Activation of human immune cells by the oncolytic parvovirus H-1 combined with chemotherapeutic or targeted agents

Oncolytic viruses, such as autonomous parvoviruses (PV) and their therapeutic vectors are known to stimulate potent antitumoral immune responses in vitro and in vivo. The parvovirus H-1 efficiently infects and lyses human tumor cells, including human melanoma, hepatoma, colon- and gastric cancer cells. The aim of our research project was now to further evaluate the biologic and immunologic effects of H-1PV-induced tumor cell lysis (TCL) and its combination with chemotherapeutic and molecular targeted agents in two human melanoma models with adjacent characterized human cytotoxic T cells (CTL) and HLA-A2 restricted dendritic cells (DC).

Methods and results: The cytotoxic effect of H-1PV in MZ7-Mel cells was determined and resulted in cell growth reduction to >50%. Apoptosis was the preferred mode of H-1PV-induced tumor cell killing which correlated with the viral NS1 expression levels. Differently prepared TCL were phagocytosed by DCs and maturation of DCs was measured depending on the treatment of melanoma cells. Immature DCs incubated with H-1PV-induced MZ7-Mel cell lysates (TCL) induced a significant increase of DC maturation compared to non-infected or necrotic melanoma cells and dependent of time points of H-1PV-induced cell killing. Cytokine-release of TNF-α and IL-6 increased immensely in these DCs incubated with H-1PV-induced TCL. Even more, cytokine levels were higher in DC-TCL cocultures. Furthermore, tumor cell killing by H-1PV was enhanced by either combination with chemotherapeutic agents or with the multityrosine kinase inhibitor sunitinib. Again, combination of H-1PV-induced TCL with chemotherapeutic agents or sunitinib enhanced DC maturation compared to cytotoxic agents or targeted therapy alone. In addition, combination of H-1PV with cisplatin or vincristine led to a further increased release of IL-6 in TCL treated DC cocultured with CTL.

Conclusion: Combination strategies of oncolytic tumor cell lysis by the autonomous parvovirus H-1 with chemotherapeutic or targeted agents may overcome apoptosis resistance of tumor cells and may effectively stimulate the human immune system by pronounced DC maturation and CTL activation, further promoting the clinical assessment of H1 PV oncolytic tumor therapy.