Exosome-mediated genetic reprogramming of tumor-associated macrophages

Codiak BioSciences a clinical-stage biopharmaceutical company pioneering the development of exosome-based therapeutics as a new class of medicines, today announced the online publication of a new manuscript, Exosome mediated genetic reprogramming of tumor associated macrophages by exoASO-STAT6 leads to potent monotherapy anti-tumor efficacy, in the American Association for the Advancement of Science’s journal, Science Advances.

exoASO™-STAT6 is a novel, engineered exosome precision medicine candidate in development for the treatment of macrophage-rich tumors. This publication details the findings from the preclinical development program and highlights the ability of exoASO-STAT6 to selectively target tumor associated immune-suppressive macrophages (TAMs) and precisely disrupt STAT6 signaling to generate impressive monotherapy anti-tumor activity in cancer models.

“Based on our preclinical observations, we believe exoASO-STAT6 is the first macrophage targeting candidate to show single agent anti-tumor activity of this magnitude, thus offering the potential to overcome significant barriers to prior drug development efforts aimed at transcription factors,” said Sriram Sathyanarayanan, Ph.D., Chief Scientific Officer, Codiak. “This publication describes the unique attributes and anti-tumor activity of exoASO-STAT6 in several preclinical cancer models, including colorectal and hepatocellular carcinomas, the latter of which we intend to be the focus of our initial clinical investigations of this candidate.”

TAMs promote tumor growth by exhibiting an immune suppressive M2 phenotype. Reprogramming TAMs toward a pro-inflammatory M1 phenotype is a novel approach to induce anti-tumor immunity. The M2 phenotype is controlled by key transcription factors such as STAT6, which have proven difficult to drug selectively in TAMs by prior approaches. Codiak has demonstrated that exosomes – naturally occurring, extracellular nanoparticle vesicles – can be engineered using its proprietary engEx™ Platform to preferentially deliver STAT6 targeted antisense oligonucleotides to TAMs.

Model describing antitumor activity mediated by genetic reprogramming of TAMs by exoASO-STAT6

STAT6 expressing TAMs are critical determinants of an immunosuppressive TME by promoting recruitment of T_regs and inhibition of CD8 cytotoxic T cells. The ability of exoASO-STAT6 to selectively knock down STAT6 expression in immunosuppressive TAMs results in effective reprogramming to an M1 phenotype that promotes the induction of a cytotoxic immune response and an antitumoral TME. T_H2, T helper 2; CTL, cytotoxic T lymphocytes.

Source – Eurekalert