Kamerkar et al. engineered exosomes bearing an antisense oligonucleotide (ASO) targeting STAT6 (exoASO-STAT6) that preferentially delivered ASOs, silenced STAT6 in tumor-associated macrophages, and reprogrammed immunosuppressive M2 macrophages. Intratumoral single-agent exoASO-STAT6 reduced Tregs and monocytes/macrophages with M2-polarized markers, increased the M1-polarized population, induced potent T cell-mediated antitumor activity, and generated immune memory in CT26 and HCC tumor models. A STAT6 signature based on exoASO-STAT6-mediated gene expression changes correlated with poor survival in HCC.
Contributed by Shishir Pant
ABSTRACT: 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.
Author Info: (1) Codiak BioSciences Inc., Cambridge, MA 02140, USA. (2) Codiak BioSciences Inc., Cambridge, MA 02140, USA. (3) Codiak BioSciences Inc., Cambridge, MA 02140, USA. (4) Codiak BioS
Author Info: (1) Codiak BioSciences Inc., Cambridge, MA 02140, USA. (2) Codiak BioSciences Inc., Cambridge, MA 02140, USA. (3) Codiak BioSciences Inc., Cambridge, MA 02140, USA. (4) Codiak BioSciences Inc., Cambridge, MA 02140, USA. (5) Codiak BioSciences Inc., Cambridge, MA 02140, USA. (6) Codiak BioSciences Inc., Cambridge, MA 02140, USA. (7) Codiak BioSciences Inc., Cambridge, MA 02140, USA. (8) Codiak BioSciences Inc., Cambridge, MA 02140, USA. (9) Codiak BioSciences Inc., Cambridge, MA 02140, USA. (10) Codiak BioSciences Inc., Cambridge, MA 02140, USA. (11) Codiak BioSciences Inc., Cambridge, MA 02140, USA. (12) Codiak BioSciences Inc., Cambridge, MA 02140, USA. (13) Codiak BioSciences Inc., Cambridge, MA 02140, USA. (14) Codiak BioSciences Inc., Cambridge, MA 02140, USA. (15) Codiak BioSciences Inc., Cambridge, MA 02140, USA. (16) Codiak BioSciences Inc., Cambridge, MA 02140, USA. (17) Codiak BioSciences Inc., Cambridge, MA 02140, USA. (18) Codiak BioSciences Inc., Cambridge, MA 02140, USA.
