Pre-existing immunity to adenovirus does not prevent tumor regression following intratumoral administration of a vector expressing IL-12 but inhibits virus dissemination
Pre-existing immunity to adenovirus does not prevent tumor regression following intratumoral administration of a vector expressing IL-12 but inhibits virus dissemination
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DOI：
10.1038/sj.gt.3300508
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发表时间：
1997-10-01
期刊：
影响因子：
5.1
通讯作者：
Graham, FL
中科院分区：
文献类型：
--
作者：
Bramson, JL;Hitt, M;Graham, FL
腺病毒（Ad）载体作为肿瘤基因治疗的载体正在被深入研究。我们一直在探索直接瘤内注射表达细胞因子的Ads用于免疫治疗的益处。我们以前的工作表明，使用表达白细胞介素-12（AdmIL-12.1）的载体的治疗在约80%的治疗肿瘤中产生了消退，支持进一步的临床前研究。最近的报道表明，对Ad的免疫可能是Ad介导的基因转移的主要限制因素。由于大多数使用Ad载体的动物研究涉及非免疫宿主，因此仍然难以预测这些治疗在人类中的有效性，其中大多数个体先前都暴露于Ad。为了解决这个问题，我们比较了AdmIL-12.1治疗在幼稚和Ad免疫小鼠中的有效性。我们发现两组对治疗的反应同样良好，并且两组中对AdmIL-12.1的反应导致产生对肿瘤抗原具有反应性的CTL，表明实现了抗肿瘤免疫。与非免疫小鼠相比，在Ad免疫动物中肿瘤中的峰值转基因表达仅降低了2.4倍。还观察到，在未处理动物中，注射后病毒从肿瘤部位扩散，并且在72 h时，在外周器官中检测到大量转基因表达，最明显的是肝脏。在Ad免疫动物的肝脏中的转基因表达相对于在幼稚小鼠中的转基因表达减少了大于1000倍。这些结果强烈支持基于Ad的癌症基因治疗的临床效用，并表明Ad免疫可能是有利的，因为它不是肿瘤中基因转移的完全阻断，并且它大大减少了病毒传播。
Adenovirus (Ad) vectors are being intensively studied as vehicles for cancer gene therapy. We have been exploring the benefits of direct intratumoral injection of Ads expressing cytokines for immunotherapy. Our previous work demonstrated that therapy using a vector expressing interleukin-12 (AdmIL-12.1) produced regressions in approximately 80% of treated tumors, supporting further preclinical investigations. Recent reports have shown that immunity to Ad can be a major limiting factor in Ad-mediated gene transfer. As most animal studies with Ad vectors have involved nonimmune hosts, it remains difficult to predict how effective these treatments will be in humans, where the majority of individuals have previous exposure to Ad. To address this question, we compared the effectiveness of the AdmIL-12.1 therapy in naive and Ad-immune mice. We found that both groups responded equally well to treatment and that the response to AdmIL-12.1 in both groups resulted in the generation of CTL reactive against tumor antigen, indicating that antitumor immunity was achieved. Peak transgene expression in the tumor was only reduced by 2.4-fold in Ad-immune animals compared with nonimmune mice. It was also observed that in naive animals, the virus disseminated from the site of the tumor following injection and by 72 h substantial transgene expression was detected in peripheral organs, most notably the liver. Transgene expression in the liver of Ad-immune animals was reduced by greater than 1000-fold relative to that in naive mice. These results strongly support the clinical utility of Ad-based cancer gene therapy and suggest that Ad immunity may be advantageous in that it is not a complete block to gene transfer in the tumor and it greatly reduces virus dissemination.