Randomized Multicenter Trial of the Effects of Melanoma-Associated Helper Peptides and Cyclophosphamide on the Immunogenicity of a Multipeptide Melanoma Vaccine

Abstract

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.

Targeting CD4+ T-Helper Cells Improves the Induction of Antitumor Responses in Dendritic Cell–Based Vaccination

“…However, our findings are in contrast to previously published trials on peptide vaccination in patients with melanoma (37)(38)(39). In a recent randomized multicentre trial, Slingluff and colleagues report on 167 patients with stage IIB to IV melanoma vaccinated with either MHC-I-or MHC-I/II-restricted peptides, with or without cyclophosphamide pretreatment (37).…”

“…In a recent randomized multicentre trial, Slingluff and colleagues report on 167 patients with stage IIB to IV melanoma vaccinated with either MHC-I-or MHC-I/II-restricted peptides, with or without cyclophosphamide pretreatment (37). In this trial, the inclusion of melanoma-associated helper peptides paradoxically decreased CD8 þ T-cell responses.…”

Phase II Clinical Trial of Multiple Peptide Vaccination for Advanced Head and Neck Cancer Patients Revealed Induction of Immune Responses and Improved OS

“…To our knowledge, this study is the first to show a promising result indicating that therapeutic cancer vaccination with multiple peptides can potentially improve the prognosis of patients with advanced HNSCC refractory to standard therapy. Several phase II and III clinical trials have recently demonstrated promising and therapeutic results of cancer vaccination (19,(24)(25)(26)(27)(28)(29)(30)(31)(32). However, most of these studies were performed using single antigen-based vaccination with several modifications, and the clinical benefits appeared to be limited.…”

HAGE in Triple-Negative Breast Cancer Is a Novel Prognostic, Predictive, and Actionable Biomarker: A Transcriptomic and Protein Expression Analysis

“…Given that the HAGE antigen is immunogenic and is highly associated with TILs, one should consider targeting HAGE along with other CSAs using immunotherapeutic interventions in conjunction with chemotherapy for TNBC. Although in the past, cancer vaccines have had a poor clinical track record due to poor clinical results (34), in recent trials using immunotherapy, clinical outcomes have shown improved progression-free survival, or overall survival (35)(36)(37)(38). In fact, it is proposed that chemotherapies could be used to condition the immune system and tumor, and create an environment in which cancer vaccines have a better chance of success (34,39).…”