title: Intravenously usable fully serotype 3 oncolytic adenovirus coding for CD40L as an enabler of dendritic cell therapy.
abstract: Vaccination with dendritic cells (DCs), the most potent professional antigen-presenting cells in the body, is a promising approach in cancer immunotherapy. However, tumors induce immunosuppression in their microenvironment that suppresses and impairs the function of DCs. Therefore, human clinical trials with DC therapy have often been disappointing. To improve the therapeutic efficacy and to overcome the major obstacles of DC therapy, we generated a novel adenovirus, Ad3-hTERT-CMV-hCD40L, which is fully serotype 3 and expresses hCD40L for induction of antitumor immune response. The specific aim is to enhance DCs function. Data from a human cancer patient indicated that this capsid allows effective transduction of distant tumors through the intravenous route. Moreover, patient data suggested that virally produced hCD40L can activate DCsin situ. The virus was efficientin vitroand had potent antitumor activityin vivo.In a syngeneic model, tumors treated with Ad5/3-CMV-mCD40L virus plus DCs elicited greater antitumor effect as compared with either treatment alone. Moreover, virally coded CD40L induced activation of DCs, which in turn, lead to the induction of a Th1 immune response and increased tumor-specific T cells. In conclusion, Ad3-hTERT-CMV-hCD40L is promising for translation into human trials. In particular, this virus could enable successful dendritic cell therapy in cancer patients.
authors.affiliation: Cancer Gene Therapy Group, Department of Oncology, University of Helsinki , Helsinki, Finland.
authors.forename: Sadia
authors.initials: S
authors.lastname: Zafar
authors.affiliation: Cancer Gene Therapy Group, Department of Oncology, University of Helsinki, Helsinki, Finland; TILT Biotherapeutics Ltd, Helsinki, Finland.
authors.forename: Suvi
authors.initials: S
authors.lastname: Parviainen
authors.affiliation: Cancer Gene Therapy Group, Department of Oncology, University of Helsinki, Helsinki, Finland; TILT Biotherapeutics Ltd, Helsinki, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Siurala
authors.affiliation: Cancer Gene Therapy Group, Department of Oncology, University of Helsinki , Helsinki, Finland.
authors.forename: Otto
authors.initials: O
authors.lastname: Hemminki
authors.affiliation: Cancer Gene Therapy Group, Department of Oncology, University of Helsinki , Helsinki, Finland.
authors.forename: Riikka
authors.initials: R
authors.lastname: Havunen
authors.affiliation: Cancer Gene Therapy Group, Department of Oncology, University of Helsinki , Helsinki, Finland.
authors.forename: Siri
authors.initials: S
authors.lastname: Tähtinen
authors.affiliation: Cancer Gene Therapy Group, Department of Oncology, University of Helsinki , Helsinki, Finland.
authors.forename: Simona
authors.initials: S
authors.lastname: Bramante
authors.affiliation: Cancer Gene Therapy Group, Department of Oncology, University of Helsinki , Helsinki, Finland.
authors.forename: Lotta
authors.initials: L
authors.lastname: Vassilev
authors.affiliation: Division of Medical Genetics, University of Washington , Seattle, WA, USA.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Wang
authors.affiliation: Division of Medical Genetics, University of Washington, Seattle, WA, USA; Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Andre
authors.initials: A
authors.lastname: Lieber
authors.affiliation: Institute of Molecular Life Sciences, University of Zurich , Zurich, Switzerland.
authors.forename: Silvio
authors.initials: S
authors.lastname: Hemmi
authors.affiliation: VU University Medical Center , Amsterdam, the Netherlands.
authors.forename: Tanja
authors.initials: T
authors.lastname: de Gruijl
authors.affiliation: Cancer Gene Therapy Group, Department of Oncology, University of Helsinki, Helsinki, Finland; Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kanerva
authors.affiliation: Cancer Gene Therapy Group, Department of Oncology, University of Helsinki, Helsinki, Finland; TILT Biotherapeutics Ltd, Helsinki, Finland; Helsinki University Comprehensive Cancer Center, Helsinki, Finland.
authors.forename: Akseli
authors.initials: A
authors.lastname: Hemminki
keywords: CD40 ligand; T-cells; dendritic cells; oncolytic adenovirus; tumor microenvironment