Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, 450052, Zhengzhou, China.
CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China.
Nat Commun. 2017 Nov 9;8(1):1395. doi: 10.1038/s41467-017-01385-8.
Interleukin-12 (IL-12) has emerged as one of the most potent agents for anti-tumor immunotherapy. However, potentially lethal toxicity associated with systemic administration of IL-12 precludes its clinical application. Here we redesign the molecule in such a way that its anti-tumor efficacy is not compromised, but toxic effects are eliminated. Deletion of the N-terminal signal peptide of IL-12 can effect such a change by preventing IL-12 secretion from cells. We use a newly designed tumor-targeted oncolytic adenovirus (Ad-TD) to deliver non-secreting (ns) IL-12 to tumor cells and examine the therapeutic and toxic effects in Syrian hamster models of pancreatic cancer (PaCa). Strikingly, intraperitoneal delivery of Ad-TD-nsIL-12 significantly enhanced survival of animals with orthotopic PaCa and cured peritoneally disseminated PaCa with no toxic side effects, in contrast to the treatment with Ad-TD expressing unmodified IL-12. These findings offer renewed hope for development of IL-12-based treatments for cancer.
白细胞介素-12（IL-12）已成为抗肿瘤免疫治疗最有效的药物之一。然而，由于其全身给药具有潜在的致命毒性，限制了其临床应用。在这里，我们对该分子进行了重新设计，在不影响其抗肿瘤疗效的情况下消除其毒性作用。通过去除 IL-12 的 N 端信号肽，可以实现这种改变，从而阻止 IL-12 从细胞中分泌。我们使用一种新设计的肿瘤靶向溶瘤腺病毒（Ad-TD）将非分泌型（ns）IL-12 递送至肿瘤细胞，并在叙利亚仓鼠胰腺癌（PaCa）模型中检查其治疗和毒性作用。令人惊讶的是，与表达未修饰 IL-12 的 Ad-TD 相比，腹腔内给予 Ad-TD-nsIL-12 可显著提高荷瘤动物的存活率，并治愈腹腔内播散的 PaCa，而无毒性副作用。这些发现为基于 IL-12 的癌症治疗方法的发展带来了新的希望。
