Dendritic cells (DCs) induce primary T cell responses and are being extensively evaluated as vehicles for antigen (Ag) delivery in cancer immunotherapy. One strategy employs the use of hybrid cells generated by fusing DCs with tumor cells. Technically, fusion using chemical fusogens such as polyethylene glycol (PEG) or viruses has been plagued by low efficiency, toxicity and poor reproducibility. We recently developed an electrofusion protocol with which heterokaryons are generated with high fusion rates. In pre-clinical studies, fusion cells stimulated IFN? secretion from both CD4 and CD8 immune T cells, and for immunotherapy, a single vaccination resulted in tumor regression. Based on these observations, we have recently designed a clinical trial for the treatment of metastatic melanoma by vaccination with fusion of autologous DCs and allogeneic melanoma cell lines (PMCV or CanvaxinTU). In this protocol, 3 selected allogeneic tumor cells provide a source of tumor-associated Ags. However, little laboratory analysis has focused on defining the immunogenicity and potential therapeutic effects of this approach. Because of the immune response to histo-incompatible allo-Ags on allogeneic tumor cells, immune responses to tumor Ags may be subjected to down- or up-regulation. The mechanisms of allogeneic tumor vaccine need to be analyzed. In this proposal, two animal tumor systems will be used for the development of allogeneic vaccine. The first system will utilize beta-galactosidase (beta-gal) as a surrogate tumor rejection Ag that has been introduced into the B16/F10 (H-2b) melanoma and 4T1 (H-2d) breast carcinoma. The second system consists of three murine melanomas [B16 (H-2b), K1735 (H-2k) and cloudman S91 (H-2d)] of different haplotypes but sharing a number of natural tumor-associated Ags. These allogeneic tumors will be electrofused with syngeneic DCs. Their molecular characteristics, immunogenicities, and therapeutic effects will be analyzed against syngeneic tumors.
The specific aims are: 1) To determine the immunogenicity and therapeutic efficacy of syngeneic DC-allogeneic tumor (allo-DC-tumor) hybrids generated by electrofusion; 2) To characterize and analyze immune responses to tumor-associated Ags and to allogeneic histocompatibility Ags; 3) Active immunotherapy against advanced tumors; and 4) To generate tumor-immune T cells from mice immunized with allo-DC-tumor hybrid cells for adoptive immunotherapy.
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