Potentiating Cancer Immunotherapy Using an Oncolytic Virus

被引:137
作者
Bridle, Byram W. [1 ]
Stephenson, Kyle B. [1 ]
Boudreau, Jeanette E. [1 ]
Koshy, Sandeep [1 ]
Kazdhan, Natasha [1 ]
Pullenayegum, Eleanor [2 ]
Brunelliere, Jerome [1 ]
Bramson, Jonathan L. [1 ]
Lichty, Brian D. [1 ]
Wan, Yonghong [1 ]
机构
[1] McMaster Univ, Dept Pathol & Mol Med, Ctr Gene Therapeut, Hamilton, ON L8N 3Z5, Canada
[2] McMaster Univ, Dept Clin Epidemiol & Biostat, Ctr Evaluat Med, Hamilton, ON L8N 3Z5, Canada
基金
加拿大健康研究院;
关键词
VESICULAR STOMATITIS-VIRUS; NEWCASTLE-DISEASE VIRUS; HERPES-SIMPLEX-VIRUS; ANTITUMOR IMMUNITY; RECOMBINANT ADENOVIRUS; CELLULAR VEHICLES; VACCINE VECTOR; TUMOR-CELLS; GM-CSF; DELIVERY;
D O I
10.1038/mt.2010.98
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Oncolytic viruses (OVs) are highly immunogenic and this limits their use in immune-competent hosts. Although immunosuppression may improve viral oncolysis, this gain is likely achieved at the cost of antitumoral immunity. We have developed a strategy wherein the immune response against the OV leads to enhanced therapeutic outcomes. We demonstrate that immunization with an adenoviral (Ad) vaccine before treatment with an oncolytic vesicular stomatitis virus (VSV) expressing the same tumor antigen (Ag) leads to significantly enhanced antitumoral immunity. Intratumoral replication of VSV was minimally attenuated in Ad-immunized hosts but extending the interval between treatments reduced the attenuating effect and further increased antitumoral immunity. More importantly, our combination approach shifted the immune response from viral Ags to tumor Ags and further reduced OV replication in normal tissues, leading to enhancements in both efficacy and safety. These studies also highlight the benefits of using a replicating, OV to boost a pre-existing antitumoral immune response as this approach generated larger responses versus tumor Ag in tumor-bearing hosts than could be achieved in tumor-free hosts. This strategy should be applicable to other vector combinations, tumor Ags, and tumor targets.
引用
收藏
页码:1430 / 1439
页数:10
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