An Engineered AAV6-Based Vaccine Induces High Cytolytic Anti-Tumor Activity by Directly Targeting DCs and Improves Ag Presentation

被引:22
作者
Krotova, Karina [1 ]
Day, Andrew [1 ]
Aslanidi, George [1 ]
机构
[1] Univ Minnesota, Hormel Inst, 301 16th Ave NE, Austin, MN 55912 USA
来源
MOLECULAR THERAPY-ONCOLYTICS | 2019年 / 15卷
关键词
T-CELL RESPONSES; INNATE IMMUNE-RESPONSES; DENDRITIC CELLS; ANTIGEN PRESENTATION; GENE-THERAPY; HUMAN TYROSINASE; REGULATORY T; AAV6; VECTORS; TUMOR-CELLS; VIRUS;
D O I
10.1016/j.omto.2019.10.001
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
We have previously shown that an AAV6-based vaccine generates high levels of antigen-specific CD8(+) T cells. Further modifications described here led to significantly increased levels of antigen-specific CD8(+) and CD4(+) T cells, enhanced formation of memory cells, and superior antigen-specific killing capacity in a murine model. By tracking reporter-gene-positive dendritic cells, we showed that they were directly targeted with modified AAV6 in vivo. Our vaccine's anti-cancer potential was evaluated with the antigen ovalbumin against a B16F10 melanoma cell line stably expressing ovalbumin. The vaccination showed superior protection in a murine model of metastatic melanoma. The vaccination significantly delayed solid tumor growth but did not completely prevent tumor development. We show that tumors in immunized mice escaped vaccine-induced killing by losing ovalbumin expression. The vaccine induced massive tumor infiltration with NK and CD8(+) T cells with upregulated PD-1 expression. Thus, a vaccination of a combination of anti-PD-1 antibodies demonstrated significant improvement in the treatment efficacy. To summarize, we showed that a bioengineered AAV6-based vaccine elicits strong and long-lasting cellular and humoral responses against an encoded antigen. To increase AAV vaccine efficiency and mitigate tumor escape through antigen loss, we intended to target several antigens in combination with treatments targeting the tumor microenvironment.
引用
收藏
页码:166 / 177
页数:12
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