Immunotherapy for breast cancer using EpCAM aptamer tumor-targeted gene knockdown

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Most solid tumors resist current cancer immunotherapy strategies, necessitating novel approaches.
• Epithelial Cell Adhesion Molecule (EpCAM) is a tumor-associated antigen highly expressed on common epithelial cancers and their tumor-initiating cells.
• Targeting EpCAM offers a potential strategy to selectively deliver therapeutic agents to cancer cells.

Purpose of the Study:

• To develop and evaluate aptamer-linked small-interfering RNA chimeras (AsiCs) for targeted gene knockdown in EpCAM+ tumors.
• To enhance cancer visibility to the immune system by modulating genes involved in tumor immunity.
• To assess the efficacy of AsiCs in aggressive triple-negative and HER2+ breast cancer models.

Main Methods:

• Designed AsiCs targeting EpCAM+ tumors for selective gene knockdown.
• Selected gene targets (Upf2, Parp1, Apex1, Cd47, Cd274, Mcl1) predicted to modulate tumor immunity.
• Evaluated AsiC efficacy in orthotopic, metastatic, and genetically engineered mouse breast cancer models.
• Assessed tumor growth inhibition and tumor-infiltrating immune cell functions.

Main Results:

• Four of six tested AsiCs (Upf2, Parp1, Cd47, Mcl1) demonstrated potent tumor growth inhibition.
• AsiCs significantly boosted tumor-infiltrating immune cell functions.
• Mixtures of AsiCs were more effective than individual AsiCs and synergized with anti-PD-1 checkpoint inhibition.

Conclusions:

• EpCAM-targeted AsiCs represent a promising strategy for cancer immunotherapy.
• Targeted gene knockdown using AsiCs can enhance anti-tumor immune responses.
• Combination therapy with AsiCs and checkpoint inhibitors may overcome resistance in solid tumors.