Insights in AAV-mediated antigen-specific immunity and a strategy for AAV vaccine dose reduction through AAV-extracellular vesicle association.

IF 4.6 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Molecular Therapy-Methods & Clinical Development Pub Date : 2024-10-18 eCollection Date: 2024-12-12 DOI:10.1016/j.omtm.2024.101358
Ester Molina, Marcos Tejero, Ozgun Firat Duzenli, Hisae Kuoch, Colin Caine, Karina Krotova, Michael Paulaitis, George Aslanidi
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Abstract

We previously showed therapeutic advantages of using a capsid-modified and encoded antigen-optimized AAV-based cancer vaccine to initiate strong antigen-specific immune responses and increase survival in a syngeneic mouse model of melanoma. In this study, we further explore AAV vaccine dose reduction and possible mechanisms of the immune response. Immunization with extracellular vesicle (EV)-associated AAV6-S663V encoded ovalbumin (OVA) or tyrosinase-related protein 1 (TRP-1) induced significantly higher levels of antigen-specific CD8+ T cells compared with standard AAV in mice. Importantly, a higher number of specific CD8+ T cells was achieved with EV-AAV several logs lower than optAAV-based doses. EV-optAAV-OVA was used in a dose 100 times lower, and EV-optTRP-1 10 times lower than optOVA and optTRP-1 correspondingly. Our data suggest that significant dose reduction for optimized AAV-based vaccines is possible without sacrificing efficiency. In addition, we studied the role of conventional type 1 dendritic cells (cDC1) in optimized AAV-based immunization using a C57BL/6-Irf8em1Kmm (Irf8 + 32-/-) mouse model lacking cDC1. Interestingly, we found that cDC1 are not essential for conveying effector T cell responses to AAV-encoded tumor antigens.

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对 AAV 介导的抗原特异性免疫的见解以及通过 AAV 与细胞外囊泡结合减少 AAV 疫苗剂量的策略。
我们以前曾在一个黑色素瘤合成小鼠模型中展示了使用经过囊壳修饰和编码的抗原优化 AAV 癌症疫苗启动强抗原特异性免疫反应和提高存活率的治疗优势。在本研究中,我们进一步探讨了 AAV 疫苗剂量的减少和免疫应答的可能机制。与标准 AAV 相比,用细胞外囊泡 (EV) 相关的 AAV6-S663V 编码卵清蛋白 (OVA) 或酪氨酸酶相关蛋白 1 (TRP-1) 免疫小鼠可诱导出更高水平的抗原特异性 CD8+ T 细胞。重要的是,与基于 optAAV 的剂量相比,EV-AAV 的剂量要低几个对数,但却能获得更多的特异性 CD8+ T 细胞。EV-optAAV-OVA的剂量比optOVA和optTRP-1低100倍,EV-optTRP-1的剂量比optOVA和optTRP-1低10倍。我们的数据表明,在不牺牲效率的情况下,大幅降低优化 AAV 疫苗的剂量是可能的。此外,我们还利用缺乏 cDC1 的 C57BL/6-Irf8em1Kmm (Irf8 + 32-/-)小鼠模型研究了传统 1 型树突状细胞(cDC1)在优化 AAV 免疫中的作用。有趣的是,我们发现 cDC1 对于传递效应 T 细胞对 AAV 编码肿瘤抗原的反应并不是必不可少的。
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来源期刊
Molecular Therapy-Methods & Clinical Development
Molecular Therapy-Methods & Clinical Development Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
9.90
自引率
4.30%
发文量
163
审稿时长
12 weeks
期刊介绍: The aim of Molecular Therapy—Methods & Clinical Development is to build upon the success of Molecular Therapy in publishing important peer-reviewed methods and procedures, as well as translational advances in the broad array of fields under the molecular therapy umbrella. Topics of particular interest within the journal''s scope include: Gene vector engineering and production, Methods for targeted genome editing and engineering, Methods and technology development for cell reprogramming and directed differentiation of pluripotent cells, Methods for gene and cell vector delivery, Development of biomaterials and nanoparticles for applications in gene and cell therapy and regenerative medicine, Analysis of gene and cell vector biodistribution and tracking, Pharmacology/toxicology studies of new and next-generation vectors, Methods for cell isolation, engineering, culture, expansion, and transplantation, Cell processing, storage, and banking for therapeutic application, Preclinical and QC/QA assay development, Translational and clinical scale-up and Good Manufacturing procedures and process development, Clinical protocol development, Computational and bioinformatic methods for analysis, modeling, or visualization of biological data, Negotiating the regulatory approval process and obtaining such approval for clinical trials.
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