Multimodal approach using oncolytic adenovirus, cetuximab, chemotherapy and radiotherapy in HNSCC low passage tumour cell cultures

Dias, João D.; Guse, Kilian; Nokisalmi, Petri; Eriksson, Minna; Chen, Dung-Tsa; Diaconu, Iulia; Tenhunen, Mikko; Liikanen, Ilkka; Grénman, Reidar; Savontaus, Mikko; Pesonen, Sari; Cerullo, Vincenzo; Hemminki, Akseli

doi:10.1016/j.ejca.2009.11.005

« Previous Next »European Journal of Cancer
Volume 46, Issue 3 , Pages 625-635, February 2010

Multimodal approach using oncolytic adenovirus, cetuximab, chemotherapy and radiotherapy in HNSCC low passage tumour cell cultures

João D. Dias
- Cancer Gene Therapy Group, Molecular Cancer Biology Program and Transplantation Laboratory and Haartman Institute and Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland
- HUSLAB, Helsinki University Central Hospital, Helsinki, Finland
Kilian Guse
- Cancer Gene Therapy Group, Molecular Cancer Biology Program and Transplantation Laboratory and Haartman Institute and Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland
- HUSLAB, Helsinki University Central Hospital, Helsinki, Finland
Petri Nokisalmi
- Cancer Gene Therapy Group, Molecular Cancer Biology Program and Transplantation Laboratory and Haartman Institute and Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland
- HUSLAB, Helsinki University Central Hospital, Helsinki, Finland
Minna Eriksson
- Cancer Gene Therapy Group, Molecular Cancer Biology Program and Transplantation Laboratory and Haartman Institute and Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland
- HUSLAB, Helsinki University Central Hospital, Helsinki, Finland
Dung-Tsa Chen
- Biostatistics Division, Department of Interdisciplinary Oncology, Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, USA
Iulia Diaconu
- Cancer Gene Therapy Group, Molecular Cancer Biology Program and Transplantation Laboratory and Haartman Institute and Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland
- HUSLAB, Helsinki University Central Hospital, Helsinki, Finland
Mikko Tenhunen
- Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland
Ilkka Liikanen
- Cancer Gene Therapy Group, Molecular Cancer Biology Program and Transplantation Laboratory and Haartman Institute and Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland
- HUSLAB, Helsinki University Central Hospital, Helsinki, Finland
Reidar Grénman
- Department of Otorhinolaryngology – Head and Neck Surgery and Medical Biochemistry, Turku University and Turku University Central Hospital, Turku, Finland
Mikko Savontaus
- Turku Centre for Biotechnology, Department of Medicine, University of Turku, Turku, Finland
Sari Pesonen
- Cancer Gene Therapy Group, Molecular Cancer Biology Program and Transplantation Laboratory and Haartman Institute and Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland
- HUSLAB, Helsinki University Central Hospital, Helsinki, Finland
Vincenzo Cerullo
- Cancer Gene Therapy Group, Molecular Cancer Biology Program and Transplantation Laboratory and Haartman Institute and Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland
- HUSLAB, Helsinki University Central Hospital, Helsinki, Finland
- These authors contributed equally to this work.
- Corresponding author: Address: Biomedicum, Haartmaninkatu 8, 00014 University of Helsinki, Helsinki, Finland. Tel.: +11 358 919125464; fax: +11 358 919125155.
Akseli Hemminki
- Cancer Gene Therapy Group, Molecular Cancer Biology Program and Transplantation Laboratory and Haartman Institute and Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland
- HUSLAB, Helsinki University Central Hospital, Helsinki, Finland
- These authors contributed equally to this work.
- Corresponding author: Address: Biomedicum, Haartmaninkatu 8, 00014 University of Helsinki, Helsinki, Finland. Tel.: +11 358 919125464; fax: +11 358 919125155.

Received 27 August 2009; accepted 12 November 2009. published online 14 December 2009.

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.

Keywords: Cancer gene therapy, Oncolytic adenoviruses, Cetuximab, Radiotherapy, Chemotherapy