Tumors Resistant to Checkpoint Inhibitors Can Become Sensitive after Treatment with Vascular Disrupting Agents

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Cancer immunotherapy, particularly checkpoint inhibitors, has shown promise but faces limitations due to patient non-response.
• Tumor vascularization plays a critical role in the tumor microenvironment and immune cell infiltration.
• Vascular disrupting agents (VDAs) target tumor vasculature, potentially altering the tumor microenvironment.

Purpose of the Study:

• To investigate if VDAs can convert immune unresponsive tumors into responders to immunotherapy.
• To evaluate the efficacy of combining VDAs (combretastatin A-4 phosphate [CA4P] and OXi4503) with checkpoint inhibitors (anti-PD-1, PD-L1, CTLA-4).

Main Methods:

• Pre-clinical study using CDF1 mice bearing C3H mammary carcinomas.
• Administration of CA4P, OXi4503, and/or checkpoint inhibitors (anti-PD-1, PD-L1, CTLA-4) twice weekly for two weeks.
• Tumor growth time (TGT5) was used as the primary endpoint; histological assessment of CD4/CD8 expression was also performed.

Main Results:

• Checkpoint inhibitors alone did not affect tumor growth time.
• CA4P and OXi4503 significantly increased tumor growth time compared to controls.
• Combination therapy of VDAs with specific checkpoint inhibitors (anti-PD-L1 for CA4P; anti-PD-L1 or anti-CTLA-4 for OXi4503) further enhanced tumor growth inhibition, dependent on VDA dose and inhibitor type.

Conclusions:

• VDAs can overcome unresponsiveness to checkpoint inhibitors in a pre-clinical model of mammary carcinoma.
• The combination of VDAs with specific checkpoint inhibitors shows potential for enhancing anti-cancer immune responses.
• The precise mechanism by which VDAs sensitize tumors to immunotherapy requires further investigation, as indicated by decreased CD4/CD8 expression post-treatment.