Mechanistic factors limiting utility of adenovirus vectors for treatment of neopla

摘要 基于腺病毒的载体是开发用于治疗的新型候选药物的非常有吸引力的平台 许多遗传性疾病和癌症。目前，流行的观点是， 癌症治疗剂包括i）有效的细胞毒性能力， ii）刺激适应性抗肿瘤免疫的能力， 反应虽然开发有效的溶瘤治疗剂的早期努力主要集中在利用或 甚至增加病毒介导的肿瘤细胞毒性，新的数据表明，在体内， 具有低细胞毒性能力的病毒与高效的病毒相当或甚至更好， 在体外杀死癌细胞这种疗效和效力之间不匹配的机制因素， vivo仍然知之甚少。在评价全身给药的 在小鼠播散性肺癌模型中，我们发现病毒剂量递增 导致荷瘤小鼠的中位存活率降低。在发展为“无反应”的小鼠中， 表型，髓样细胞响应于腺病毒施用而变得高度活化。基于这些 研究结果我们提出了“修复性呼叫”的新概念， 触发肿瘤相关骨髓细胞的活化，其进而分泌促肿瘤生长因子， 引发肿瘤加速生长该项目旨在全面解决机械方面的问题 通过分析细胞毒效力如何影响基于Ad的全身病毒治疗的疗效， 向量。我们将确定肿瘤来源的IL-33在驱动髓系细胞活化中的机制作用，并将 开发表达可溶性IL-33 R的新型Ad载体以阻断IL-33依赖性肿瘤细胞活化。我们将 进一步分析表达可溶性IL-33 R的Ad载体与临床应用的联合治疗的疗效， 靶向骨髓细胞和PD-1通路的相关药物。该项目的成功完成将 显著推进我们对有效临床翻译的关键基本因素的理解， 用于治疗肿瘤疾病的基于广告的载体系统。

ABSTRACT Adenovirus-based vectors are a very attractive platform for development of novel drug candidates for treatment of numerous genetic diseases and cancer. Currently, the prevailing view of requisites for effective virus-based cancer therapeutics includes i) a potent cytotoxic capacity to trigger virus-mediated killing of as many tumor cells as possible in the shortest period of time, and ii) the capacity for stimulating adaptive anti-tumor immune response. While early efforts to develop potent oncolytic therapeutics were primarily focused on harnessing or even increasing virus-mediated tumor cell cytotoxicity, new data suggest that in vivo, therapeutic efficacy of viruses with low cytotoxic capacity is comparable or even better than that of viruses which are highly effective at killing cancer cells in vitro. The mechanistic factors underlying this mismatch between efficacy and potency in vivo remain poorly understood. While evaluating the therapeutic efficacy of systemically administered adenovirus-based vectors in a mouse model of disseminated lung cancer, we found that virus dose escalation leads to a reduction in median survival of tumor-bearing mice. In mice that developed a ‘non-responder’ phenotype, myeloid cells become highly activated in response to adenovirus administration. Based on these findings we propose the novel concept of a “reparative call”, whereby efficient tumor cell killing by the virus triggers activation of tumor-associated myeloid cells, which in turn secrete pro-tumorigenic growth factors, triggering accelerated tumor growth. This project is designed to comprehensively address mechanistic aspects of this concept by analyzing how cytotoxic potency may affect the efficacy of systemic virotherapy with Ad-based vectors. We will determine the mechanistic role of tumor-derived IL-33 in driving myeloid cell activation and will develop novel Ad vectors expressing soluble IL-33R to block IL-33-dependent tumor-cell activation. We will further analyze the therapeutic efficacy of soluble IL-33R-expressing Ad vectors in combination with clinically relevant drugs that target myeloid cells and the PD-1 pathway. The successful completion of this project will significantly advance our understanding of fundamental factors that are critical for effective clinical translation of Ad-based vector systems for therapy of neoplastic disease.