High Therapeutic Efficacy of a New Survivin LSP-Cancer Vaccine Containing CD4+ and CD8+ T-Cell Epitopes

Abstract

The efficacy of an antitumoral vaccine relies both on the choice of the antigen targeted and on its design. The tumor antigen survivin is an attractive target to develop therapeutic cancer vaccines because of its restricted over-expression and vital functions in most human tumors. Accordingly, several clinical trials targeting survivin in various cancer indications have been conducted. Most of them relied on short peptide-based vaccines and showed promising, but limited clinical results. In this study, we investigated the immunogenicity and therapeutic efficacy of a new long synthetic peptide (LSP)-based cancer vaccine targeting the tumor antigen survivin (SVX). This SVX vaccine is composed of three long synthetic peptides containing several CD4+ and CD8+ T-cell epitopes, which bind to various HLA class II and class I molecules. Studies in healthy individuals showed CD4+ and CD8+ T-cell immunogenicity of SVX peptides in human, irrespective of the individual's HLA types. Importantly, high frequencies of spontaneous T-cell precursors specific to SVX peptides were also detected in the blood of various cancer patients, demonstrating the absence of tolerance against these peptides. We then demonstrated SVX vaccine's high therapeutic efficacy against four different established murine tumor models, associated with its capacity to generate both specific cytotoxic CD8+ and multifunctional Th1 CD4+ T-cell responses. When tumors were eradicated, generated memory T-cell responses protected against rechallenge allowing long-term protection against relapses. Treatment with SVX vaccine was also found to reshape the tumor microenvironment by increasing the tumor infiltration of both CD4+ and CD8+ T cells but not Treg cells therefore tipping the balance toward a highly efficient immune response. These results highlight that this LSP-based SVX vaccine appears as a promising cancer vaccine and warrants its further clinical development.

Cancer therapeutics using survivin BIRC5 as a target: what can we do after over two decades of study?

“…These authors further showed that the survivin peptide cocktail vaccine has high therapeutic efficacy against four different murine tumor models established, and is associated with vaccine capacity to generate both specific cytotoxic CD8+ and multifunctional Th1 CD4+ T-cell responses [173]. When tumors were eradicated, generated memory T-cell responses protected against rechallenge, allowing long-term protection against relapses [173]. Treatment with the survivin peptide cocktail vaccine was also found to reshape the tumor microenvironment by increasing the tumor infiltration of both CD4+ and CD8+ T cells but not Treg cells, therefore tipping the balance toward a highly efficient immune response [173].…”

“…Studies in healthy individuals showed that CD4+ and CD8+ T-cell immunogenicity of the survivin peptide cocktail happened in humans, irrespective of the individual's HLA types. High frequencies of spontaneous T-cell precursors specific to the survivin peptide cocktail were also detected in the blood of various cancer patients [173], demonstrating the absence of tolerance against these peptides. These authors further showed that the survivin peptide cocktail vaccine has high therapeutic efficacy against four different murine tumor models established, and is associated with vaccine capacity to generate both specific cytotoxic CD8+ and multifunctional Th1 CD4+ T-cell responses [173].…”

“…High frequencies of spontaneous T-cell precursors specific to the survivin peptide cocktail were also detected in the blood of various cancer patients [173], demonstrating the absence of tolerance against these peptides. These authors further showed that the survivin peptide cocktail vaccine has high therapeutic efficacy against four different murine tumor models established, and is associated with vaccine capacity to generate both specific cytotoxic CD8+ and multifunctional Th1 CD4+ T-cell responses [173]. When tumors were eradicated, generated memory T-cell responses protected against rechallenge, allowing long-term protection against relapses [173].…”

“…Additionally, a study of an HLA-DR restricted survivinderived CD4+ T cell epitope in a multi-peptide cocktail immunotherapy trial for prostate carcinoma patients indicated that the survivin peptides are promiscuously presented by several human HLA-DRB1 molecules, and they are naturally processed through dendritic cells. In vaccinated patients, it was able to induce frequent, robust and multifunctional CD4+ T cell responses [170] Finally, based on the previous finding of the survivin or survivin peptide-derived HLA class I-restricted CD8+ T-cell epitopes [150,152,171,172], 3 long survivin peptides, 17-34 (18aa), 84-110 (27aa) and 122-142 (21as) that cover all of the previously identified epitopes were used as a cocktail for vaccination [173]. Studies in healthy individuals showed that CD4+ and CD8+ T-cell immunogenicity of the survivin peptide cocktail happened in humans, irrespective of the individual's HLA types.…”

“…When tumors were eradicated, generated memory T-cell responses protected against rechallenge, allowing long-term protection against relapses [173]. Treatment with the survivin peptide cocktail vaccine was also found to reshape the tumor microenvironment by increasing the tumor infiltration of both CD4+ and CD8+ T cells but not Treg cells, therefore tipping the balance toward a highly efficient immune response [173]. These authors highlighted that this survivin long peptide cocktail-based survivin vaccine appears to be a promising cancer vaccine strategy and warrants further clinical development [173].…”