Abstract
The incidence of cancer increases significantly in later life, yet few pre-clinical studies of cancer immunotherapy use mice of advanced age. A novel vaccine delivery platform (VacciMax®,VM) is described that encapsulates antigens and adjuvants in multilamellar liposomes in a water-in-oil emulsion. The therapeutic potential of VM-based vaccines administered as a single dose was tested in HLA-A2 transgenic mice of advanced age (48–58 weeks old) bearing large palpable TC1/A2 tumors. The VM-based vaccines contained one or more peptides having human CTL epitopes derived from HPV 16 E6 and E7. VM formulations contained a single peptide, a mixture of four peptides or the same four peptides linked together in a single long peptide. All VM formulations contained PADRE and CpG as adjuvants and ISA51 as the hydrophobic component of the water-in-oil emulsion. VM-formulated vaccines containing the four peptides as a mixture or linked together in one long peptide eradicated 19-day old established tumors within 21 days of immunization. Peptide-specific cytotoxic cellular responses were confirmed by ELISPOT and intracellular staining for IFN-γ producing CD8+ T cells. Mice rendered tumor-free by vaccination were re-challenged in the opposite flank with 10 million HLF-16 tumor cells, another HLA-A2/E6/E7 expressing tumor cell line. None of these mice developed tumors following the re-challenge. In summary, this report describes a VM-formulated therapeutic vaccine with the following unprecedented outcome: a) eradication of large tumors (> 700 mm3) b) in mice of advanced age c) in less than three weeks post-immunization d) following a single vaccination.
Highlights
Decreased immunity in the elderly has been documented and associated with decreased T cell differentiation and aging of naïve T cells, as well as aging of peripheral memory cells [1,2,3]
We have previously described such a highly effective single administration vaccine platform (VacciMax®,VM) that uses liposomes in a water-in-oil emulsion to deliver a peptide derived from HPV 16 E7 having a CTL epitope fused to PADRE with CpG adjuvant [6]
Eradication of large TC1/A2 tumors HLA-A2 transgenic mice represent a versatile animal model for preclinical studies of HLA-A*0201 restricted CTL responses and represent a mouse model which is closer than C57BL6 for human cervical cancer
Summary
Decreased immunity in the elderly has been documented and associated with decreased T cell differentiation and aging of naïve T cells, as well as aging of peripheral memory cells [1,2,3]. To counter decreasing immunity in the elderly, studies on influenza vaccination have shown that immune responses in the elderly could be elevated by designing vaccines with enhanced immunogenicity, by using strong adjuvants and increasing access to professional antigen presenting cells This resulted in stimulating the Th1 arm of the immune system, and increasing durable memory T cells [4,5]. We have previously described such a highly effective single administration vaccine platform (VacciMax®,VM) that uses liposomes in a water-in-oil emulsion to deliver a peptide derived from HPV 16 E7 having a CTL epitope fused to PADRE with CpG adjuvant [6] The efficacy of this vaccine platform was evaluated using a well-described mouse model based on HPV 16-expressing C3 tumor cells [7]. The aim of this study was to investigate whether VM-formulated vaccine incorporating human MHC restricted HPV-16 peptides would be efficacious in rejection of large established tumors in humanized mice of advanced age
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