Listeria-based cancer vaccines that segregate immunogenicity from toxicity
Listeria-based cancer vaccines that segregate immunogenicity from toxicity
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DOI：
10.1073/pnas.0406035101
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发表时间：
2004-09-21
影响因子：
11.1
通讯作者：
Dubensky, TW
中科院分区：
文献类型：
--
作者：
Brockstedt, DG;Giedlin, MA;Dubensky, TW
兼性细胞内细菌单核细胞增生李斯特菌由于其诱导有效的先天性和适应性免疫的能力而被开发为癌症疫苗平台。为了成功的临床应用，必须开发一种安全但保留基于野生型细菌的疫苗效力的李斯特菌平台菌株。在这里，我们报告了一种重组减毒活疫苗平台菌株的开发，与野生型李斯特菌相比，该菌株保留了完全毒性病原体的效力，并且毒性降低了>1,000倍。通过选择性地删除两种毒力因子ActA（triangleactA）和Internalin B（triangleinl B），李斯特菌的免疫效力得以维持，并且其体内毒性得以降低，这主要是通过阻断Internalin B介导的对非吞噬细胞（如肝细胞）的直接感染以及通过从相邻吞噬细胞的细胞间传播的间接ActA介导的感染。相反，吞噬细胞的感染不受影响，使李斯特菌刺激先天免疫和诱导抗原特异性细胞应答的能力保持不变。基于李斯特菌triangleactA/triangleinlB的疫苗在免疫后从小鼠中快速清除，并诱导有效且持久的效应和记忆T细胞应答，而没有可测量的肝毒性。携带鼠CT 26结肠肿瘤肺转移或可触知的皮下接种的BALB/c小鼠的治疗性疫苗接种用表达内源性肿瘤抗原的重组李斯特菌triangleactA/triangleinlB感染肿瘤（>100 mm（3））导致自身耐受性的破坏和长期存活。我们提出，表达人类肿瘤相关抗原的重组李斯特菌triangleactA/triangleinlB代表了一种有吸引力的治疗策略，用于进一步开发和在人类临床试验中进行测试。
The facultative intracellular bacterium Listeria monocytogenes is being developed as a cancer vaccine platform because of its ability to induce potent innate and adaptive immunity. For successful clinical application, it is essential to develop a Listeria platform strain that is safe yet retains the potency of vaccines based on wild-type bacteria. Here, we report the development of a recombinant live-attenuated vaccine platform strain that retains the potency of the fully virulent pathogen, combined with a >1,000-fold reduction in toxicity, as compared with wild-type Listeria. By selectively deleting two virulence factors, ActA (triangleactA) and Internalin B (triangleinlB), the immunopotency of Listeria was maintained and its toxicity was diminished in vivo, largely by blocking the direct internalin B-mediated infection of nonphagocytic cells, such as hepatocytes, and the indirect ActA-mediated infection by cell-to-cell spread from adjacent phagocytic cells. In contrast, infection of phagocytic cells was not affected, leaving intact the ability of Listeria to stimulate innate immunity and to induce antigen-specific cellular responses. Listeria triangleactA/triangleinlB-based vaccines were rapidly cleared from mice after immunization and induced potent and durable effector and memory T-cell responses with no measurable liver toxicity. Therapeutic vaccination of BALB/c mice bearing murine CT26 colon tumor lung metastases or palpable s.c. tumors (>100 mm(3)) with recombinant Listeria triangleactA/triangleinlB expressing an endogenous tumor antigen resulted in breaking of self-tolerance and long-term survival. We propose that recombinant Listeria triangleactA/triangleinlB expressing human tumor-associated antigens represents an attractive therapeutic strategy for further development and testing in human clinical trials.