Oncolytic virus and anti-4-1BB combination therapy elicits strong anti-tumor immunity against established cancer
Menée sur des modèles murins, cette étude évalue l'efficacité antitumorale d'une stratégie combinant un virus oncolytique et un anticorps agoniste spécifique de la molécule 4-1BB
Oncolytic virotherapy utilizing vaccinia virus (Vv) has shown some encouraging anti-tumor responses in mouse models and patients, but the breadth of efficacy in clinical trials has been somewhat limited. Given that anti-tumor effects have correlated with increased host immune responses, we hypothesized that improved therapeutic outcomes may be achieved by utilizing oncolytic virus in combination with a potent immune agonist reagent. In this study, we performed a preclinical evaluation of a genetically engineered strain of oncolytic vaccinia virus (Vvdd) for its capacity to induce anti-tumor responses when combined with an agonist antibody (Ab) specific for the co-stimulatory molecule 4-1BB (CD137). In immune competent syngeneic mouse models of cancer, this combination therapy significantly reduced the growth of established subcutaneous tumors relative to either treatment alone. Importantly, the development of pulmonary metastatic lesions was also reduced. Tumor growth inhibition was associated with increased numbers of CD11b+ and CD11c+ myeloid cells in the tumor-draining lymph nodes, greater infiltration of CD8+ effector T and NK cells and a more sustained presence of neutrophils at the tumor site. Depletion of T or NK cells or neutrophils reduced efficacy, confirming their contribution to an effective therapeutic response. We further extended this conclusion through results from IFN-gamma-deficient mice. In summary, our findings offered a proof of concept for a combinatorial approach to enhance the antitumor efficacy of an oncolytic virus, suggesting a strategy to improve their use as an immunotherapeutic strategy for cancer treatment.