Human dendritic cells adenovirally-engineered to express three defined tumor antigens promote broad adaptive and innate immunity

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Abstract

Dendritic cell (DC) immunotherapy has shown a promising ability to promote anti-tumor immunity in vitro and in vivo. Many trials have tested single epitopes and single antigens to activate single T cell specificities, and often CD8+ T cells only. We previously found that determinant spreading and breadth of antitumor immunity correlates with improved clinical response. Therefore, to promote activation and expansion of polyclonal, multiple antigen-specific CD8+ T cells, as well as provide cognate help from antigen-specific CD4+ T cells, we have created an adenovirus encoding three full length melanoma tumor antigens (tyrosinase, MART-1 and MAGE-A6, "AdVTMM"). We previously showed that adenovirus (AdV)-mediated antigen engineering of human DC is superior to peptide pulsing for T cell activation, and has positive biological effects on the DC, allowing for efficient activation of not only antigen-specific CD8+ and CD4+ T cells, but also NK cells. Here we describe the cloning and testing of "AdVTMM2," an E1/E3-deleted AdV encoding the three melanoma antigens. This novel three-antigen virus expresses mRNA and protein for all antigens, and AdVTMM-transduced DC activate both CD8+ and CD4+ T cells which recognize melanoma tumor cells more efficiently than single antigen AdV. Addition of physiological levels of interferon-a (IFNa) further amplifies melanoma antigen-specific T cell activation. NK cells are also activated, and show cytotoxic activity. Vaccination with multi-antigen engineered DC may provide for superior adaptive and innate immunity and ultimately, improved antitumor responses. © 2012 Landes Bioscience.

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Blalock, L. A. T., Landsberg, J., Messmer, M. N., Shi, J., Pardee, A. D., Haskell, R. E., … Butterfield, L. H. (2012). Human dendritic cells adenovirally-engineered to express three defined tumor antigens promote broad adaptive and innate immunity. OncoImmunology, 1(3), 287–357. https://doi.org/10.4161/onci.18628

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