Krawczyk and Zolov et al. engineered T cells to secrete CLEC12AxCD3 bispecific engager molecule, which enhanced activation and cytotoxicity against target cells in vitro and antitumor efficacy in an AML mouse model. CLEC12A-ENG cells were then further engineered with a chimeric IL-7 receptor that binds to a second AML-associated antigen, CD123, to simulate IL-7 signaling. When AML expressed both targets, CLEC12A-ENG.CD123IL7Rα showed enhanced activation and antitumor function (dependent on IL7Rα-mediated downstream signaling) in vitro and increased expansion in vivo, increasing survival in treated mice.
The development of engineered T cells to treat acute myeloid leukemia (AML) is challenging due to difficulty in target selection and the need for robust T-cell expansion and persistence. We designed a T cell stimulated to kill AML cells based on recognition of the AML-associated surface marker CLEC12A, via secretion of a CLEC12AxCD3 bispecific "engager" molecule (CLEC12A-ENG). CLEC12A-ENG T cells are specifically activated by CLEC12A, are not toxic to hematopoietic progenitor cells, and exhibit antigen-dependent AML killing. Next, we coupled stimulation of T-cell survival to triggering of a chimeric IL7 receptor with an ectodomain that binds a second AML-associated surface antigen, CD123. The resulting T cells, identified as CLEC12A-ENG.CD123IL7Ralpha T cells, demonstrate improved activation upon dual target recognition, kill AML, and exhibit antitumor activity in xenograft models. Enhanced T-cell activation conferred by CD123.IL7Ralpha was dependent both on recognition of the CD123 target and on IL7Ralpha-mediated downstream signaling. Expression of a chimeric IL7R targeted to a second tumor-associated antigen (TAA) should improve T-cell activity not only against hematological malignancies, but perhaps against all cancers.
Author Info: (1) Pediatrics, University of Michigan-Ann Arbor. (2) Pediatrics, University of Michigan-Ann Arbor. (3) Pediatrics, University of Michigan-Ann Arbor. (4) Pediatrics, University of
Author Info: (1) Pediatrics, University of Michigan-Ann Arbor. (2) Pediatrics, University of Michigan-Ann Arbor. (3) Pediatrics, University of Michigan-Ann Arbor. (4) Pediatrics, University of Michigan-Ann Arbor cbonifa2@jhmi.edu.
