Mechanistic factors limiting utility of adenovirus vectors for treatment of neopla

摘要 腺病毒载体是开发新的治疗候选药物的一个非常有吸引力的平台 许多遗传性疾病和癌症。目前，有效的基于病毒的必备条件的流行观点 癌症治疗包括：1)强大的细胞毒能力，能够触发病毒介导的对尽可能多的肿瘤细胞的杀伤 在最短的时间内，以及ii)激发适应性抗肿瘤免疫的能力 回应。虽然早期开发有效的溶瘤疗法的努力主要集中在利用或 即使病毒介导的肿瘤细胞毒性增加，新的数据表明，在体内，治疗效果 低细胞毒能力的病毒与高效的病毒相当，甚至更好。 在体外杀死癌细胞。药效和药效不匹配背后的机械性因素 VIVO仍然鲜为人知。在评价全身给药治疗效果的同时 腺病毒载体在小鼠播散性肺癌模型中发现病毒剂量递增 导致荷瘤小鼠的中位存活率降低。在小鼠身上出现了“无反应者” 表型，髓系细胞对腺病毒注射高度激活。基于这些 我们提出了“修复呼叫”的新概念，即病毒有效地杀死肿瘤细胞。 触发肿瘤相关髓系细胞的激活，这些髓系细胞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 通过分析细胞毒力如何影响基于Ad的系统性病毒治疗的疗效来验证这一概念 向量。我们将确定肿瘤来源的IL-33在驱动髓系细胞激活中的机制作用，并将 开发表达可溶性IL-33R的新型Ad载体以阻断IL-33依赖的肿瘤细胞的激活。我们会 进一步分析表达IL-33R的可溶性腺病毒载体联合临床治疗的疗效 针对髓系细胞和PD-1途径的相关药物。这一项目的成功完成将 显著提高我们对有效的临床翻译的关键基本因素的理解 基于广告的载体系统用于肿瘤疾病的治疗。

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.