使用基于 NFkB 的启动子进行肿瘤内表达可增强 IL12 抗肿瘤功效。,Cancer Gene Therapy

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使用基于 NFkB 的启动子进行肿瘤内表达可增强 IL12 抗肿瘤功效。
Cancer Gene Therapy ( IF 4.8 ) Pub Date : 2019-01-09 , DOI: 10.1038/s41417-018-0076-4
Guillermo Garaulet _{1,

2} , Gema Pérez-Chacon _{3,

4} , Hernan Alarcón ₁ , Arantzazu Alfranca ₅ , Francisca Mulero ₂ , Jorge Martínez-Torrecuadrada ₆ , Juan M Zapata _{3,

4} , Antonio Rodríguez ₁

Affiliation

白细胞介素 12 是一种很有前途的抗癌剂；然而，IL12 全身给药受到副作用的阻碍。尽管 IL12 的瘤内给药在临床试验中取得了可喜的结果，但只有一小部分患者表现出完全的治疗反应。通过控制 IL12 表达窗口可以改善这一结果。在这项工作中，我们在同基因肿瘤模型中使用炎症调节的慢载体测试了自我处理 P2A 和密码子优化的鼠 IL12 (mIL12Pop) 的功效。我们的结果表明，使用强组成型 SFFV 启动子或基于 NFkB 的启动子植入表达 mIL12Pop 的细胞可减少肿瘤生长，导致 CD8+ T 细胞活化并增加 IFNγ 产生。重要的，NFkBp-mIL12Pop 的使用增加了 CD8+ TIL 的数量，并在不增加 IL12 血清浓度的情况下提高了缓解率。进一步的实验表明，必须达到阈值肿瘤内 IL12 浓度才能触发有效的抗肿瘤反应，而一旦超过阈值会导致有害的全身副作用。总之，这些结果表明使用 NFKBp-mIL12Pop 显着提高了小鼠的总体存活率。总之，这种新的炎症调节表达系统可能有助于开发具有改善的抗肿瘤活性和有限毒性的新型 IL12 递送系统。进一步的实验表明，必须达到阈值肿瘤内 IL12 浓度才能触发有效的抗肿瘤反应，而一旦超过阈值会导致有害的全身副作用。总之，这些结果表明使用 NFKBp-mIL12Pop 显着提高了小鼠的总体存活率。总之，这种新的炎症调节表达系统可能有助于开发具有改善的抗肿瘤活性和有限毒性的新型 IL12 递送系统。进一步的实验表明，必须达到阈值肿瘤内 IL12 浓度才能触发有效的抗肿瘤反应，而一旦超过阈值会导致有害的全身副作用。总之，这些结果表明使用 NFKBp-mIL12Pop 显着提高了小鼠的总体存活率。总之，这种新的炎症调节表达系统可能有助于开发具有改善的抗肿瘤活性和有限毒性的新型 IL12 递送系统。

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

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.

更新日期：2019-05-16

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