Generation of chimeric antigen receptor-macrophages by using human induced pluripotent stem cells

Cancer immunotherapy using chimeric antigen receptor (CAR) cells shows high therapeutic efficacy against several types of leukemia. Among acute lymphoblastic leukemias (ALLs), B cell-derived ALL can be cured by CAR-expressing T cells (CAR-Ts); however, CAR-T cells cannot be simply applied for T cell-derived ALL (T-ALL) because antigens expressed by T-ALL cells, but not by CAR-T cells, have not yet been identified. To apply CAR-T therapy for T-ALL, gene editing of CAR-T cells is required to avoid attacking CAR-T cells themselves. Alternatively, CAR-expressing macrophages (CAR-Ms) have proven to be effective against various cancers, suggesting that CAR-Ms may also be effective against T-ALL. Recently, we developed an efficient differentiation induction system to generate a large number of macrophages from human induced pluripotent stem cells (iPSCs). Here, we asked whether these human iPSC-derived macrophages (iPS-MACs) can be used to develop and evaluate CAR-based immunotherapy against T-ALLs. When non-transduced iPS-MACs were co-cultured with human T-ALL-derived cells, the iPS-MACs appeared to phagocytose parts of T-ALL cells; this method of phagocytosis operated mainly through incorporation of small, "bite-sized" vesicles derived from the T-ALL cells into iPS-MACs (similar to trogocytosis). By contrast, when CAR-expressing iPS-MACs were co-cultured with T-ALL cells, iPS-MACs engulfed the whole T-ALL cell. Thus, our differentiation induction system may be a promising tool for building up CAR-M therapy for T-ALLs.