Abstract B44: Selective stimulation of RIG-I with a novel synthetic RNA induces strong anti-tumor immunity in mouse tumor models

Abstract

Abstract We describe a novel immunotherapy approach in which a natural viral defense system is harnessed to stimulate anti-tumor immunity. Cancer immunotherapy has revolutionized oncology in recent years, yet many tumors become resistant or do not respond to current treatments such as checkpoint inhibitors. Stimulation of the innate immune system opens a new therapeutic strategy that could be combined effectively with other immunotherapeutic regimens. The ubiquitously expressed cytosolic RNA receptor retinoic acid inducible gene I (RIG-I) recognizes double-stranded RNA bearing a 5'-triphosphate. RIG-I plays a prominent role in antiviral defense. Its activation induces apoptosis preferentially in tumor cells and simultaneously activates the innate immune system via type I interferon (IFN) signaling. We developed an optimized, fully synthetic oligonucleotide, designated RGT100, which is a RIG-I selective ligand. RGT100 activates the RIG-I pathway leading to the induction of cytokines, including IFN-α and IFN-β. The treatment of tumor-bearing mice with RGT100 induced potent anti-tumor activity against large established B16 melanoma and CT26 colon carcinoma tumors. RGT100 also was efficacious in a spontaneous melanoma model. Histological and flow cytometric analysis of the tumors revealed infiltration and activation of immune cells after RGT100 treatment. RGT100 induced a strong and durable type I IFN response in tumors. Treatment of subcutaneous tumors by intratumor injection led to efficacy of both the treated tumors as well as untreated contralateral tumors. Furthermore, systemic delivery of RGT100 was efficacious against both local subcutaneous B16 melanoma as well as lung metastases. Data support both rapid natural killer (NK) cell-mediated and long-term T cell-mediated anti-tumor activities. Depletion of NK cells blocked the immediate anti-tumor activity of RGT100. In summary, Rigontec's RIG-I-selective ligand RGT100 shows strong anti-tumor activity in several clinically relevant mouse tumor models, while bearing an advantageous safety profile. RGT100 is rapidly progressing toward clinical evaluation in cancer patients. This agent will be evaluated both for single-agent activity as well as in combination with checkpoint inhibitors. Citation Format: Jim Barsoum, Marcel Renn, Christine Schuberth, Christopher Jakobs, Anna Schwickart, Martin Schlee, Jasper van den Boorn, Gunther Hartmann. Selective stimulation of RIG-I with a novel synthetic RNA induces strong anti-tumor immunity in mouse tumor models. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B44.