Maluski et al. generated mouse hematopoietic progenitor cells (HSPC) expressing CD19-specific chimeric antigen receptors (CAR). Early during in vitro CAR-HSPC differentiation, CAR signaling potentiated by the CD28 costimulatory and ITAM domains reduced expression of transcription factor BCL11B and shifted cells from T cell to NK-cell-like development. Co-transfer of differentiated CAR-HSPCs and T cell-depleted bone marrow cells induced MHC-unrestricted killer cells of limited persistence that eliminated CD19+ B cells or leukemia cells. Lineage fate of CD19-specific human CAR-HSPCs also shifted in vitro, dependent on CD19 signaling.
Contributed by Paula Hochman
The transcription factor B Cell CLL/Lymphoma 11B (BCL11B) is indispensable for T lineage development of lymphoid progenitors. Here we show that chimeric antigen receptor (CAR) expression early in ex vivo generated lymphoid progenitors suppressed BCL11B, leading to suppression of T cell-associated gene expression and acquisition of natural killer (NK) cell-like properties. Upon adoptive transfer into hematopoietic stem cell transplant recipients they differentiated into CAR-induced killer cells (CARiK) that mediated potent antigen-directed antileukemic activity even across MHC barriers. A CD28 and active immune-receptor-tyrosine-based-activation-motifs were critical for a functional CARiK phenotype. These results give important insights into differentiation of murine and human lymphoid progenitors driven by synthetic CAR transgene-expression and encourage further evaluation of ex vivo generated CARiK cells for targeted immunotherapy.
Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14)
Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14)
