Development of"immunostimulatory virotherapy"to treat various malignancies

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Though DC-based cancer immunotherapy has been suggested as a potential treatment for various kinds of malignancies, its clinical efficacies are still insufficient in many human trials. Especially, malignant ascites(MA) is a highly intractable and immunotherapy-resistant state of advanced gastrointestinal and ovarian cancers.First, floating cultivation of mononuclear cells from cancer patients under an optimized cytokine cocktail(GM-CSF/SCF) led these cells to stable proliferation and to DC differentiation. As are seen in conventional DCs, expanded DCs showed dendrites after maturation, and endocytotic activities. Expanded DCs also expressed HLA-DR, adhesion molecules, and co-stimulatory molecules and produced inflammatory cytokines as well as conventional DCs did. Functionally, MLR assay revealed that expanded DCs could stimulate allogenic T-cell proliferation to the same extent as conventional DCs.Next, using a murine model of MA with CT26 colon cancer cells, we here determined that the imbalance between the VEGF-A and its decoy receptor, soluble fms-like tryrosine kinase receptor-1(sFLT-1), was a major cause of MA resistance to DC-based immunotherapy. We found that the ratio of VEGF-A/sFLT-1 was increased not only in murine but also in human MA, and F-gene. deleted recombinant Sendai virus(rSeV/dF)-mediated secretion of human sFLT-1 by DCs augmented not only the activity of DCs themselves, but also dramatically improved the survival of tumor-bearing animals associated with enhanced CTL activity and its infiltration to peritoneal tumors.