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Targeting inflammation with chimeric antigen receptor macrophages using a signal switch.

Qi Cao1, Yiping Wang2, Jianwei Chen2

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Summary

Engineered CAR macrophages (CAR-Ms) target inflammatory molecule TNF to reduce inflammation in acute and chronic diseases. This novel therapy shows promise for treating inflammatory conditions by reprogramming immune cells.

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Area of Science:

  • Immunology
  • Cell Therapy
  • Inflammatory Diseases

Background:

  • Chimeric antigen receptor (CAR) T-cell therapy is successful in cancer treatment.
  • CAR strategies offer potential for other clinical applications.
  • Inflammatory diseases require new therapeutic approaches.

Purpose of the Study:

  • To develop CAR macrophages (CAR-Ms) for treating inflammatory diseases.
  • To program macrophages with an anti-inflammatory function.
  • To evaluate CAR-M efficacy in preclinical models of inflammation.

Main Methods:

  • Engineered CAR macrophages to recognize tumor necrosis factor (TNF).
  • Activated an intracellular IL-4 signaling pathway for anti-inflammatory programming.
  • Tested CAR-M therapy in mouse models of kidney ischemia-reperfusion injury and Adriamycin-induced nephropathy.
  • Assessed CAR-M function in human cells.

Main Results:

  • CAR-M therapy demonstrated efficacy in acute and chronic inflammatory disease models.
  • CAR-Ms attenuated kidney ischemia-reperfusion injury by adopting an anti-inflammatory phenotype.
  • CAR-Ms maintained anti-inflammatory function for weeks in chronic models, improving kidney outcomes.
  • CAR-Ms reduced tissue injury in the liver and showed functional anti-inflammatory capacity in human cells.

Conclusions:

  • CAR-M therapy, utilizing a signal-switching design, effectively treats inflammatory diseases.
  • Engineered macrophages can be programmed for targeted anti-inflammatory functions.
  • CAR-M therapy holds promise for a wide range of acute and chronic inflammatory conditions.