Inhibition of glioma development by doxorubicin-photochemical internalization generated macrophage vaccine: A survival study in rats

Abstract

BackgroundThe process known as immunogenic cell death (ICD) is characterized by dead and dying cancer cells exposing and releasing so-called damage associated molecular patterns (DAMPs). ICD has been shown to enhance the efficacy of antigen presenting cell (APC) immunotherapy. Both anthracycline drugs such as doxorubicin (DOX), and photodynamic therapy (PDT) have been shown to be inducers of ICD. It was therefore hypothesized that combined PDT and DOX i.e. photochemical internalization of DOX (DOX-PCI) would increase ICD compared to DOX acting as a single agent. Materials and methodsF98 glioma cells were treated with DOX-PCI in vitro and the ICD markers HMGB1, HSP70, and HSP90 were determined by ELISA assay. Peritoneal macrophages (Ma), obtained from Fisher rats acting as APCs, were co-incubated with dead F98 glioma cells killed via DOX or DOX-PCI treatment ex vivo. The pulsed Ma (Ma DOX or Ma DOX-PCI) were used to inoculate the animals either before (preventive) or after (curative) intra-cranially implantation of the glioma cells. ResultsF98 cells, treated with DOX-PCI in vitro, induced a significantly higher level of HGMB1, HSP70, and HSP90 than DOX acting alone. Ma DOX-PCI inoculated animals, in both preventive and curative protocols, had a pronounced survival benefit compared to either the non-treatment or MaDOX control groups. In the curative protocol, a second booster inoculation significantly improved survival, with 60% of the animals alive at day 60. ConclusionMacrophages primed with DOX-PCI treated glioma cells appeared to be highly effective as APCs and, when injected into host animals, could delay and, in some cases, prevent tumor development.