Stealthy lentiviral vectors: Breaking the barriers to systemic in vivo gene delivery

Lentiviral vector (LVV)-mediated chimeric antigen receptor (CAR)-T cell therapy has transformed the landscape for blood cancer treatment through genetic modification of patients' T cells. Yet, the complexity of the manufacturing process makes this therapy inaccessible for many patients. Systemic intravenous delivery of LVV is an attractive prospect not only for CAR-T therapeutics but also extends the potential benefit to inherited monogenic diseases. However, immunogenicity to LVV is a major hurdle to safe and efficacious gene delivery in vivo. Here, we categorize the immune responses into three main challenges: displacement of LVV from its intended target cells by components of the blood, inefficient transduction of target cells due to evolutionarily conserved viral detection and restriction, and clearance of the transduced cell population by the adaptive immune system. We review the progress toward in vivo delivery and the many approaches explored to circumvent immune barriers, from direct engineering of the LVV itself to pharmacological intervention. We report that while many approaches demonstrate improved efficacy, they often tackle only one aspect in isolation in a selected animal model. Therefore, we recommend researchers adopt a more holistic approach, testing a cocktail of strategies in a model that best recapitulates gene delivery to patients.