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

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Title Oncolytic Virus and Anti–4-1BB Combination Therapy Elicits Strong Antitumor Immunity against Established Cancer
Author John, Liza B.; Howland, Linda J.; Flynn, Jacqueline K.; West, Alison C.; Devaud, Christel; Duong, Connie P.; Stewart, Trina; Westwood, Jenny A.; Guo, Z. Sheng; Bartlett, David L.; Smyth, Mark J.; Kershaw, Michael H.; Darcy, Phillip K.
Journal Name Cancer Research
Year Published 2012
Place of publication United States
Publisher American Association for Cancer Research
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 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 CD11bþ and CD11cþ myeloid cells in the tumor draining lymph nodes, greater infiltration of CD8þ 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 IFNg 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.
Peer Reviewed Yes
Published Yes
Alternative URI http://dx.doi.org/10.1158/0008-5472.CAN-11-2788
Volume 72
Issue Number 7
Page from 1651
Page to 1660
ISSN 0008-5472
Date Accessioned 2012-09-07
Language en_US
Faculty Griffith Health Faculty
Subject Tumour Immunology
URI http://hdl.handle.net/10072/47647
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1x

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