Attenuated Dengue virus PV001-DV induces oncolytic tumor cell death and potent immune responses.

BACKGROUND: Viral therapies developed for cancer treatment have classically prioritized direct oncolytic effects over their immune activating properties. However, recent clinical insights have challenged this longstanding prioritization and have shifted the focus to more immune-based mechanisms. Through the potential utilization of novel, inherently immune-stimulating, oncotropic viruses there is a therapeutic opportunity to improve anti-tumor outcomes through virus-mediated immune activation. PV001-DV is an attenuated strain of Dengue virus (DEN-1 #45AZ5) with a favorable clinical safety profile that also maintains the potent immune stimulatory properties characterstic of Dengue virus infection. METHODS: In this study, we utilized in vitro tumor killing and immune multiplex assays to examine the anti-tumor effects of PV001-DV as a potential novel cancer immunotherapy. RESULTS: In vitro assays demonstrated that PV001-DV possesses the ability to directly kill human melanoma cells lines as well as patient melanoma tissue ex vivo. Importantly, further work demonstrated that, when patient peripheral blood mononuclear cells (PBMCs) were exposed to PV001-DV, a substantial induction in the production of apoptotic factors and immunostimulatory cytokines was detected. When tumor cells were cultured with the resulting soluble mediators from these PBMCs, rapid cell death of melanoma and breast cancer cell lines was observed. These soluble mediators also increased dengue virus binding ligands and immune checkpoint receptor, PD-L1 expression. CONCLUSIONS: The direct in vitro tumor-killing and immune-mediated tumor cytotoxicity facilitated by PV001-DV contributes support of its upcoming clinical evaluation in patients with advanced melanoma who have failed prior therapy.

Overcoming tumor immune evasion with an unique arbovirus.

Combining dendritic cell vaccination with the adjuvant effect of a strain of dengue virus may be a way to overcome known tumor immune evasion mechanisms. Dengue is unique among viruses as primary infections carry lower mortality than the common cold, but secondary infections carry significant risk of hypovolemic shock. While current immuno-therapies rely on a single axis of attack, this approach combines physiological (hyperthermic reduction of tumor perfusion), immunological (activation of effector cells of the adaptive and innate immune system), and apoptosis-inducing pathways (sTRAIL) to destroy tumor cells. The premise of using multiple mechanisms of action in synergy with a decline in the ability of the tumor cells to employ resistance methods suggests the potential of this combination approach in cancer immunotherapy.