Beclin1-armed oncolytic Vaccinia virus enhances the therapeutic efficacy of R-CHOP against lymphoma in vitro and in vivo

Non-Hodgkin lymphoma (NHL) is a form of lymphoid malignancy, with diffuse large B cell lymphoma (DLBCL) being the most common NHL isoform. Approximately half of patients with DLBCL are successfully cured via first-line Rituximab, Cyclophosphamide, Epirubicin, Vindesine, Prednisolone (R-CHOP) treatment. However, 30-40% of patients with DLBCL ultimately suffer from treatment-refractory or relapsed disease. These patients often suffer from high mortality rates owing to a lack of suitable therapeutic options, and all patients are at a high risk of serious treatment-associated dose-dependent toxicity. As such, it is essential to develop novel treatments for NHL that are less toxic and more efficacious. Oncolytic Vaccinia virus (OVV) has shown promise as a means of treating numerous types of cancer. Gene therapy strategies further enhance OVV-based therapy by improving tumor cell recognition and immune evasion. Beclin1 is an autophagy-associated gene that, when upregulated, induces excess autophagy and cell death. The present study aimed to develop an OVV-Beclin1 therapy capable of inducing autophagic tumor cell death. OVV-Beclin1 was able to efficiently kill NHL cells and to increase the sensitivity of these cells to R-CHOP, thereby decreasing the dose-dependent toxic side effects associated with this chemotherapeutic regimen. The combination of OVV-Beclin1 and R-CHOP also significantly improved tumor growth inhibition and survival in a BALB/c murine model system owing to the synergistic induction of autophagic cell death. Together, these findings suggest that OVV-Beclin1 infection can induce significant autophagic cell death in NHL, highlighting this as a novel means of inducing tumor cell death via a mechanism that is distinct from apoptosis and necrosis.