Bispecific binder redirected lentiviral vector enables in vivo engineering of CAR-T cells.
JOURNAL FOR IMMUNOTHERAPY OF CANCER(2021)
Abstract
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.
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Key words
immunotherapy, cell engineering, receptors, chimeric antigen, antibody specificity
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