A novel minigene scaffold for therapeutic cancer vaccines

Luigi Aurisicchio, Arthur Fridman, Ansuman Bagchi, Elisa Scarselli, Nicola La Monica, Gennaro Ciliberto

Research output: Contribution to journalArticle

Abstract

Genetic vaccines are emerging as a powerful modality to induce T-cell responses to target tumor associated antigens (TAA). Viral or plasmid DNA or RNA vectors harbor an expression cassette encoding the antigen of choice delivered in vivo by vaccination. In this context, immunizations with minigenes containing selected, highly antigenic, T-cell epitopes of TAA s may have several advantages relative to full-length proteins. The objective of this study was to identify an optimal scaffold for minigene construction. We generated a number of minigenes containing epitopes from the carcinoembryonic antigen (CEA) model TAA and utilized muscle DNA electro-gene-transfer (DNA-EGT) to vaccinate HLA-A*0201 (HHD) and CEA/HHD double transgenic mice. The components utilized to construct the minigenes included CD8+ T cell epitopes and (or) anchor modified analogs that were selected on the basis of their predicted binding to HLA-*A0201, their uniqueness in the human proteome, and the likelihood of cancer cell natural processing and presentation via MHC-I. Other candidate components comparatively tested included: helper CD4+ T-cell epitopes, flanking regions for optimal epitope processing (including both proteasome-dependent and furin-dependent polypeptide processing mechanisms), and immunoenhancing moieties. Through a series of comparative studies and iterations we have identified an optimal minigene scaffold comprising the following elements: human tissue plasminogen activator (TPA) signal peptide, T-cell epitopes connected by furin sensitive linkers, and the E. Coli enterotoxin B subunit. The selected epitope modified minigenes (EMM) delivered by DNA -EG T were able to break immune tolerance in CEA/HH D mice and induce a strong immune response against all epitopes tested, independently of their relative positions within the scaffold. Furthermore, the optimized EMMs delivered via DNA -EG T were more immunogenic and exerted more powerful antitumor effects in a B16-CEA/HH D metastatic melanoma model than a DNA vector encoding the full-length protein or a mixture of the same peptides injected subcutaneously. Our data may shed light on the optimal design of a universal vehicle for epitopetargeted, genetic cancer vaccines.

Original languageEnglish
Article numbere27529
JournalOncoImmunology
Volume3
Issue number1
DOIs
Publication statusPublished - 2014

Keywords

  • Cancer vaccine
  • Epitope prediction
  • Minigene

ASJC Scopus subject areas

  • Immunology and Allergy
  • Oncology
  • Immunology

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  • Cite this

    Aurisicchio, L., Fridman, A., Bagchi, A., Scarselli, E., Monica, N. L., & Ciliberto, G. (2014). A novel minigene scaffold for therapeutic cancer vaccines. OncoImmunology, 3(1), [e27529]. https://doi.org/10.4161/onci.27529