Traditional CAR-T therapies require expensive, complex ex vivo T-cell engineering. While in vivo CAR-T generation using lentiviral vectors offers a faster, cheaper alternative, preclinical testing is limited by graft-versus-host disease (GVHD) in immunodeficient mouse models. To overcome this, GemPharmatech developed the NCG-MHC-dKO mouse, featuring dual MHC I/II knockout to minimize GVHD while maintaining human immune cell engraftment. Testing an anti-CD19 CAR lentiviral vector in this model demonstrated successful in vivo CAR-T generation and potent tumor suppression, with no significant GVHD. The NCG-MHC-dKO model enables reliable, long-term evaluation of in vivo CAR-T therapies, enhancing translational research.