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

Abstract

Immune therapy improves cancer outcomes, yet many patients do not respond. This pre-clinical study investigated whether vascular disrupting agents (VDAs) could convert an immune unresponsive tumor into a responder. CDF1 mice, with 200 mm3 C3H mammary carcinomas in the right rear foot, were intraperitoneally injected with combretastatin A-4 phosphate (CA4P), its A-1 analogue OXi4503, and/or checkpoint inhibitors (anti-PD-1, PD-L1, or CTLA-4 antibodies), administered twice weekly for two weeks. Using the endpoint of tumor growth time (TGT5; time to reach five times the starting volume), we found that none of the checkpoint inhibitors (10 mg/kg) had any effect on TGT5 compared to untreated controls. However, CA4P (100 mg/kg) or OXi4503 (5-50 mg/kg) did significantly increase TGT5. This further significantly increased by combining the VDAs with checkpoint inhibitors, but was dependent on the VDA, drug dose, and inhibitor. For CA4P, a significant increase was found when CA4P (100 mg/kg) was combined with anti-PD-L1, but not with the other two checkpoint inhibitors. With OXi4503 (50 mg/kg), a significant enhancement occurred when combined with anti-PD-L1 or anti-CTLA-4, but not anti-PD-1. We observed no significant improvement with lower OXi4503 doses (5-25 mg/kg) and anti-CTLA-4, although 30% of tumors were controlled at the 25 mg/kg dose. Histological assessment of CD4/CD8 expression actually showed decreased levels up to 10 days after treatment with OXi4503 (50 mg/kg). Thus, the non-immunogenic C3H mammary carcinoma was unresponsive to checkpoint inhibitors, but became responsive in mice treated with VDAs, although the mechanism remains unclear.

• Authors: Michael R Horsman, Thomas R Wittenborn, Patricia S Nielsen, Pernille B Elming
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 13 (Jul 06 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 32640548 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents, Phytogenic
• B7-H1 Antigen
• Bibenzyls
• CD274 protein, human
• CTLA-4 Antigen
• CTLA4 protein, human
• Diphosphates
• Immune Checkpoint Inhibitors
• Oxi 4503
• Stilbenes
• combretastatin

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• B7-H1 Antigen (antagonists & inhibitors, immunology)
• Bibenzyls (pharmacology)
• CTLA-4 Antigen (antagonists & inhibitors, immunology)
• Diphosphates (pharmacology)
• Disease Progression
• Drug Resistance, Neoplasm (drug effects)
• Female
• Immune Checkpoint Inhibitors (immunology, pharmacology)
• Male
• Mammary Neoplasms, Animal (drug therapy, immunology, pathology)
• Mice
• Mice, Inbred C3H
• Neovascularization, Pathologic (drug therapy, immunology, pathology)
• Stilbenes (pharmacology)
• Treatment Outcome