title: Chemovirotherapy for head and neck squamous cell carcinoma with EGFR-targeted and CD/UPRT-armed oncolytic measles virus.
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.
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Zaoui
authors.forename: S
authors.initials: S
authors.lastname: Bossow
authors.forename: C
authors.initials: C
authors.lastname: Grossardt
authors.forename: M F
authors.initials: MF
authors.lastname: Leber
authors.forename: C
authors.initials: C
authors.lastname: Springfeld
authors.forename: P K
authors.initials: PK
authors.lastname: Plinkert
authors.forename: C von
authors.initials: Cv
authors.lastname: Kalle
authors.forename: G
authors.initials: G
authors.lastname: Ungerechts
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D043525:Cytosine Deaminase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005437:Flucytosine / Q000493:pharmacokinetics / Q000494:pharmacology; D005472:Fluorouracil / Q000493:pharmacokinetics / Q000494:pharmacology; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D006801:Humans; D008459:Measles virus / Q000235:genetics / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D050130:Oncolytic Virotherapy / Q000379:methods*; D010430:Pentosyltransferases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D011355:Prodrugs / Q000493:pharmacokinetics; D000077195:Squamous Cell Carcinoma of Head and Neck; D014709:Vero Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: D011355:Prodrugs; D005437:Flucytosine; D010430:Pentosyltransferases; C023269:uracil phosphoribosyltransferase; D066246:ErbB Receptors; D043525:Cytosine Deaminase; D005472:Fluorouracil