Synthetic RNA-Based Immunomodulatory Gene Circuits for Cancer Immunotherapy

Abstract

SUMMARY 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.

Harnessed viruses in the age of metagenomics and synthetic biology: an update on infectious clone assembly and biotechnologies of plant viruses

“…Recombinant viral vectors are common means to genetically reprogramme mammalian cells for basic research and therapeutic purposes. Engineered human viruses have proven to be effective oncolytic agents and delivery vehicles for gene therapy and genetic circuitries, and are studied in an increasing number of clinical trials (Kaufman et al, 2015;Kotterman et al, 2015;Nissim et al, 2017). In 2005, a genetically modified adenovirus was approved as an oncolytic drug for cancer treatment.…”

Development of a Multi-gene-based Immune Prognostic Signature in Ovarian Cancer

“…Immunomodulatory gene circuit platform is potential for tumor-speci c immune-stimulation by de novo cancer-speci c promoter synthesis, with RNA-based design and transcription factors encoding. Differentiated TFs were identi ed and multiple binding motifs for cancer-speci c TFs were encoded to generate synthetic OC-speci c promoters, resulting in compact and tumor-speci c promoters [12]. It is promising that we can identify the speci c TFs for promoters encoding.…”

Synthetic Biology: Engineering Mammalian Cells To Control Cell‐to‐Cell Communication at Will

“…In order to increaset he efficacy of cell-based cancer therapy by controlling cell-contact-based cell-to-cell communication, an interesting approachm ight be to engineer cancerc ells themselves. For example, Nissim et al reported ap roof-of-concept immunomodulatory RNA-based gene circuit that enables tumour-specific expression of immunomodulator proteins,i ncluding surfaceTcell engagers, several cytokines anda nti-PD1 antibody, [42] therebye nhancing the effect of cancer immunotherapy.A lthough delivery of this kind of circuit to cancerc ells is achallenge, it may offer away to control communication between immunec ells and cancer cells in the future.…”