Chemovirotherapy for head and neck squamous cell carcinoma with EGFR-targeted and CD/UPRT-armed oncolytic measles virus

• Verfasst von: Plath, Karim [VerfasserIn]
• Verfasst von: Bossow, Sascha [VerfasserIn]
• Verfasst von: Großardt, Christian [VerfasserIn]
• Verfasst von: Leber, Mathias Felix [VerfasserIn]
• Verfasst von: Springfeld, Christoph [VerfasserIn]
• Verfasst von: Plinkert, Peter K. [VerfasserIn]
• Verfasst von: Kalle, Christof von [VerfasserIn]
• Verfasst von: Ungerechts, Guy [VerfasserIn]
• Titel: Chemovirotherapy for head and neck squamous cell carcinoma with EGFR-targeted and CD/UPRT-armed oncolytic measles virus
• Verf.angabe: K. Zaoui, S. Bossow, C. Grossardt, M. F. Leber, C. Springfeld, P. K. Plinkert, C. von Kalle and G. Ungerechts
• Jahr: 2012
• Umfang: 11 S.
• Fussnoten: Published online 11 November 2011 ; Gesehen am 22.08.2018
• Titel Quelle: Enthalten in: Cancer gene therapy
• Ort Quelle: New York, NY : Nature Publ. Group, 1999
• Jahr Quelle: 2012
• Band/Heft Quelle: 19(2012), 3, Seite 181-191
• ISSN Quelle: 1476-5500
• DOI: doi:10.1038/cgt.2011.75
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1580295592

Abstract

First-line treatment of recurrent and/or refractory head and neck squamous cell carcinoma (HNSCC) is based on platinum, 5-fluorouracil (5-FU) and the monoclonal antiEGFR antibody cetuximab. However, in most cases this chemoimmunotherapy does not cure the disease, and more than 50% of HNSCC patients are dying because of local recurrence of the tumors. In the majority of cases, HNSCC overexpress the epidermal growth factor receptor (EGFR), and its presence is associated with a poor outcome. In this study, we engineered an EGFR-targeted oncolytic measles virus (MV), armed with the bifunctional enzyme cytosine deaminase/uracil phosphoribosyltransferase (CD/UPRT). CD/UPRT converts 5-fluorocytosine (5-FC) into the chemotherapeutic 5-FU, a mainstay of HNSCC chemotherapy. This virus efficiently replicates in and lyses primary HNSCC cells in vitro. Arming with CD/UPRT mediates efficient prodrug activation with high bystander killing of non-infected tumor cells. In mice bearing primary HNSCC xenografts, intratumoral administration of MV-antiEGFR resulted in statistically significant tumor growth delay and prolongation of survival. Importantly, combination with 5-FC is superior to virus-only treatment leading to significant tumor growth inhibition. Thus, chemovirotherapy with EGFR-targeted and CD/UPRT-armed MV is highly efficacious in preclinical settings with direct translational implications for a planned Phase I clinical trial of MV for locoregional treatment of HNSCC.