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

Area of Science:

• Oncolytic virotherapy
• Immunotherapy
• Breast cancer research

Background:

• Metastatic triple-negative breast cancer (TNBC) presents significant therapeutic challenges and is a leading cause of cancer mortality.
• Current treatments for TNBC have limited efficacy, necessitating novel therapeutic strategies.

Purpose of the Study:

• To evaluate the efficacy of a novel oncolytic adenovirus, rAd.sT.GM, engineered to inhibit transforming growth factor-beta (TGF-β) and stimulate granulocyte-macrophage colony-stimulating factor (GM-CSF).
• To assess the combined therapeutic effect of rAd.sT.GM and immune checkpoint inhibitors (ICIs) in a preclinical model of TNBC.

Main Methods:

• Development of rAd.sT.GM, an oncolytic adenovirus expressing a TGF-β decoy (sTGFβRIIFc) and GM-CSF.
• Testing rAd.sT.GM in a subcutaneous mouse model of TNBC (4T1).
• Evaluation of combination therapy with rAd.sT.GM and ICIs, including analysis of immune biomarkers in various tissues and serum.

Main Results:

• Intratumoral administration of rAd.sT.GM demonstrated safety and superior control of tumor progression and lung metastasis compared to control adenoviruses.
• Combination therapy with rAd.sT.GM and ICIs significantly inhibited tumor growth and metastasis.
• The combination treatment stimulated key anti-tumor immune responses, including Th1 cytokines (IL-2, IL-4, IFN-γ) and cytotoxic markers (Granzyme B, perforin).

Conclusions:

• rAd.sT.GM is a safe and effective oncolytic agent for TNBC.
• Combination therapy of rAd.sT.GM with ICIs shows promising results in enhancing anti-tumor immunity and controlling TNBC progression and metastasis.
• These findings support the clinical advancement of rAd.sT.GM and ICI combination therapy for TNBC patients.