Co-administered internalizing RGD peptide boosts anti-PD-L1 therapy in hepatocellular carcinoma.

Area of Science:

• Oncology
• Immunology
• Drug Delivery

Background:

• Immune checkpoint inhibitors (ICIs) offer improved outcomes for solid tumors like hepatocellular carcinoma (HCC).
• However, a significant portion of patients do not respond to ICI therapy, partly due to poor intratumoral drug delivery.
• The tumor-penetrating peptide iRGD enhances vascular permeability, potentially improving drug penetration into tumors.

Purpose of the Study:

• To investigate if co-administration of the iRGD peptide with anti-PD-L1 enhances intratumoral delivery and therapeutic efficacy in HCC mouse models.
• To assess the impact of iRGD and anti-PD-L1 combination therapy on tumor growth, immune cell composition, and tumor microenvironment.

Main Methods:

• Intravenous administration of anti-PD-L1, with or without iRGD, to mice with endogenous HCCs (TGFα/c-myc and DEN/CCl4 models).
• Monitoring tumor growth via MRI, analyzing immune cell populations and activation by flow cytometry.
• Performing RNA sequencing on whole tumors and isolated intratumoral CD45+ immune cells.

Main Results:

• Combination therapy significantly reduced tumor growth compared to anti-PD-L1 monotherapy in both HCC models.
• Objective response rates increased substantially in the combination group, with enhanced T cell activation markers and reduced immunosuppression.
• RNA sequencing indicated decreased immunosuppression and increased vascular permeability; immunoblotting confirmed enhanced intratumoral accumulation of anti-PD-L1 with iRGD.

Conclusions:

• Co-administration of iRGD with anti-PD-L1 significantly improves therapeutic efficacy in HCC mouse models.
• The enhanced efficacy is attributed to increased intratumoral anti-PD-L1 delivery and improved alleviation of the immunosuppressive tumor microenvironment.
• This non-conjugated, systemic approach holds strong translational potential for enhancing ICI responses in patients with HCC.