Vaccination of Dendritic Cells Loaded with Interleukin-12-Secreting Cancer Cells Augments In vivo Antitumor Immunity: Characteristics of Syngeneic and Allogeneic Antigen-Presenting Cell Cancer Hybrid Cells
ABSTRACT Cancer immunotherapy by fusion of antigen-presenting cells and tumor cells has been shown to induce potent antitumor immunity. In this study, we characterized syngeneic and allogeneic, murine macrophage/dendritic cell (DC)-cancer fusion cells for the antitumor effects. The results showed the superiority of allogeneic cells as fusion partners in both types of antigen-presenting cells in an in vivo immunotherapy model. A potent induction of tumor-specific CTLs was observed in these immunized conditions. In addition, the immunization with DC-cancer fusion cells was better than that with macrophage-cancer fusion cells. Both syngeneic and allogeneic DC-cancer fusion cells induced higher levels of IFN-gamma production than macrophage-cancer fusion cells. Interestingly, allogeneic DC-cancer fusion cells were superior in that they efficiently induced Th1-type cytokines but not the Th2-type cytokines interleukin (IL)-10 and IL-4, whereas syngeneic DC-cancer fusion cells were powerful inducers of both Th1 and Th2 cytokines. These results suggest that allogeneic DCs are suitable as fusion cells in cancer immunotherapy. To further enhance the antitumor immunity in the clinical setting, we prepared DCs fused with IL-12 gene-transferred cancer cells and thus generated IL-12-secreting DC-cancer fusion cells. Immunization with these gene-modified DC-cancer fusion cells was able to elicit a markedly enhanced antitumor effect in the in vivo therapeutic model. This novel IL-12-producing fusion cell vaccine might be one promising intervention for future cancer immunotherapy.
- SourceAvailable from: Giordano Nicoletti
[Show abstract] [Hide abstract]
- "Thanks to these features, immunostimulatory DC have drawn attention as a useful component for cancer vaccines  . DC fused with tumor cells (TCs), more than DC variably loaded with antigenic peptides or apoptotic cells, effectively elicited anti-tumor immunity, both in animal models and in cancer patients     . DC–TC hybrids should provide costimulatory proteins and cytokines, in addition to a complete array of tumor antigens presented in the context of class I and II MHC molecules. "
ABSTRACT: Main obstacles to cancer vaccine efficacy are pre-existing antigenic load and immunoescape mechanisms, including tolerance against self tumor-associated antigens. Here we explored the role of tolerance in an antimetastatic vaccine approach based on dendritic cell-tumor cell (DC-TC) hybrids, thanks to the comparison between BALB-neuT mice, transgenic for and tolerant to rat HER-2/neu, with their non-tolerant strain of origin BALB/c. Allogeneic DC-TC hybrid vaccine displayed a high antimetastatic activity in non-tolerant mice, but was far less effective in tolerant mice, even with intensified vaccine schedule. Tolerant BALB-neuT mice revealed a reduced ability to mount polarized Th1 responses. A further attempt to increase the antimetastatic activity by using LPS-matured DC hybrids failed. Allogeneic LPS-matured DC-TC hybrids induced high IFN-γ levels, but concomitantly also the highest production of IL-4 and IL-10 suggesting activation of mechanisms sustaining regulatory cells able to blunt vaccine efficacy. Our data in tolerant versus non-tolerant hosts suggest that clinical translation of effective DC-based strategies could benefit from more extensive investigations in tolerant transgenic models.Vaccine 06/2011; 29(29-30):4690-7. DOI:10.1016/j.vaccine.2011.04.096 · 3.49 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Fusions of dendritic cells (DC) and tumor cells are increasingly used in tumor immunotherapy. The strategy for DC-tumor fusion vaccine is based on the fact that DC are the most potent antigen-presenting cells in the body, whereas tumor cells express abundant tumor antigens. The fusion of these two cell types creates a heterokaryon with both DC-derived costimulatory molecules, efficient antigen-processing and -presentation machinery, and tumor-derived antigens. In animal and human studies, fusion-cell (FC) vaccines have been shown to possess the elements essential for processing and presenting tumor antigens to host immune cells, for inducing effective immune response, and for breaking T-cell tolerance to tumor-associated antigens. Moreover, FC vaccines provide protection against challenge with tumor cells and mediate regression of established tumors. Despite these unique features of DC-tumor fusion cells and the observation of tumor eradication in animal studies, only limited, yet encouraging, success has been seen in clinical trials. This chapter describes the methods used for preparation of DC-tumor fusion cells, summarizes the effect of FC in stimulating T cell responses, analyzes factors influencing the success or failure of FC-mediated immunotherapy and discusses recent advances in concept and techniques of DC-tumor fusions. KeywordsAntitumor immunity-cancer-cell-cell fusion-dendritic cell-fusion cell vaccine-immune therapy01/1970: pages 315-350;
- [Show abstract] [Hide abstract]
ABSTRACT: Recent progress in the approach towards immunotherapy of cancer consists in molecular definition of tumor antigens, new tools for phenotypical and functional characterization of tumor-specific effector cells and clinical use of novel adjuvants for optimal stimulation of a cancer-specific immune response such as dendritic cells. In spite of these advances and immunological as well as clinical responses in selected patients, mechanisms involved in dendritic-cell-based cancer immunotherapy are still poorly understood. Therefore, a standardized study design and small pilot trials are needed to explore open scientific questions in future clinical trials. This review focuses on the different parameters of dendritic cell biology relevant to cancer immunotherapy and on innovative approaches to hopefully enhance the efficacy of dendritic cell vaccination.Skin pharmacology and physiology 02/2006; 19(3):124-31. DOI:10.1159/000092592 · 1.96 Impact Factor