CRISPR/Cas9-based generation of CAR-expressing natural killer-like cells against acute myeloid leukemia

Relapsed acute myeloid leukemia (AML) is difficult to cure. Novel treatment strategies are of high medical need. Cell therapies using chimeric antigen receptor (CAR) T cells have shown promising results in B cell malignancies. We have shown that CAR expression during early lymphoid development suppresses the transcription factor B cell CLL/lymphoma 11B (BCL11B). Lymphoid differentiation shifts towards CAR-induced killer (CARiK) cells, however, this requires tonic CAR signaling activity, which is currently an exclusion criterion for its further clinical development. Obstacles in AML relapse are the collection of autologous T cells in sufficient quantity and quality. Here we present proof of principle for an “off-the-shelf” cell product based on CAR-engineered lymphoid progenitors. We generated novel functional and “clinically” suitable CARs targeting the AML antigen CD123 without tonic signaling activity. They mediate potent antileukemic activity even across HLA barriers upon co-transplantation in leukemia bearing mice. CRISPR/Cas9-mediated Bcl11b disruption facilitates CARiK development in lymphoid progenitors laying the basis for an “off-the-shelf” immunotherapy against AML.

Publication History

Article published online:
17 May 2022