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.

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.

• Autonomous, inducible and localized expression of effector molecules along with constitutive immune receptor expression in a single vector system may improve efficacy and/or limit toxicities of adoptive cancer immunotherapy
• Single vector gene delivery achieves a homogenous population of engineered immune cells without screening steps, improving T-cell manufacturing work-flows and reducing manufacturing costs.
• “Plug-and-play” single lentiviral system to generate a combination of different immune receptors and immune modulators, with varying levels of expression
• This platform enables high-throughput and quantitative screening and identification of antigen specific immune cells, such as CAR T cells, TCR modified cells or endogenous TILs.

• Provides a simplified platform for inducible expression of effector molecules in immune receptor-engineered T-cells for clinical applications.
• This single vector expression system provides an effective platform for researchers to construct and screen the combination of CAR/TCR and immune modulators of interest.
• Selected constructs can be used in adoptive cancer immunotherapy (e.g. CAR T) to improve the efficacy and/or minimize treatment-related complications (e.g., CRS, off-target toxicities) of engineered T-cells.
• This platform enables high-throughput and quantitative screening and identification of antigen specific immune cells, such as CAR T cells, TCR modified cells or endogenous TILs.