Hodge J W, McLaughlin J P, Kantor J A, Schlom J
Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Vaccine. 1997 Apr-May;15(6-7):759-68. doi: 10.1016/s0264-410x(96)00238-1.
Recombinant vaccinia viruses containing tumor associated genes represent an attractive vector to induce immune responses to weak immunogens in cancer immunotherapy protocols. The property of intense immunogenicity of vaccinia proteins, however, also serves to limit the number of inoculations of recombinant vaccinia viruses. Host immune responses to the first immunization have been shown to limit the replication of subsequent vaccinations and thus reduce effectiveness of boost inoculations. The use of recombinant avian pox viruses (avipox) such as the canarypox (ALVAC) or fowlpox are potential candidates for immunization protocols in that they can infect mammalian cells and express the inserted transgene, but do not replicate in mammalian cells. We report here the construction and characterization of a canarypox (ALVAC) recombinant expressing the human carcinoembryonic antigen (CEA) gene (designated ALVAC-CEA). Antibody, lymphoproliferative and cytolytic T-cell responses as well as tumor inhibition were shown to be elicited by the ALVAC-CEA recombinant in a murine model. The utilization of a diversified immunization scheme using a recombinant vaccinia virus followed by recombinant avian pox virus was shown to be far superior than the use of either one alone in eliciting CEA-specific T-cell responses. Experiments were conducted to determine if the use of a diversified immunization scheme using a recombinant vaccinia virus (rV-CEA) and ALVAC-CEA would be superior to the use of either one alone in eliciting CEA-specific T-cell responses. When mice were immunized with rV-CEA and then ALVAC-CEA. CEA-specific T-cell responses were at least four times greater, and for superior to those achieved with three immunizations of ALVAC-CEA. Multiple boosts of ALVAC-CEA following rV-CEA immunization further potentiated anti-tumor effects and CEA specific T-cell responses. These studies demonstrate the proof of concept of the advantage of diversified immunization protocols employing both recombinant vaccinia and recombinant avipox vectors.
含有肿瘤相关基因的重组痘苗病毒是癌症免疫治疗方案中诱导针对弱免疫原的免疫反应的一种有吸引力的载体。然而，痘苗蛋白强烈的免疫原性也限制了重组痘苗病毒的接种次数。已表明宿主对首次免疫的反应会限制后续疫苗接种的复制，从而降低加强接种的效果。使用重组禽痘病毒，如金丝雀痘病毒（ALVAC）或鸡痘病毒，作为免疫方案的潜在候选者，因为它们可以感染哺乳动物细胞并表达插入的转基因，但不在哺乳动物细胞中复制。我们在此报告了一种表达人癌胚抗原（CEA）基因的金丝雀痘病毒（ALVAC）重组体（命名为ALVAC-CEA）的构建和特性。在小鼠模型中，ALVAC-CEA重组体可引发抗体、淋巴细胞增殖和细胞溶解T细胞反应以及肿瘤抑制。结果表明，使用重组痘苗病毒后再使用重组禽痘病毒的多样化免疫方案在引发CEA特异性T细胞反应方面远比单独使用其中任何一种优越。进行实验以确定使用重组痘苗病毒（rV-CEA）和ALVAC-CEA的多样化免疫方案在引发CEA特异性T细胞反应方面是否优于单独使用其中任何一种。当用rV-CEA免疫小鼠，然后再用ALVAC-CEA免疫时，CEA特异性T细胞反应至少大四倍，且优于三次接种ALVAC-CEA所达到的反应。在rV-CEA免疫后多次加强接种ALVAC-CEA进一步增强了抗肿瘤作用和CEA特异性T细胞反应。这些研究证明了采用重组痘苗病毒和重组禽痘病毒载体的多样化免疫方案优势的概念验证。
