COMPOSITION COMPRISING FURIN-INHIBITED CAR MACROPHAGES AND USES THEREOF

CAR macrophages (CAR-M) can phagocyte tumor cells expressing a target antigen. It is herein shown that the proprotein convertase furin is over-expressed in human primary macrophages in the presence of tumor cells, which is a way to redirect these macrophages towards an anti-inflammatory phenotype. Conversely, inhibition of furin leads to the maintenance of their pro-inflammatory phenotype, even in a tumor cell environment. The present invention proposes to use furin-inhibited CAR-M derived from primary blood monocytes as a therapeutic strategy to treat solid tumors. Surprisingly, the generated furin-inhibited CAR-M display enhanced anti-tumor phagocytic activity against breast cancer cell lines and breast cancer patient-derived tumoroids and a persistent pro-inflammatory phenotype compared to furin-expressing CAR-M. Moreover, it was found that furin-inhibited CAR-M secreted factors can enhance T-cell proliferation and can thereby modulate the tumor microenvironment. Furin-inhibited CAR-M therefore represent a second-generation CAR-M therapeutic strategy for solid tumors.

Keywords: CAR-Macrophage, Cell Therapy, Oncology
Patent Application number: International Procedure (PCT) - 23 Févr. 2024 - PCT/IB2024/000093
Inventors:
ZIANE CHAOUCHE Lydia; DUHAMEL Marie
Publications:
Ziane-Chaouche L, Raffo-Romero A, Hajjaji N, Kobeissy F, Pinheiro D, Aboulouard S, Cozzani A, Mitra S, Fournier I, Cizkova D, Salzet M, Duhamel M. Inhibition of furin in CAR macrophages directs them toward a proinflammatory phenotype and enhances their antitumor activities. Cell Death Dis. 2024 Dec 4;15(12):879. doi: 10.1038/s41419-024-07267-4. PMID: 39632807; PMCID: PMC11618602.

Reference:

BIO24003-T1

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Patent filling date: 2024-02-23

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