Exosome-mediated genetic reprogramming of tumor-associated macrophages by exoASO-STAT6 leads to potent monotherapy antitumor activity.

Autor:	Kamerkar S; Codiak BioSciences Inc., Cambridge, MA 02140, USA., Leng C; Codiak BioSciences Inc., Cambridge, MA 02140, USA., Burenkova O; Codiak BioSciences Inc., Cambridge, MA 02140, USA., Jang SC; Codiak BioSciences Inc., Cambridge, MA 02140, USA., McCoy C; Codiak BioSciences Inc., Cambridge, MA 02140, USA., Zhang K; Codiak BioSciences Inc., Cambridge, MA 02140, USA., Dooley K; Codiak BioSciences Inc., Cambridge, MA 02140, USA., Kasera S; Codiak BioSciences Inc., Cambridge, MA 02140, USA., Zi T; Codiak BioSciences Inc., Cambridge, MA 02140, USA., Sisó S; Codiak BioSciences Inc., Cambridge, MA 02140, USA., Dahlberg W; Codiak BioSciences Inc., Cambridge, MA 02140, USA., Sia CL; Codiak BioSciences Inc., Cambridge, MA 02140, USA., Patel S; Codiak BioSciences Inc., Cambridge, MA 02140, USA., Schmidt K; Codiak BioSciences Inc., Cambridge, MA 02140, USA., Economides K; Codiak BioSciences Inc., Cambridge, MA 02140, USA., Soos T; Codiak BioSciences Inc., Cambridge, MA 02140, USA., Burzyn D; Codiak BioSciences Inc., Cambridge, MA 02140, USA., Sathyanarayanan S; Codiak BioSciences Inc., Cambridge, MA 02140, USA.
Jazyk:	angličtina
Zdroj:	Science advances [Sci Adv] 2022 Feb 18; Vol. 8 (7), pp. eabj7002. Date of Electronic Publication: 2022 Feb 18.
DOI:	10.1126/sciadv.abj7002
Abstrakt:	Effectiveness of checkpoint immunotherapy in cancer can be undermined by immunosuppressive tumor-associated macrophages (TAMs) with an M2 phenotype. Reprogramming TAMs toward a proinflammatory M1 phenotype is a novel approach to induce antitumor immunity. The M2 phenotype is controlled by key transcription factors such as signal transducer and activator of transcription 6 (STAT6), which have been "undruggable" selectively in TAMs. We describe an engineered exosome therapeutic candidate delivering an antisense oligonucleotide (ASO) targeting STAT6 (exoASO-STAT6), which selectively silences STAT6 expression in TAMs. In syngeneic models of colorectal cancer and hepatocellular carcinoma, exoASO-STAT6 monotherapy results in >90% tumor growth inhibition and 50 to 80% complete remissions. Administration of exoASO-STAT6 leads to induction of nitric oxide synthase 2 ( NOS2 ), an M1 macrophage marker, resulting in remodeling of the tumor microenvironment and generation of a CD8 T cell-mediated adaptive immune response. Collectively, exoASO-STAT6 represents the first platform targeting transcription factors in TAMs in a highly selective manner.
Databáze:	MEDLINE
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