Targeting BCL11B in CAR-engineered lymphoid progenitors drives NK-like cell development with prolonged anti-leukemic activity.

in Molecular therapy : the journal of the American Society of Gene Therapy by Franziska Baatz, Arnab Ghosh, Jessica Herbst, Saskia Polten, Johann Meyer, Manuel Rhiel, Tobias Maetzig, Robert Geffers, Michael Rothe, Antonella Lucia Bastone, Philipp John-Neek, Jörg Frühauf, Britta Eiz-Vesper, Agnes Bonifacius, Christine S Falk, Constantin V Kaisenberg, Toni Cathomen, Axel Schambach, Marcel R M van den Brink, Michael Hust, Martin G Sauer

TLDR

  • The study found that targeting the transcription factor BCL11B using CRISPR/Cas9 gene editing can enhance the anti-leukemia functionality of CAR-engineered lymphoid progenitor cells.

Abstract

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.

Overview

  • The study focuses on the role of the transcription factor B cell CLL/lymphoma 11B (BCL11B) in the development of CAR-induced killer (CARiK) cells from lymphoid progenitors.
  • The researchers used CRISPR/Cas9 gene editing to knockout BCL11B in human and murine early lymphoid progenitors, and then transferred these cells into hematopoietic stem cell recipients.
  • The primary objective of the study is to investigate how targeting BCL11B can be used to improve the anti-leukemia functionality of CAR-engineered lymphoid progenitor cells.

Comparative Analysis & Findings

  • The study found that CRISPR/Cas9-mediated Bcl11b knockout in human and murine early lymphoid progenitors caused distinct modulation of CARiK cell development, either alone or in combination with a CAR.
  • The research showed that Bcl11b-edited progenitors mediated innate-like antigen-independent anti-leukemic immune responses when adoptively transferred into hematopoietic stem cell recipients.
  • The combination of Bcl11b editing with CAR expression led to the development of progeny with prolonged anti-leukemic activity in vivo.

Implications and Future Directions

  • The study provides important insights into how Bcl11b-targeting can be used to tailor anti-leukemia functionality of CAR-engineered lymphoid progenitor cells.
  • Future research directions may include investigating how Bcl11b-targeting can be combined with other gene editing strategies or immunotherapy approaches to improve anti-leukemia effectiveness.
  • The study's findings also highlight the potential for using gene editing to modify CAR-engineered lymphoid progenitor cells for use in cancer immunotherapy.
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