VV169, an Intravenously Delivered, CD3-Targeted, Transcriptionally Regulated T-Cell Specific Vector Generates aBCMA-CAR-T Cells In Vivo and Efficiently Clears Disseminated Multiple Myeloma Tumors in a Preclinical Model

We recently developed the VSV-G pseudotyped CD3-targeted lentiviral vector LV-169 which delivers a BCMA CAR transgene to primary T cells in vivo. Re-targeting was achieved by modifying the VSV-G protein which was de-targeted (blinded) from its natural LDL receptor by deleting a single residue, and re-targeted to T cells by fusing it to a CD3-specific scFv. However, BCMA-CAR proteins expressed from a constitutive EF1a promoter were incorporated into the LV envelope during packaging and this led to undesirable off-target transduction of malignant plasma cells. To prevent CAR transgene expression during packaging we reconfigured the vector genome to express CAR under a T-cell lineage specific Lck promoter and reversed the orientation of the expression cassette relative to the 5’ LTR.