Exosome Targeting of Tumor Antigens Expressed by Cancer Vaccines Can Improve Antigen Immunogenicity and Therapeutic Efficacy
Exosome Targeting of Tumor Antigens Expressed by Cancer Vaccines Can Improve Antigen Immunogenicity and Therapeutic Efficacy
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DOI：
10.1158/0008-5472.can-10-4076
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发表时间：
2011-08-01
期刊：
影响因子：
11.2
通讯作者：
Delcayre, Alain
中科院分区：
文献类型：
--
作者：
Rountree, Ryan B.;Mandl, Stefanie J.;Delcayre, Alain
MVA-BN-PRO（BN ImmunoTherapeutics）是一种用于治疗前列腺癌的候选免疫治疗产品。它编码 2 种肿瘤相关抗原、前列腺特异性抗原 (PSA) 和前列腺酸性磷酸酶 (PAP)，源自高度减毒的改良安卡拉牛痘 (MVA) 病毒原种（称为 MVA-BN）。过去的工作表明，可以通过将抗原定位到外泌体来提高抗原的免疫原性，外泌体是大多数细胞类型分泌的直径为 50 至 100 nm 的小囊泡。外泌体靶向是通过将抗原融合到乳粘素蛋白的 C1C2 结构域来实现的。为了测试外泌体靶向是否会提高 PSA 和 PAP 的免疫原性，生产了另外 2 个版本的 MVA-BN-PRO，将 PSA (MVA-BN-PSA-C1C2) 或 PAP (MVA-BN-PAP-C1C2) 靶向外泌体，同时使第二个转基因未靶向。用 MVA-BN-PAP-C1C2 治疗小鼠导致针对 PAP 的免疫反应显着增强。抗 PAP 抗体滴度发展得更快，达到的水平比用 MVA-BN-PRO 治疗的小鼠高 10 至 100 倍。此外，与 MVA-BN-PRO 治疗的小鼠相比，MVA-BN-PAP-C1C2 治疗使 PAP 特异性 T 细胞的频率增加了 5 倍。这些改进转化为表达 PAP 的实体瘤模型中肿瘤排斥的频率更高。同样，与 MVA-BN-PRO 治疗相比，MVA-BN-PSA-C1C2 治疗增加了 PSA 的抗原性，并导致表达 PSA 的肿瘤模型中抗肿瘤功效有改善的趋势。这些实验证实，将抗原定位到外泌体是提高 MVA-BN-PRO 在人类中的治疗潜力的可行方法。癌症研究； 71(15)； 5235-44。 (c) 2011 年 AACR。
MVA-BN-PRO (BN ImmunoTherapeutics) is a candidate immunotherapy product for the treatment of prostate cancer. It encodes 2 tumor-associated antigens, prostate-specific antigen (PSA), and prostatic acid phosphatase (PAP), and is derived from the highly attenuated modified vaccinia Ankara (MVA) virus stock known as MVA-BN. Past work has shown that the immunogenicity of antigens can be improved by targeting their localization to exosomes, which are small, 50- to 100-nm diameter vesicles secreted by most cell types. Exosome targeting is achieved by fusing the antigen to the C1C2 domain of the lactadherin protein. To test whether exosome targeting would improve the immunogenicity of PSA and PAP, 2 additional versions of MVA-BN-PRO were produced, targeting either PSA (MVA-BN-PSA-C1C2) or PAP (MVA-BN-PAP-C1C2) to exosomes, while leaving the second transgene untargeted. Treatment of mice with MVA-BN-PAP-C1C2 led to a striking increase in the immune response against PAP. Anti-PAP antibody titers developed more rapidly and reached levels that were 10- to 100-fold higher than those for mice treated with MVA-BN-PRO. Furthermore, treatment with MVA-BN-PAP-C1C2 increased the frequency of PAP-specific T cells 5-fold compared with mice treated with MVA-BN-PRO. These improvements translated into a greater frequency of tumor rejection in a PAP-expressing solid tumor model. Likewise, treatment with MVA-BN-PSA-C1C2 increased the antigenicity of PSA compared with treatment with MVA-BN-PRO and resulted in a trend of improved antitumor efficacy in a PSA-expressing tumor model. These experiments confirm that targeting antigen localization to exosomes is a viable approach for improving the therapeutic potential of MVA-BN-PRO in humans. Cancer Res; 71(15); 5235-44. (c) 2011 AACR.