Dendritic cells (DCs) are vital antigen-presenting cells and they are a central part of the immune system. They play a crucial role in detection and elimination of pathogens and cancer cells. DCs based vaccination is a safe and promising approach in cancer immunotherapy. Tumor microenvironment derived immunosuppression inhibits and weakens the function of DCs by hampering their maturation and activation. The outcomes of human clinical trial with DCs monotherapy have shown limited efficacy. This study hypothesized that activated DCs would further activate tumor specific cytotoxic T cells and result in therapeutic antitumor immune responses. Oncolytic viruses kill cancer cells by replicating selectively at tumor site. They enhance antitumor immunological effects by releasing tumor epitopes in the presence of pathogens and danger associated signals.
In this study, we used a fully serotype 3 oncolytic adenovirus (Ad3-hTERT-CMV-hCD40L; TILT-234) expressing human CD40L for the stimulation of DC and induction of antitumor immune response in prostate tumor microenvironment. The therapeutic benefits of Ad3-hTERT-CMV-hCD40L virus and DCs was evaluated in vivo and ex vivo. A Humanized mouse model was used to determine antitumor efficacy in vivo. The cytotoxic ability of viruses is evaluated ex vivo using single cell digestion of tumor samples obtained from patients.
Enhanced antitumor responses and improved cancer specific survival is observed when prostate tumors were treated with Ad3-hTERT-CMV-hCD40L virus and DCs in vivo. Complete cells killing was evident ex vivo when tumors were treated with virus using MTS viability assay. Upregulated expression of DCs maturation marker such as CD86/CD83/CD80 was evident when patient samples were treated with virus indicating virus induced DCs maturation. A prominent increase in pro-inflammatory cytokines was observed ex vivo indicating the virus induced immunostimulatory modulation in the tumor.
Ad3-hTERT-CMV-hCD40L virus can modulate the immunosuppressive tumor microenvironment ex vivo in patient samples. Importantly, this virus could enable successful dendritic cell therapy in prostate cancer models and patient explants.
Legal entity responsible for the study
Cancer Gene Therapy Group.
KLTO (Doctoral School for Clinical Research programme at the University of Helsinki), Jane and Aatos Erkko Foundation, HUCH Research Funds (VTR), Sigrid Juselius Foundation, Finnish Cancer Organizations, University of Helsinki, Novo Nordisk Foundation, Päivikki and Sakari Sohlberg Foundation and TILT Biotherapeutics Ltd. Albert Ehrnrooth and Karl Fazer for research support.
All authors have declared no conflicts of interest.