1. KBMA Listeria monocytogenes is an effective vector for DC-mediated induction of antitumor immunity
- Author
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Skoberne, Mojca, Yewdall, Alice, Bahjat, Keith S., Godefroy, Emmanuelle, Lauer, Peter, Lemmens, Edward, Liu, Weiqun, Luckett, Will, Leong, Meredith, Dubensky, Thomas W., Brockstedt, Dirk G., and Bhardwaj, Nina
- Subjects
Cancer vaccines -- Genetic aspects ,Cancer vaccines -- Research ,Dendritic cells -- Physiological aspects ,Dendritic cells -- Genetic aspects ,Dendritic cells -- Research ,Listeria monocytogenes -- Usage - Abstract
Vaccine strategies that utilize human DCs to enhance antitumor immunity have yet to realize their full potential. Approaches that optimally target a spectrum of antigens to DCs are urgently needed. Here we report the development of a platform for loading DCs with antigen. It is based on killed but metabolically active (KBMA) recombinant Listeria monocytogenes and facilitates both antigen delivery and maturation of human DCs. Highly attenuated KBMA L. monocytogenes were engineered to express an epitope of the melanoma-associated antigen MelanA/Mart-1 that is recognized by human [CD8.sup.+] T cells when presented by the MHC class I molecule HLAA* 0201. The engineered KBMA L. monocytogenes induced human DC upregulation of costimulatory molecules and secretion of pro-Th1 cytokines and type I interferons, leading to effective priming of Mart-1-specific human [CD8.sup.+] T cells and lysis of patient-derived melanoma cells. KBMA L. monocytogenes expressing full-length NY-ESO-1 protein, another melanoma-associated antigen, delivered the antigen for presentation by MHC class I and class II molecules independent of the MHC haplotype of the DC donor. A mouse therapeutic tumor model was used to show that KBMA L. monocytogenes efficiently targeted APCs in vivo to induce protective antitumor responses. Together, our data demonstrate that KBMA L. monocytogenes may be a powerful platform that can both deliver recombinant antigen to DCs for presentation and provide a potent DC-maturation stimulus, making it a potential cancer vaccine candidate., Introduction Melanoma is one of the most rapidly growing cancers worldwide, yet there is no satisfactory treatment either in the adjuvant setting or when it has advanced to metastatic disease. [...]
- Published
- 2008