Generation of dendritic cell-based vaccine using high hydrostatic pressure for non-small cell lung cancer immunotherapy
Abstract
High hydrostatic pressure (HHP) induces immunogenic death of tumor cells which confer protective anti-tumor immunity in vivo. Moreover, DC pulsed with HHP-treated tumor cells induced therapeutic effect in mouse cancer model.
In this study, we tested the immunogenicity, stability and T cell stimulatory activity of human monocyte-derived dendritic cell (DC)based HHP lung cancer vaccine generated in GMP compliant serum free medium using HHP 250 MPa. DC pulsed with HHP-killed lung cancer cells and poly(I:C) enhanced DC maturation, chemotactic migration and production of pro-inflammatory cytokines after 24h.
Moreover, DC-based HHP lung cancer vaccine showed functional plasticity after transfer into serum-containing media and stimulation with LPS or CD40L after additional 24h. LPS and CD40L stimulation further differentially enhanced the expression of costimulatory molecules and production of IL-12p70.
DC-based HHP lung cancer vaccine decreased the number of CD4(+) CD25(+) Foxp3(+) T regulatory cells and stimulated IFN-gamma-producing tumor antigenspecific CD4(+) and CD8(+) T cells from non-small cell lung cancer (NSCLC) patients. Tumor antigen specific CD8(+) and CD4(+) T cell responses were detected in NSCLC patient's against a selected tumor antigens expressed by lung cancer cell lines used for the vaccine generation.
We also showed for the first time that protein antigen from HHP-killed lung cancer cells is processed and presented by DC to CD8(+) T cells. Our results represent important preclinical data for ongoing NSCLC Phase I/II clinical trial using DC-based active cellular immunotherapy (DCVAC/LuCa) in combination with chemotherapy and immune enhancers.