Bispecific binder redirected lentiviral vector enables in vivo engineering of CAR-T cells.

Background: Chimeric antigen receptor (CAR) T cells have shown considerable promise as a personalized cellular immunotherapy against B cell malignancies. However, the complex and lengthy manufacturing processes involved in generating CAR T cell products ex vivo result in substantial production time delays and high costs. Furthermore, ex vivo expansion of T cells promotes cell differentiation that reduces their in vivo replicative capacity and longevity.
Methods: Here, to overcome these limitations, CAR-T cells are engineered directly in vivo by administering a lentivirus expressing a mutant Sindbis envelope, coupled with a bispecific antibody binder that redirects the virus to CD3 ⁺ human T cells.
Results: This redirected lentiviral system offers exceptional specificity and efficiency; a single dose of the virus delivered to immunodeficient mice engrafted with human peripheral blood mononuclear cells generates CD19-specific CAR-T cells that markedly control the growth of an aggressive pre-established xenograft B cell tumor.
Conclusions: These findings underscore in vivo engineering of CAR-T cells as a promising approach for personalized cancer immunotherapy.
Competing Interests: Competing interests: TMJ has an equity interest in Dualogics LLC, a company aimed at commercializing bispecific antibodies.
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