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

被引:36
|
作者
Zaoui, K. [1 ,2 ]
Bossow, S. [1 ]
Grossardt, C. [1 ]
Leber, M. F. [1 ]
Springfeld, C. [3 ]
Plinkert, P. K. [2 ]
von Kalle, C. [1 ]
Ungerechts, G. [1 ]
机构
[1] German Canc Res Ctr, Dept Translat Oncol, Natl Ctr Tumor Dis, D-69120 Heidelberg, Germany
[2] Heidelberg Univ, Dept Otorhinolaryngol & Head & Neck Surg, Univ Heidelberg Hosp, Heidelberg, Germany
[3] Natl Ctr Tumor Dis, Dept Med Oncol, Heidelberg, Germany
关键词
cetuximab; EGFR; HNSCC; oncolytic measles virus; prodrug converting enzyme; virotherapy; PHASE-I; CYTOSINE DEAMINASE; GENE-THERAPY; CANCER; ADENOVIRUS; ANTIGEN; FUSION; REPLICATION; EXPRESSION; STRAINS;
D O I
10.1038/cgt.2011.75
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
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 anti EGFR 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. Cancer Gene Therapy (2012) 19, 181-191; doi:10.1038/cgt.2011.75; published online 11 November 2011
引用
收藏
页码:181 / 191
页数:11
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