title: Multimodal approach using oncolytic adenovirus, cetuximab, chemotherapy and radiotherapy in HNSCC low passage tumour cell cultures.
abstract: Head and neck squamous cell carcinoma (HNSCC) is a common and often devastating disease without curative treatment when advanced or recurrent. The aim of this study was to assess whether capsid-modified oncolytic adenoviruses have therapeutic efficacy in HNSCC low passage tumour cell cultures and if it could be further improved by combination with cetuximab, radiotherapy and chemotherapy. We investigated which adenoviral capsid modifications allow best gene transfer and cell killing of HNSCC substrates. Gene transfer was assessed using replication-deficient adenoviruses expressing luciferase. Cell killing was studied in vitro and in vivo using oncolytic adenoviruses, which kill tumour cell by viral replication. The most effective capsid-modified oncolytic adenoviruses were combined with HNSCC standard therapies and their efficacy was assessed in vitro as well as in vivo. Cell killing was assessed in vitro by MTS assay and in vivo by HNSCC subcutaneous tumour growth follow-up in nude mice. Cetuximab treatment was found to enrich CD133+ and CD44+ tumour-initiating type cells in tumours grown in mice. Capsid-modified viruses showed increased transduction and oncolysis of HNSCC substrates in comparison to Ad5-based agents. Polylysine (pK7)-modified oncolytic virus resulted in significant tumour growth reduction in vivo. Combination of chemotherapy (cisplatin and 5-fluorouracil), radiotherapy and cetuximab with oncolytic adenovirus therapy resulted in further increases in cell killing effect in vitro and complete eradication of tumours in vivo. Our pre-clinical data suggest that it is feasible and efficacious to combine oncolytic adenoviruses with HNSCC standard therapies into a multimodality treatment regimen for clinical testing in HNSCC patients.
authors.affiliation: Transplantation Laboratory and Haartman Institute and Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: João D
authors.initials: JD
authors.lastname: Dias
authors.forename: Kilian
authors.initials: K
authors.lastname: Guse
authors.forename: Petri
authors.initials: P
authors.lastname: Nokisalmi
authors.forename: Minna
authors.initials: M
authors.lastname: Eriksson
authors.forename: Dung-Tsa
authors.initials: DT
authors.lastname: Chen
authors.forename: Iulia
authors.initials: I
authors.lastname: Diaconu
authors.forename: Mikko
authors.initials: M
authors.lastname: Tenhunen
authors.forename: Ilkka
authors.initials: I
authors.lastname: Liikanen
authors.forename: Reidar
authors.initials: R
authors.lastname: Grénman
authors.forename: Mikko
authors.initials: M
authors.lastname: Savontaus
authors.forename: Sari
authors.initials: S
authors.lastname: Pesonen
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerullo
authors.forename: Akseli
authors.initials: A
authors.lastname: Hemminki
mesh_terms: D000071916:AC133 Antigen; D000256:Adenoviridae; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000032:analysis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000473:pathology / Q000628:therapy*; D016923:Cell Death; D000068818:Cetuximab; D003131:Combined Modality Therapy; D005240:Feasibility Studies; D005260:Female; D018014:Gene Transfer Techniques; D006023:Glycoproteins / Q000032:analysis; D006258:Head and Neck Neoplasms / Q000473:pathology / Q000628:therapy*; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D010455:Peptides / Q000032:analysis; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000071916:AC133 Antigen; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000970:Antineoplastic Agents; C497483:CD44 protein, human; D006023:Glycoproteins; D018960:Hyaluronan Receptors; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D000068818:Cetuximab