Virus-Like Particle-Drug Conjugates Induce Protective, Long-lasting Adaptive Antitumor Immunity in the Absence of Specifically Targeted Tumor Antigens.

Abstract

This study examined the ability of a papillomavirus-like particle drug conjugate, belzupacap sarotalocan (AU-011), to eradicate subcutaneous tumors after intravenous injection and to subsequently elicit long-term antitumor immunity in the TC-1 syngeneic murine tumor model. Upon in vitro activation with near-infrared light (NIR), AU-011-mediated cell killing was proimmunogenic in nature, resulting in the release of damage-associated molecular patterns such as DNA, ATP, and HMGB-1, activation of caspase-1, and surface relocalization of calreticulin and HSP70 on killed tumor cells. A single in vivo administration of AU-011 followed by NIR caused rapid cell death, leading to long-term tumor regression in ∼50% of all animals. Within hours of treatment, calreticulin surface expression, caspase-1 activation, and depletion of immunosuppressive leukocytes were observed in tumors. Combination of AU-011 with immune-checkpoint inhibitor antibodies, anti-CTLA-4 or anti-PD-1, improved therapeutic efficacy, resulting in 70% to 100% complete response rate that was durable 100 days after treatment, with 50% to 80% of those animals displaying protection from secondary tumor rechallenge. Depletion of CD4+ or CD8+ T cells, either at the time of AU-011 treatment or secondary tumor rechallenge of tumor-free mice, indicated that both cell populations are vital to AU-011's ability to eradicate primary tumors and induce long-lasting antitumor protection. Tumor-specific CD8+ T-cell responses could be observed in circulating peripheral blood mononuclear cells within 3 weeks of AU-011 treatment. These data, taken together, support the conclusion that AU-011 has a direct cytotoxic effect on tumor cells and induces long-term antitumor immunity, and this activity is enhanced when combined with checkpoint inhibitor antibodies.

• Authors: Rhonda C Kines, Cynthia D Thompson, Sean Spring, Zhenyu Li, Elisabet de Los Pinos, Stephen Monks, John T Schiller
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 9 Issue 6 Pg. 693-706 (06 2021) ISSN: 2326-6074 [Electronic] United States
• PMID: 33853825 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Antigens, Neoplasm
• Cancer Vaccines
• Immune Checkpoint Inhibitors
• Vaccines, Virus-Like Particle

Topics

• Adaptive Immunity
• Animals
• Antigens, Neoplasm (immunology)
• CD8-Positive T-Lymphocytes (drug effects, immunology)
• Cancer Vaccines (pharmacology)
• Cell Line, Tumor
• Combined Modality Therapy
• Drug Synergism
• Female
• Humans
• Immune Checkpoint Inhibitors (pharmacology)
• Immunotherapy
• Infrared Rays (therapeutic use)
• Leukocytes, Mononuclear (drug effects, immunology)
• Mice
• Mice, Inbred C57BL
• Neoplasms, Experimental (immunology, metabolism, therapy)
• Vaccines, Virus-Like Particle (pharmacology)