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Alum with Interleukin-12 Augments Immunity to a Melanoma Peptide Vaccine: Correlation with Time to Relapse in Patients with Resected High-Risk Disease

Authors' Affiliations: ¹ The Angeles Clinic and Research Institute, Santa Monica; ² Department of Medicine, University of Southern California/Norris Comprehensive Cancer Center; and ³ Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California

Requests for reprints: Jeffrey S. Weber, University of Southern California/Norris Comprehensive Cancer Center, Suite 3440, 1441 Eastlake Avenue, Los Angeles, CA 90089. Phone: 323-865-3962; Fax: 323-865-0061; E-mail: jweber{at}usc.edu.

Purpose: We attempted to augment immunity to melanoma antigens using interleukin-12 (IL-12) with aluminum hydroxide (alum) for sustained release or granulocyte macrophage colony-stimulating factor (GM-CSF) added to a multipeptide vaccine.

Experimental Design: Sixty patients with high-risk resected melanoma were randomized to receive melanoma peptides gp100_209-217 (210M), MART-1_26-35 (27L), and tyrosinase_368-376 (370D) with adjuvant Montanide ISA 51 and either IL-12 at 30 ng/kg with alum (group A), IL-12 at 100 ng/kg with alum (group B), or IL-12 at 30 ng/kg with 250 µg GM-CSF (group C).

Results: Three patients had stage IIC (5%), 50 had stage III (83%), and 7 had stage IV (12%) melanoma. Most toxicities were grade 1/2 and resolved rapidly. Significant toxicity included grade 3 colitis and visual changes and grade 3 headache resolving after stopping IL-12 but continuing peptide vaccine. A higher rate of post-vaccine 6-month immune response to gp100 and MART-1 was observed in group A (15 of 19) or B (19 of 20) that received IL-12 plus alum versus group C with IL-12/GM-CSF (4 of 21; P < 0.001). Post-vaccine enzyme-linked immunospot response rates to peptide analogues in group B were higher than group A (P = 0.031 for gp100 and P = 0.010 for MART-1); both were higher than group C (P < 0.001 for gp100 and P < 0.026 for MART-1). With a median of 24 months of follow-up, 23 patients have relapsed. Post-vaccine immune response to MART-1 was associated with relapse-free survival (P = 0.012).

Conclusions: IL-12 with alum augmented an immune response to melanoma antigens compared with IL-12 with GM-CSF. Immune response was associated with time to relapse.

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