Oncolytic adenovirus inhibits TNBC tumor growth/metastasis in mice by targeting TGF-β and overexpressing GM-CSF.

Despite therapeutic advancements, metastatic triple-negative breast cancer (TNBC) remains mostly incurable and is a frequent cause of cancer-related deaths. We tested the hypothesis that inhibiting suppressive signals sustained by transforming growth factor (TGF)-β and concurrently stimulating recruitment of inflammatory cells with granulocyte-macrophage colony-stimulating factor (GM-CSF) by oncolytic viruses would result in improved anti-tumor responses. Thus, we developed a new oncolytic adenovirus rAd.sT.GM (AMUN-003) that expresses both sTGFβRIIFc (a TGF-β decoy), and GM-CSF and tested it in a mouse TNBC (4T1) subcutaneous model. rAd.sT.GM was safe to use and more effective in controlling tumor progression and lung metastasis following intratumoral injections when compared with control adenoviruses without modifications. In the same model, combinations of immune checkpoint inhibitor (ICI) therapy with rAd.sT.GM resulted in better inhibition of tumor growth and metastasis. Furthermore, we examined key immune response and prognosis biomarkers in sera, lungs, spleens, and tumors to evaluate the treatment efficacy. We found several key anti-tumor Th1 cytokines such as interleukin (IL)-2, IL-4, and interferon-γ, were stimulated by the combination therapy either systemically or in tumors or both, as well as anti-tumor biomarkers such as Granzyme B and perforin. These results support advancement to clinical testing with the combination therapy of rAd.sT.GM and ICIs for TNBC patients.