Nissim et al. developed a gene circuit platform in which synthetic, cancer-specific promoters, when mutually activated, generate multiple coding RNAs that yield immunomodulatory outputs. When the platform was designed to output a combination of a cell-surface antigen (STE), a cytokine (IL-12), a chemokine (CCL21), and a checkpoint inhibitor antibody (anti-PD-1), the researchers observed T cell-mediated killing of cancer cells without harm to normal cells in vitro, and tumor reduction and prolonged survival in vivo.
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.
Author Info: (1) Synthetic Biology Group, Research Laboratory of Electronics , Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (2) Synthetic Biology Group, Research Laboratory
Author Info: (1) Synthetic Biology Group, Research Laboratory of Electronics , Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (2) Synthetic Biology Group, Research Laboratory of Electronics , Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (3) Synthetic Biology Group, Research Laboratory of Electronics , Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (4) Synthetic Biology Group, Research Laboratory of Electronics , Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (5) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (6) Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, and Hadassah Medical School, The Hebrew University of Jerusalem, 91120 Jerusalem, Israel. (7) Synthetic Biology Group, Research Laboratory of Electronics , Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (8) Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, and Hadassah Medical School, The Hebrew University of Jerusalem, 91120 Jerusalem, Israel. (9) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (10) 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; Synthetic Biology Center, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Electrical Engineering and Computer Science , Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Biophysics Program, Harvard University, Boston, MA 02115, USA; Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: timlu@mit.edu.
