Abstract B047: Next-generation gene expression enables tumor-focused immuno-oncology therapies

Abstract

To move cancer immuno-therapies forward, the tumor must participate in treatment. The goal is treatments that provoke tumors to activate cancer-killing immunity, but the basic research technologies to develop these therapies were sorely lacking until now. Our next-generation gene expression system can mimic pharmacologic intervention for any target in growing tumors in mice, enabling high-confidence target assessments before committing to compound development. We have used this technology to understand the mechanisms controlling CTL-activating apoptosis—Immunizing Cell Death (ICD)—and have identified drug-able pathways that will synergize with existing clinical cytotoxic drugs and cause tumors to provoke antitumor immunity. Developed over 8 years at the MIT Koch Institute, our patented Switch expression system is the only “translation control” system and is 1000-times faster than existing “transcription-based” technologies. This speed enables gene expression with drug-like kinetics. More importantly, our novel control enables unmatched drug target assessments by mimicking targeted therapy in growing tumors. Switch is designed to express a first gene and then “switch” for a second gene (e.g., express a kinase and replace with kinase-dead to mimic kinase inhibitors) in growing tumors or in vitro. Switch has been used in 20+ cell lines and transplantable tumor models and is the follow-on to CRISPR-based efforts where the endogenous gene is deleted. Delivered into cancer cells with optimized lentiviral vectors, Switch can replace the CRISPRed genomic target and then cells may be transplanted into mice or grown/ differentiated in vitro. When engineered cells reach the desired point (e.g., a mature tumor), Tamoxifen-CreER recombination causes deletion of the first gene and expression of the second gene. This strategy recapitulates the “logic” of drug treatment—acute functional perturbation of a target protein—and elevates preclinical drug RD Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B047.