Intradermal DNA electroporation induces survivin-specific CTLs, suppresses angiogenesis and confers protection against mouse melanoma

Abstract

Survivin is an intracellular tumor-associated antigen that is broadly expressed in a large variety of tumors and also in tumor associated endothelial cells but mostly absent in differentiated tissues. Naked DNA vaccines targeting survivin have been shown to induce T cell as well as humoral immune responses in mice. However, the lack of epitope-specific CD8+ T cell detection and modest tumor protection observed highlight the need for further improvements to develop effective survivin DNA vaccination approaches. Here, the efficacy of a human survivin DNA vaccine delivered by intradermal electroporation (EP) was tested. The CD8+ T cell epitope surv(20-28) restricted to H-2 Db was identified based on in-silico epitope prediction algorithms and binding to MHC class I molecules. Intradermal DNA EP of mice with a human survivin encoding plasmid generated CD8+ cytotoxic T lymphocyte (CTL) responses cross-reactive with the mouse epitope surv(20-28), as determined by intracellular IFN-gamma staining, suggesting that self-tolerance has been broken. Survivin-specific CTLs displayed an activated effector phenotype as determined by CD44 and CD107 up-regulation. Vaccinated mice displayed specific cytotoxic activity against B16 and peptide-pulsed RMA-S cells in vitro as well as against surv(20-28) peptide-pulsed target cells in vivo. Importantly, intradermal EP with a survivin DNA vaccine suppressed angiogenesis in vivo and elicited protection against highly aggressive syngeneic B16 melanoma tumor challenge. We conclude that intradermal EP is an attractive method for delivering a survivin DNA vaccine that should be explored also in clinical studies.

Self-adjuvanting nanoemulsion targeting dendritic cell receptor Clec9A enables antigen-specific immunotherapy

“…WH-neoepitope-TNE but not G-actin-neoepitope-TNE significantly suppressed tumor growth and enhanced survival ( Figure 7, A and B) and induced strong IFN-γ immunity to pooled B16 epitopes and to the universal tumor antigen, survivin (ref. 42 and Figure 7C). Immunogenicity and antitumor effects of the WH-neoepitope-TNE vaccine were Th cell-dependent, as the significant tumor suppression observed with WH-TNE was lost if CD4 + T cells were depleted during treatment ( Figure 7D).…”

Genetic Immunization with Plasmid DNA Mediated by Electrotransfer

“…The effect of the immune response was amplified when HER2 immunization was combined to a temporary regulatory T-cell depletion treatment, but only if the microscopic cancer was small enough (not palpable, Rolla et al, 2010). Other recent results describe the efficacy of the xenogenic chicken HSP70 antigen in a prime boost strategy for a canine transmissible venereal tumor (Yu et al, 2011), metalloproteinase MMP11 antigen in a colon cancer mouse model (Peruzzi et al, 2009), cancer testis antigen PASD1 fused to the tetanus toxin DOM epitope in a multiple myeloma mouse model ( Joseph-Pietras et al, 2010), a human surviving epitope against the B16 melanoma mouse model after intradermal delivery (Lladser et al, 2010), or secreted telomerase combined with an adenovirus boost in a dog lymphoma model (Peruzzi et al, 2010).…”

Vaccination approach to anti-angiogenic treatment of cancer

“…Lladser et al published two reports on a naked DNA vaccine targeting survivin [72,71]. In the first report mice were given three intramuscular injections with human survivin expressing plasmids together with a plasmid coding for the murine granulocyte-macrophage colony-stimulating factor (pGM-CSF).…”

“…In an in-vivo matrigel plug assay anti-angiogenic properties of this vaccine were demonstrated. Unfortunately, no attempts were made to investigate the humoral immune response and its possible role in tumor protection [71].…”