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ID3-enhanced, TGFBR2-deleted GPC3-targeted CAR-iMac is an off-the-shelf, induced pluripotent stem cell (iPSC)-derived chimeric antigen receptor macrophage (CAR-iMac) therapy designed for the treatment of hepatocellular carcinoma (HCC). The therapy is engineered with an anti-GPC3 CAR containing the ID3 (inhibitor of DNA binding 3) transcription factor to enhance pluripotency and maintain CAR expression during myeloid differentiation. Additionally, the cells are edited using CRISPR-Cas9 to delete the TGFBR2 (transforming growth factor-beta receptor type 2) gene, rendering them resistant to the immunosuppressive effects of transforming growth factor-beta (TGF-β) in the tumor microenvironment. This dual modification promotes a pro-inflammatory M1-like phenotype, enhances tumor-cell phagocytosis, and improves infiltration and antitumor efficacy in preclinical models of HCC.
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