Generation of multiepitope cancer vaccines based on large combinatorial libraries of survivin-derived mutant epitopes

摘要

Immune tolerance is the main challenge in the field of cancer vaccines, so modified peptide sequences or naturally occurring mutated versions of cancer-related wild-type (WT) antigens represent a promising pathway. However, the low immunogenicity of mutation-induced neoantigens and, particularly, their incapacity to activate CD8(+)T cells are generating doubts on the success of neoantigen-based cancer vaccines in clinical trials. We developed a novel vaccine approach based on a new class of vaccine immunogens, called variable epitope libraries (VELs). We used three regions of survivin (SVN), composed of 40, 49 and 51 amino acids, along with the complete SVN protein to generate the VELs as multiepitope vaccines. BALB/c mice, challenged with the aggressive and highly metastatic 4T1 cell line, were vaccinated in a therapeutic setting. We showed significant tumor growth inhibition and, most importantly, strong suppression of lung metastasis after a single immunization using VEL vaccines. We demonstrated vaccine-induced broad cellular immune responses concomitant with extensive tumor infiltration of T cells, the activation of CD107a(+) IFN-gamma T+ cells in the spleen and a significant increase in the number of CD3(+) CD8(+) Ly6C(+)effector T cells. In addition, we observed the presence of interferon-gamma-, granzyme B- and perforin-producing lymphocytes along with modifications in the amount of CD11b(+) Ly6C(int/low) Ly6G(+)granulocytic myeloid-derived suppressor cells and CD4(+) CD25(+) FoxP3(+)regulatory T cells in the lungs and tumors of mice. In summary, we showed that the VELs represent a potent new class of cancer immunotherapy and propose the application of the VEL vaccine concept as a true alternative to currently available vaccine platforms.