A single lentiviral vector system as an expression platform for constitutive immune receptor expression and inducible antigen-dependent immunomodulatory molecule expression in primary immune cells for enhanced immunotherapy efficacy
Adoptive cancer immunotherapy, like chimeric antigen receptor T cell (CAR T) therapy, has had extraordinary clinical outcomes in the treatment of certain blood cancers. However, challenges remain due to safety risks such as cytokine release syndrome (CRS) and off-tumor toxicities. Targeting solid tumors is challenging due to immunosuppressive mechanisms and a hostile tumor microenvironment. Therefore, more advanced engineered T cells are necessary to improve targeting, localization, and autonomous regulation in hopes of overcoming the immunosuppression of the microenvironment to improve the efficacy and safety of cancer immunotherapy.</rss.problem
Dr. Powell and colleagues have developed a novel, broadly-applicable all-in-one lentiviral system with highly optimized transcriptional elements that allow multiple functionalities to be produced simultaneously and specifically in response to contact with tumor antigen. This platform combines a constitutively expressed immune receptor (CAR/TCR) with an immunomodulatory effector molecule whose expression can be autonomously triggered by immune receptor signaling or the tumor microenvironment.
This technology facilitates efficient and localized expression of effector molecules, potentially augmenting the treatment efficacy and limiting toxicities of adoptive cancer immunotherapy. Further, compared to current two-vector systems for transducing multiple transgenes, delivery of a single vector encoding constitutively and inducible expressed modules improves transduction efficiency, homogeneity of cell product and eliminates screening steps providing improved engineered T-cell manufacturing work-flows, shorter manufacturing timelines, and reduced manufacturing costs.
Figure 1: Concept of engineered T cell with a single lentiviral vector with both constitutive immune receptor expression and autonomous antigen-induced immune modulator expression. Immune receptor (CAR or TCR) is expressed constitutively, whereupon its activation by a specific antigen the endogenous NFAT signaling is rewired to the inducible expression of immune modulator molecules from the same lentiviral construct.