Description
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
*Corresponding author
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.