Toes R E, Hoeben R C, van der Voort E I, Ressing M E, van der Eb A J, Melief C J, Offringa R
Department of Immunohematology and Blood Bank, University Hospital Leiden, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14660-5. doi: 10.1073/pnas.94.26.14660.
Vaccines harboring genes that encode functional oncoproteins are intrinsically hazardous, as their application may lead to introduction of these genes into normal cells and thereby to tumorigenesis. On the other hand, oncoproteins are especially attractive targets for immunotherapy of cancer, as their expression is generally required for tumor growth, making the arisal of tumor variants lacking these antigens unlikely. Using murine tumor models, we investigated the efficacy of polyepitope recombinant adenovirus (rAd) vaccines, which encode only the immunogenic T cell epitopes derived from several oncogenes, for the induction of protective anti-tumor immunity. We chose to employ rAd, as these are safe vectors that do not induce the side effects associated with, for example, vaccinia virus vaccines. A single polyepitope rAd was shown to give rise to presentation of both H-2 and human leukocyte antigen-restricted cytotoxic T lymphocyte (CTL) epitopes. Moreover, vaccination with a rAd encoding H-2-restricted CTL epitopes, derived from human adenovirus type 5 early region 1 and human papilloma virus type 16-induced tumors, elicited strong tumor-reactive CTL and protected the vaccinated animals against an otherwise lethal challenge with either of these tumors. The protection induced was superior compared with that obtained by vaccination with irradiated tumor cells. Thus, vaccination with polyepitope rAd is a powerful approach for the induction of protective anti-tumor immunity that allows simultaneous immunization against multiple tumor-associated T cell epitopes, restricted by various major histocompatibility complex haplotypes.
携带编码功能性癌蛋白基因的疫苗本质上具有危险性，因为其应用可能导致这些基因导入正常细胞，进而引发肿瘤形成。另一方面，癌蛋白是癌症免疫治疗特别有吸引力的靶点，因为肿瘤生长通常需要其表达，这使得缺乏这些抗原的肿瘤变体不太可能出现。利用小鼠肿瘤模型，我们研究了多表位重组腺病毒（rAd）疫苗的疗效，该疫苗仅编码源自几种癌基因的免疫原性T细胞表位，用于诱导保护性抗肿瘤免疫。我们选择使用rAd，因为这些是安全的载体，不会引发例如痘苗病毒疫苗相关的副作用。单一多表位rAd被证明可引发H-2和人类白细胞抗原限制性细胞毒性T淋巴细胞（CTL）表位的呈递。此外，用编码源自人5型腺病毒早期区域1和人乳头瘤病毒16型诱导肿瘤的H-2限制性CTL表位的rAd进行疫苗接种，可引发强烈的肿瘤反应性CTL，并保护接种疫苗的动物免受这两种肿瘤中任何一种的致命攻击。与用辐照肿瘤细胞接种所获得的保护相比，诱导产生的保护作用更优。因此，用多表位rAd进行疫苗接种是诱导保护性抗肿瘤免疫的一种有效方法，它允许同时针对多种受不同主要组织相容性复合体单倍型限制的肿瘤相关T细胞表位进行免疫。
