Targeting BCL11B in CAR-engineered lymphoid progenitors drives NK-like cell development with prolonged anti-leukemic activity
Chimeric antigen receptor (CAR)-induced suppression of the transcription factor B cell CLL/lymphoma 11B (BCL11B) propagates CAR-induced killer (CARiK) cell development from lymphoid progenitors. Here, we show that CRISPR-Cas9-mediated Bcl11b knockout in human and murine early lymphoid progenitors distinctively modulates this process either alone or in combination with a CAR. Upon adoptive transfer into hematopoietic stem cell recipients, Bcl11b-edited progenitors mediated innate-like antigen-independent anti-leukemic immune responses. With CAR expression allowing for additional antigen-specific responses, the progeny of double-edited lymphoid progenitors acquired prolonged anti-leukemic activity in vivo. These findings give important insights into how Bcl11b targeting can be used to tailor anti-leukemia functionality of CAR-engineered lymphoid progenitor cells.
Authors
- Marcel R.M. van den Brink (ORCID: https://orcid.org/0000-0003-0696-4401)
- Philipp John-Neek
- Constantin von Kaisenberg (ORCID: https://orcid.org/0000-0001-5554-1937)
- Michael Hust (ORCID: https://orcid.org/0000-0003-3418-6045)
- Tobias Maetzig (ORCID: https://orcid.org/0000-0001-8259-3150)
- Johann Meyer (ORCID: https://orcid.org/0000-0001-9521-1334)
- Britta Eiz‐Vesper (ORCID: https://orcid.org/0000-0001-8378-3298)
- Christine S. Falk (ORCID: https://orcid.org/0000-0003-1376-7318)
- Saskia Polten
- Franziska Baatz
- Axel Schambach (ORCID: https://orcid.org/0000-0003-2743-0070)
- Martin G. Sauer (ORCID: https://orcid.org/0009-0007-2151-8342)
- Antonella Lucía Bastone (ORCID: https://orcid.org/0000-0003-0356-2909)
- Robert Geffers (ORCID: https://orcid.org/0000-0003-4409-016X)
- Jessica Herbst
- Manuel Rhiel (ORCID: https://orcid.org/0000-0003-0741-2780)
- Agnes Bonifacius (ORCID: https://orcid.org/0000-0002-0112-967X)
- Arnab Ghosh (ORCID: https://orcid.org/0000-0001-9314-3059)
- Toni Cathomen (ORCID: https://orcid.org/0000-0002-7757-4630)
- Michael Rothe (ORCID: https://orcid.org/0000-0002-6813-4705)
- Jörg Frühauf
Institutions
- City Of Hope National Medical Center (US)
- Memorial Sloan Kettering Cancer Center (US)
- University of Freiburg (DE)
- University Medical Center Freiburg (DE)
- Medizinische Hochschule Hannover (DE)
- Helmholtz Centre for Infection Research (DE)
- Technische Universität Braunschweig (DE)
Publication Details
- Journal
- Molecular Therapy
- Published
- 2025-02-15
- DOI
- https://doi.org/10.1016/j.ymthe.2025.02.024
- Citations
- 1
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 1.05
Funders
- Deutsche Forschungsgemeinschaft
- Medizinischen Hochschule Hannover