MTL-CEBPA Combined with Immunotherapy or RFA Enhances Immunological Anti-Tumor Response in Preclinical Models

Area of Science:

• Immunology
• Oncology
• RNA Therapeutics

Background:

• CCAAT/enhancer-binding protein alpha (CEBPA) is crucial for liver homeostasis and myeloid differentiation, often downregulated in cancer.
• MTL-CEBPA is an investigational small activating RNA drug designed to restore CEBPA expression for hepatocellular carcinoma (HCC) treatment.

Purpose of the Study:

• To investigate the immune modulatory effects of MTL-CEBPA when combined with anti-PD-1 checkpoint inhibitors (CPIs) and/or radiofrequency ablation (RFA).
• To evaluate the efficacy of these combination therapies in preclinical cancer models.

Main Methods:

• Two preclinical models were used: mice with bilateral HCC tumors (BNL) and a CT26 colon cancer model.
• Treatments included RFA, anti-PD-1, MTL-CEBPA, and their combinations.

Main Results:

• In the BNL model, RFA + anti-PD-1 + MTL-CEBPA achieved the most significant reduction in non-treated tumors, with 7/8 animals responding.
• This combination therapy uniquely increased CD8+ and CD49b+/CD45+ tumor-infiltrating lymphocytes (TILs).
• In the CT26 model, anti-PD-1 + MTL-CEBPA significantly reduced tumor size and increased TILs, modulating the tumor immune microenvironment.

Conclusions:

• Combination therapy with CPIs, RFA, and MTL-CEBPA demonstrates synergistic immune priming effects.
• This approach enhances anti-tumor activity, including abscopal effects in RFA-treated tumors.
• These findings suggest a potential clinical role for MTL-CEBPA in combination cancer treatment strategies.