Archaeosome-adjuvanted vaccine and Checkpoint inhibitor therapy combination significantly enhances protection from murine melanoma
Felicity C. Stark, Michael J. McCluskie, Lakshmi Krishnan*
Human Health Therapeutics, National Research Council, Ottawa, ON
Archaeosomes constitute archaeal lipid vesicles; they are vaccine adjuvants that evoke a strong CD8+ T cell response to antigenic cargo. Therapeutic treatment of murine B16-OVA melanoma with Archaeosome-OVA eliminates small subcutaneous solid tumors; however, they eventually resurge despite an increased frequency of circulating and tumour infiltrating OVA-CD8+ T cells. Tumour protection could not be enhanced by repetitive and/or delayed boosting to maximize CD8+ T cell number and/or phenotype. The cytotoxicity of vaccine induced OVA-CD8+ T cells was assessed by an in vivo cytotoxicity assay and determined to be impaired in tumour bearing mice. Additionally, tumour infiltrating OVA-CD8+ T cells compared to other organ compartments had an increased expression of the program cell death protein -1 (PD1), which is an indicator of impaired function. The use of anti-PD-1 and other checkpoint inhibitors have had great success in the clinic, lengthening survival rates for patients with melanoma and other cancers. Herein we investigated a combination approach using Archaeosome-OVA alongside multiple immune checkpoint blockers in a therapeutic murine melanoma model. Combination therapy of tumour bearing mice with Archaeosome-OVA vaccine and anti-CTLA-4 administered concurrently as well as anti-PD1 & anti-PDL1 antibody administered starting day 9 after tumour challenge given every 3 days for a total of four doses, produced a significant enhanced survival rate. Following multi-combination therapy ~70 % of the mice had rapid tumor recession, with no detectable tumor mass for >80 days in comparison to a median survival of 17-22 days for untreated or experimental groups receiving single therapies. Overall, Archaeosomes offer a powerful platform for co-delivering cancer antigens, augmenting tumor specific CD8+ T cell responses and for use in checkpoint inhibitor combination vaccines.
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