Carcinogenesis

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Randomized multicenter trial of the effects of melanoma-associated helper peptides and cyclophosphamide on the immunogenicity of a multipeptide melanoma vaccine

Craig L. Slingluff Jr.; Gina R. Petroni; Kimberly A. Chianese-Bullock; Mark E. Smolkin; Merrick I. Ross; Naomi B. Haas; Margaret Von Mehren; William W. Grosh (Profiled Author: Merrick I Ross)

Journal of Clinical Oncology. 2011;29(21):2924-2932.

Purpose: This multicenter randomized trial was designed to test whether melanoma-associated helper peptides augment CD8⁺ T-cell responses to a melanoma vaccine and whether cyclophosphamide (CY) pretreatment augments CD4⁺ or CD8⁺ T-cell responses to that vaccine. Patients and Methods: In all, 167 eligible patients with resected stage IIB to IV melanoma were randomly assigned to four vaccination study arms. Patients were vaccinated with 12 class I major histocompatibility complex - restricted melanoma peptides (12MP) to stimulate CD8⁺ T cells and were randomly assigned to receive a tetanus helper peptide or a mixture of six melanoma-associated helper peptides (6MHP) to stimulate CD4⁺ T cells. Before vaccination, patients were also randomly assigned to receive CY pretreatment or not. T-cell responses were assessed by an ex vivo interferon gamma ELISpot assay. Clinical outcomes and toxicities were recorded. Results: Vaccination with 12MP plus tetanus induced CD8⁺ T-cell responses in 78% of patients and CD4⁺ T-cell responses to tetanus peptide in 93% of patients. Vaccination with 12MP plus 6MHP induced CD8⁺ responses in 19% of patients and CD4⁺ responses to 6MHP in 48% of patients. CY had no significant effect on T-cell responses. Overall 3-year survival was 79% (95% CI, 71% to 86%), with no significant differences (at this point) by study arm. Conclusion: Melanoma-associated helper peptides paradoxically decreased CD8⁺ T-cell responses to a melanoma vaccine (P < .001), and CY pretreatment had no immunologic or clinical effect. Prior work showed immunologic and clinical activity of 6MHP alone. Possible explanations for negative effects on CD8 responses include modulation of homing receptor expression or induction of antigen-specific regulatory T cells. © 2011 by American Society of Clinical Oncology.

PMID: 21690475     PMCID: PMC3138719

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