An Engineered AAV6-Based Vaccine Induces High Cytolytic Anti-Tumor Activity by Directly Targeting DCs and Improves Ag Presentation
An Engineered AAV6-Based Vaccine Induces High Cytolytic Anti-Tumor Activity by Directly Targeting DCs and Improves Ag Presentation
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DOI：
10.1016/j.omto.2019.10.001
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发表时间：
2019-12-20
影响因子：
5.7
通讯作者：
Aslanidi, George
中科院分区：
文献类型：
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作者：
Krotova, Karina;Day, Andrew;Aslanidi, George
我们之前已经证明，基于AAV 6的疫苗产生高水平的抗原特异性CD 8（+）T细胞。本文所述的进一步修饰导致抗原特异性CD 8（+）和CD 4（+）T细胞水平显著增加，记忆细胞形成增强，以及小鼠模型中的上级抗原特异性杀伤能力。通过追踪hepatocyte基因阳性树突状细胞，我们发现它们在体内被修饰的AAV 6直接靶向。我们的疫苗的抗癌潜力进行了评估与抗原卵清蛋白对B16 F10黑色素瘤细胞系稳定表达卵清蛋白。疫苗接种在转移性黑素瘤的鼠模型中显示出上级的保护作用。疫苗接种显著延迟了实体瘤的生长，但不能完全阻止肿瘤的发展。我们发现，免疫小鼠的肿瘤通过失去卵清蛋白表达而逃脱了疫苗诱导的杀伤。该疫苗诱导了NK和CD 8（+）T细胞的大量肿瘤浸润，PD-1表达上调。因此，抗PD-1抗体的组合的疫苗接种证明了治疗功效的显著改善。总而言之，我们显示了基于生物工程化AAV 6的疫苗针对编码的抗原激发了强烈且持久的细胞和体液应答。为了增加AAV疫苗效率并通过抗原损失减轻肿瘤逃逸，我们打算靶向几种抗原与靶向肿瘤微环境的治疗组合。
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.