Harnessing lentiviral vectors for in vivo gene therapy of liver metastases

Abstract

Liver metastases (LMS) commonly arise from gastrointestinal tumors, such as colorectal cancer (CRC) and pancreatic cancer (PDAC). The immunosuppressive environment of the liver favors cancer cell seeding and metastasis generation by impairing immune activation and promoting immune escape. In agreement with this observation, most pharmacological interventions, including recent immunotherapies, prove ineffective in the presence of LMS. For example, immunotherapeutic treatments, which are successful against melanoma, show reduced efficacy in the presence of LMS. 1 Thus, it is of pivotal importance to develop innovative therapeutic interventions that favor immune activation and unleash immune effector functions to eradicate LMS.To respond to this unmet clinical need, we developed a lentiviral vector (LV)-based in vivo gene therapy platform, which upon a single well-tolerated intravenous (i.v.) injection in mice, conveys expression of interferon-alpha (IFNα) to liver macrophages. 2 LVs are HIV-1-derived selfinactivating viral vectors, which do not replicate in the host upon cell transduction. Moreover, LVs efficiently transduce both proliferating as well as non-proliferating cells and integrate into the genome of the target cell enablingThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.