. Skin testing with peptides and recall reagents was performed before and after vaccinations.

RESULTS: Local pain and granuloma formation, fever, and lethargy of grade 1 or 2 were observed. Transient vaccine-related grade 3—but no grade 4—toxicity was observed. Thirty-four of 40 patients developed a positive skin test response to the gp100 peptide but none to tyrosinase. Immune responses were measured by release of gamma-interferon in an enzyme-linked immunosorbent assay (ELISA) by effector cells in the presence of peptide-pulsed antigen-presenting cells or by an antigen-specific tetramer flow cytometry assay. Thirty-three of 38 patients demonstrated an immune response by ELISA after vaccination, as did 37 of 42 patients by tetramer assay. Twenty-four of 48 patients relapsed with a median follow-up of 20 months, and 10 patients in this high-risk group have died.

CONCLUSION: These data suggest a significant proportion of patients with resected melanoma mount an antigen-specific immune response against a peptide vaccine and indicate that IL-12 may increase the immune response and supporting further development of IL-12 as a vaccine adjuvant.

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