Combination of KRAS ASO and RIG-I agonist in extracellular vesicles transforms the tumor microenvironment towards...

Area of Science:

• Oncology
• Immunology
• Gene Therapy

Background:

• KRAS gene mutations are key drivers in numerous cancers, presenting a significant therapeutic challenge.
• Current strategies for targeting KRAS mutants are limited, necessitating novel approaches.
• Activating the RIG-I pathway can enhance anti-tumor immunity.

Purpose of the Study:

• To develop a dual-action therapeutic strategy using extracellular vesicles (EVs) to simultaneously inhibit KRAS mutants and activate the RIG-I pathway.
• To evaluate the efficacy of this strategy in enhancing anti-tumor immunity and treating KRAS-driven cancers.

Main Methods:

• Loading antisense oligonucleotides against KRAS mutants (KRAS ASOs) and RIG-I agonist immunomodulatory RNA (immRNA) into EVs.
• Administering the EV-based therapy to preclinical models of colorectal, non-small cell lung cancer (NSCLC), and patient-derived pancreatic cancer.
• Assessing therapeutic effects by analyzing tumor microenvironment changes, immune cell activation (dendritic cells, T cells), tumor development, and survival.

Main Results:

• Combination therapy induced immunogenic tumor cell death and interferon upregulation in KRAS-dependent cancers.
• Therapy modulated the tumor microenvironment to an immunogenic state, activated dendritic cells, and promoted memory T cell formation in a colorectal cancer model.
• Significant anti-tumor activity and extended survival were observed in an aggressive NSCLC model without adverse effects.
• Preclinical validation in pancreatic cancer organoids demonstrated clinical translation potential.

Conclusions:

• Extracellular vesicle-mediated delivery of KRAS ASOs and immRNA is an effective strategy for inhibiting KRAS mutants and activating RIG-I.
• This approach elicits a robust anti-tumor immune response, demonstrating significant therapeutic potential for KRAS-driven cancers.
• The findings suggest a promising new avenue for improving clinical outcomes in patients with KRAS-mutant cancers.