Nissim Lior, Wu Ming-Ru, Pery Erez, Binder-Nissim Adina, Suzuki Hiroshi I, Stupp Doron, Wehrspaun Claudia, Tabach Yuval, Sharp Phillip A, Lu Timothy K
Synthetic Biology Group, Research Laboratory of Electronics , Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Cell. 2017 Nov 16;171(5):1138-1150.e15. doi: 10.1016/j.cell.2017.09.049. Epub 2017 Oct 19.
Despite its success in several clinical trials, cancer immunotherapy remains limited by the rarity of targetable tumor-specific antigens, tumor-mediated immune suppression, and toxicity triggered by systemic delivery of potent immunomodulators. Here, we present a proof-of-concept immunomodulatory gene circuit platform that enables tumor-specific expression of immunostimulators, which could potentially overcome these limitations. Our design comprised de novo synthetic cancer-specific promoters and, to enhance specificity, an RNA-based AND gate that generates combinatorial immunomodulatory outputs only when both promoters are mutually active. These outputs included an immunogenic cell-surface protein, a cytokine, a chemokine, and a checkpoint inhibitor antibody. The circuits triggered selective T cell-mediated killing of cancer cells, but not of normal cells, in vitro. In in vivo efficacy assays, lentiviral circuit delivery mediated significant tumor reduction and prolonged mouse survival. Our design could be adapted to drive additional immunomodulators, sense other cancers, and potentially treat other diseases that require precise immunological programming.
尽管癌症免疫疗法在多项临床试验中取得了成功，但仍受到可靶向肿瘤特异性抗原稀少、肿瘤介导的免疫抑制以及强效免疫调节剂全身递送引发的毒性的限制。在此，我们展示了一个概念验证性免疫调节基因回路平台，该平台能够实现免疫刺激剂的肿瘤特异性表达，这有可能克服这些限制。我们的设计包括从头合成的癌症特异性启动子，并且为了提高特异性，还设计了一个基于RNA的“与”门，只有当两个启动子都相互激活时，才会产生组合免疫调节输出。这些输出包括一种免疫原性细胞表面蛋白、一种细胞因子、一种趋化因子和一种检查点抑制剂抗体。这些回路在体外触发了选择性T细胞介导的癌细胞杀伤，但未对正常细胞造成杀伤。在体内疗效试验中，慢病毒回路递送介导了显著的肿瘤缩小并延长了小鼠存活时间。我们的设计可以进行调整，以驱动其他免疫调节剂、识别其他癌症，并有可能治疗其他需要精确免疫编程的疾病。
