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LV169-R-Lck1.3 is an investigational CD3-targeted lentiviral vector platform designed for the *in vivo* generation of CAR T cells. It utilizes a modified VSV-G envelope that has been detargeted from its natural LDL receptor and retargeted to T cells via a CD3-specific single-chain variable fragment (scFv). To address the risk of off-target transduction of malignant cells (such as plasma cells in multiple myeloma) by CAR proteins incorporated into the vector envelope, this construct employs a reverse-orientation transgene driven by a modified human distal Lck promoter (Lck1.3). The Lck1.3 promoter, which includes an inserted TATA box and CMV enhancer, ensures that the CAR transgene is transcriptionally silenced in producer cells and off-target cells but remains highly active in transduced T cells. Preclinical studies in multiple myeloma models have demonstrated that a single intravenous dose of LV169-R-Lck1.3 encoding a BCMA-targeted CAR can achieve complete tumor clearance and generate circulating anti-BCMA CAR T cells.
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