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  • Oncolytic Virus and Anti–4-1BB Combination Therapy Elicits Strong Antitumor Immunity against Established Cancer

    Author(s)
    B. John, Liza
    J. Howland, Linda
    K. Flynn, Jacqueline
    C. West, Alison
    Devaud, Christel
    P. Duong, Connie
    J. Stewart, Trina
    A. Westwood, Jenny
    Sheng Guo, Z.
    L. Bartlett, David
    J. Smyth, Mark
    H. Kershaw, Michael
    K. Darcy, Phillip
    Griffith University Author(s)
    Stewart, Trina
    Year published
    2012
    Metadata
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    Abstract
    Oncolytic virotherapy using vaccinia virus (Vv) has shown some encouraging antitumor responses in mouse models and patients, but the breadth of efficacy in clinical trials has been somewhat limited. Given that antitumor effects have correlated with increased host immune responses, we hypothesized that improved therapeutic outcomes may be achieved by using oncolytic virus (OV) in combination with a potent immune agonist reagent. In this study, we carried out a preclinical evaluation of a genetically engineered strain of oncolytic vaccinia virus (Vvdd) for its capacity to induce antitumor responses when combined with an agonist ...
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    Oncolytic virotherapy using vaccinia virus (Vv) has shown some encouraging antitumor responses in mouse models and patients, but the breadth of efficacy in clinical trials has been somewhat limited. Given that antitumor effects have correlated with increased host immune responses, we hypothesized that improved therapeutic outcomes may be achieved by using oncolytic virus (OV) in combination with a potent immune agonist reagent. In this study, we carried out a preclinical evaluation of a genetically engineered strain of oncolytic vaccinia virus (Vvdd) for its capacity to induce antitumor responses when combined with an agonist antibody (Ab) specific for the costimulatory 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 natural killer (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 IFNγ-deficient mice. In summary, our findings offered a proof-of-concept for a combinatorial approach to enhance the antitumor efficacy of an OV, suggesting a strategy to improve their use as an immunotherapeutic treatment for cancer.
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    Journal Title
    Cancer Research
    Volume
    72
    Issue
    7
    DOI
    https://doi.org/10.1158/0008-5472.CAN-11-2788
    Subject
    Tumour Immunology
    Oncology and Carcinogenesis
    Publication URI
    http://hdl.handle.net/10072/47647
    Collection
    • Journal articles

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