Single-Step Antigen Loading and Activation of Dendritic Cells by mRNA Electroporation for the Purpose of Therapeutic Vaccination in Melanoma Patients.
(2009) Clinical Cancer Research — Vol. 15, n° 10, p. 3366-3375 (2009)
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- PURPOSE: A critical factor determining the effectiveness of currently used dendritic cell (DC)-based vaccines is the DC activation or maturation status. We have recently shown that the T-cell stimulatory capacity of DCs pulsed with tumorantigen-derived peptides can be considerably increased by activating the DCs through electroporation with mRNA encoding CD40 ligand, CD70, and a constitutively active Toll-like receptor 4 (TriMix DCs). Here, we investigate whether TriMix DCs can be coelectroporated with whole tumorantigen encoding mRNA.EXPERIMENTAL DESIGN: The T-cell stimulatory capacity of TriMix DCs pulsed with the immunodominant MelanA-A2 peptide and that of TriMix DCs coelectroporated with MelanA mRNA were compared in vitro. TriMix DCs were also coelectroporated with mRNA encoding Mage-A3, Mage-C2, tyrosinase, or gp100. The capacity of these DCs to stimulate tumorantigen-specific T cells in melanoma patients was investigated both in vitro before vaccination and after DC vaccination.RESULTS: Like peptide-pulsed TriMix DCs, TriMix DCs coelectroporated with MelanA mRNA are very potent in inducing MelanA-specific CD8(+) T cells in vitro. These T cells have an activated phenotype, show cytolytic capacity, and produce inflammatory cytokines in response to specific stimulation. TriMix DCs coelectroporated with tyrosinase are able to stimulate tyrosinase-specific CD8(+) T cells in vitro from the blood of nonvaccinated melanoma patients. Furthermore, TriMix DCs coelectroporated with Mage-A3, Mage-C2, or tyrosinase are able to induce antigen-specific CD8(+) T cells through therapeutic DC vaccination.CONCLUSIONS: TriMix DCs coelectroporated with whole tumorantigen mRNA stimulate antigen-specific T cells in vitro and induce antigen-specific T-cell responses in melanoma patients through vaccination. Therefore, they represent a promising new approach for antitumor immunotherapy.
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Bonehill, A., Van Nuffel, A. M. T., Corthals, J., Tuyaerts, S., Heirman, C., François, V., Colau, D., van der Bruggen, P., Neyns, B., & Thielemans, K. (2009). Single-Step Antigen Loading and Activation of Dendritic Cells by mRNA Electroporation for the Purpose of Therapeutic Vaccination in Melanoma Patients. Clinical Cancer Research, 15(10), 3366-3375. https://doi.org/10.1158/1078-0432.CCR-08-2982 (Original work published 2009)