DOI: 10.1038/s41590-023-01687-8
Key Points:
- Research focuses on using engineered macrophages (CAR-iMACs) instead of typical CAR T cells to fight solid tumors
- Started with iPSCs (induced pluripotent stem cells) which were differentiated into macrophages and engineered with CARs
- Created two versions:
- First generation with CD3ζ domain
- Second generation with added TIR domain
- Second generation showed superior results due to TIR domain activating NFκB pathway
- Testing showed complete tumor remission in liver cancer mouse models
Mechanisms:
- TIR domain helps polarize macrophages to M1 (pro-inflammatory) state
- Two-step killing process:
1. Induces apoptosis in tumor cells
2. Cleans up debris through efferocytosis
- Confirmed mechanism through:
- Single cell RNA sequencing
- Time-lapse microscopy
- NFκB pathway activation visualization
Limitations/Challenges:
- Still preclinical (only tested in cells/mice)
- CAR-iMACs don't survive long in body
- Need more research before human trials
Clinical Implications:
- Promising for treating resistant solid tumors
- Antigen-specific targeting means fewer side effects
- Could be game-changing if survival time improved
- Works well in combination with other treatments
