文章：

肿瘤内表达基于nfkb的启动子可增强il - 12的抗肿瘤效果

Intratumoral expression using a NFkB-based promoter enhances IL12 antitumor efficacy 

原文发布日期：2019-01-09 

英文摘要：

Interleukin 12 is a promising anti-cancer agent; however, IL12 systemic administration is hampered by side-effects. Although intratumoral administration of IL12 is giving promising results in clinical trials, only a small percentage of patients show a complete therapeutic response. This outcome could be improved by controlling the IL12 expression window. In this work we have tested the efficacy of a self-processing P2A and codon optimized murine IL12 (mIL12Pop) using inflammation-regulated lentivectors in a syngeneic tumor model. Our results show that implantation of cells expressing mIL12Pop employing either the strong constitutive SFFV promoter or a NFkB-based promoter reduced tumor growth, caused CD8+ T cell activation and increased IFNγ production. Importantly, the use of NFkBp-mIL12Pop increased the number of CD8+ TILs and improved the remission rate without increasing IL12-serum concentration. Further experiments suggest that there is a threshold intratumoral IL12 concentration that must be reached to trigger an efficient antitumor response and a limit that once surpassed causes detrimental systemic side effects. Altogether, these results demonstrate that using NFKBp-mIL12Pop significantly increases the overall survival of the mice. In summary, this new inflammation-regulated expression system might be useful for the development of new IL12 delivery systems with improved anti-tumor activity and limited toxicity. 

摘要翻译： 

白细胞介素12（IL-12）是一种具有前景的抗癌制剂，但其全身给药方式受副作用限制。虽然IL-12的瘤内给药在临床试验中展现出积极效果，但仅少数患者能实现完全治疗反应。通过控制IL-12的表达窗口期有望改善这一结果。本研究采用炎症调控慢病毒载体，在同系肿瘤模型中测试了自加工P2A元件与密码子优化的鼠源IL-12（mIL12Pop）的疗效。结果表明：通过强组成型SFFV启动子或NFkB基启动子表达mIL12Pop的细胞植入后，能抑制肿瘤生长、激活CD8+ T细胞并促进IFNγ分泌。值得注意的是，使用NFkBp-mIL12Pop可在不提升血清IL-12浓度的前提下，增加CD8+肿瘤浸润淋巴细胞数量并提高缓解率。进一步实验提示，存在一个触发有效抗肿瘤反应所需的瘤内IL-12浓度阈值，以及一旦超越即引发有害全身副作用的浓度上限。总体而言，这些结果证明NFKBp-mIL12Pop能显著延长小鼠总体生存期。该炎症调控表达系统或有助于开发新型IL-12递送系统，在提升抗肿瘤活性的同时控制毒性作用。

原文链接：

Intratumoral expression using a NFkB-based promoter enhances IL12 antitumor efficacy