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CAR-macrophages with custom intronic shRNA represent a next-generation cell therapy platform developed by Carisma Therapeutics. This approach involves engineering macrophages to express a Chimeric Antigen Receptor (CAR) while simultaneously utilizing an intronic short hairpin RNA (shRNA) to knock down specific genes that inhibit macrophage activity, most notably SIRPα (Signal Regulatory Protein Alpha). SIRPα is the receptor for the CD47 "don't eat me" signal, which tumors often overexpress to evade immune destruction. By placing the shRNA within an intron of the CAR transgene, both components are expressed under a single promoter, ensuring coordinated activity and efficient genetic modification. This dual-action mechanism enhances the macrophage's ability to recognize, phagocytose, and destroy tumor cells, particularly in the immunosuppressive environment of solid tumors, while also promoting a pro-inflammatory tumor microenvironment.
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