Redirecting Specificity of T cells Using the Sleeping Beauty System to Express Chimeric Antigen Receptors by Mix-and-Matching of VL and VH Domains Targeting CD123+ Tumors
2016
Adoptive immunotherapy infusing T cells with engineered specificity for
CD19expressed on B- cell malignancies is generating enthusiasm to extend this approach to other
hematological malignancies, such as acute myelogenous leukemia (AML). CD123, or
interleukin 3 receptoralpha, is overexpressed on most AML and some lymphoid malignancies, such as
acute lymphocytic leukemia(ALL), and has been an effective target for T cells expressing
chimeric antigen receptors(CARs). The prototypical CAR encodes a VH and VL from one monoclonal antibody (mAb), coupled to a transmembrane domain and one or more cytoplasmic signaling domains. Previous studies showed that treatment of an experimental AML model with CD123-specific CAR T cells was therapeutic, but at the cost of impaired
myelopoiesis, highlighting the need for systems to define the antigen threshold for CAR recognition. Here, we show that CARs can be engineered using VH and VL chains derived from different CD123-specific mAbs to generate a panel of CAR+ T cells. While all CARs exhibited specificity to CD123, one VH and VL combination had reduced lysis of normal hematopoietic stem cells. This CAR’s in vivo anti-tumor activity was similar whether signaling occurred via chimeric
CD28or
CD137, prolonging survival in both AML and ALL models. Co-expression of inducible
caspase 9eliminated CAR+ T cells. These data help support the use of CD123-specific CARs for treatment of CD123+
hematologic malignancies.
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