Goldberg Stacie M, Bartido Shirley M, Gardner Jason P, Guevara-Patiño José A, Montgomery Stephanie C, Perales Miguel-Angel, Maughan Maureen F, Dempsey JoAnn, Donovan Gerald P, Olson William C, Houghton Alan N, Wolchok Jedd D
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Clin Cancer Res. 2005 Nov 15;11(22):8114-21. doi: 10.1158/1078-0432.CCR-05-1410.
Immunization of mice with xenogeneic DNA encoding human tyrosinase-related proteins 1 and 2 breaks tolerance to these self-antigens and leads to tumor rejection. Viral vectors used alone or in heterologous DNA prime/viral boost combinations have shown improved responses to certain infectious diseases. The purpose of this study was to compare viral and plasmid DNA in combination vaccination strategies in the context of a tumor antigen.
Using tyrosinase as a prototypical differentiation antigen, we determined the optimal regimen for immunization with plasmid DNA. Then, using propagation-incompetent alphavirus vectors (virus-like replicon particles, VRP) encoding tyrosinase, we tested different combinations of priming with DNA or VRP followed by boosting with VRP. We subsequently followed antibody production, T-cell response, and tumor rejection.
T-cell responses to newly identified mouse tyrosinase epitopes were generated in mice immunized with plasmid DNA encoding human (xenogeneic) tyrosinase. In contrast, when VRP encoding either mouse or human tyrosinase were used as single agents, antibody and T-cell responses and a significant delay in tumor growth in vivo were observed. Similarly, a heterologous vaccine regimen using DNA prime and VRP boost showed a markedly stronger response than DNA vaccination alone.
Alphavirus replicon particle vectors encoding the melanoma antigen tyrosinase (self or xenogeneic) induce immune responses and tumor protection when administered either alone or in the heterologous DNA prime/VRP boost approaches that are superior to the use of plasmid DNA alone.
用编码人酪氨酸酶相关蛋白1和2的异种DNA免疫小鼠可打破对这些自身抗原的耐受性并导致肿瘤排斥。单独使用病毒载体或采用异源DNA初免/病毒加强联合方式已显示出对某些传染病的免疫反应有所改善。本研究的目的是在肿瘤抗原背景下比较病毒和质粒DNA联合疫苗接种策略。
以酪氨酸酶作为典型的分化抗原，我们确定了质粒DNA免疫的最佳方案。然后，使用编码酪氨酸酶的无复制能力的甲病毒载体（病毒样复制子颗粒，VRP），我们测试了DNA或VRP初免后再用VRP加强的不同组合。随后我们跟踪抗体产生、T细胞反应和肿瘤排斥情况。
在用编码人（异种）酪氨酸酶的质粒DNA免疫的小鼠中产生了对新鉴定的小鼠酪氨酸酶表位的T细胞反应。相比之下，当使用编码小鼠或人酪氨酸酶的VRP作为单一制剂时，观察到抗体和T细胞反应以及体内肿瘤生长的显著延迟。同样，使用DNA初免和VRP加强的异源疫苗方案显示出比单独的DNA疫苗接种明显更强的反应。
编码黑色素瘤抗原酪氨酸酶（自身或异种）的甲病毒复制子颗粒载体单独给药或采用异源DNA初免/VRP加强方法给药时，均可诱导免疫反应并提供肿瘤保护，且优于单独使用质粒DNA。
