title: Degradation of fibrillar collagen in a human melanoma xenograft improves the efficacy of an oncolytic herpes simplex virus vector.
abstract: Oncolytic viral therapy provides a promising approach to treat certain human malignancies. These vectors improve on replication-deficient vectors by increasing the viral load within tumors through preferential viral replication within tumor cells. However, the inability to efficiently propagate throughout the entire tumor and infect cells distant from the injection site has limited the capacity of oncolytic viruses to achieve consistent therapeutic responses. Here we show that the spread of the oncolytic herpes simplex virus (HSV) vector MGH2 within the human melanoma Mu89 is limited by the fibrillar collagen in the extracellular matrix. This limitation seems to be size specific as nanoparticles of equivalent size to the virus distribute within tumors to the same extent whereas smaller particles distribute more widely. Due to limited viral penetration, tumor cells in inaccessible regions continue to grow, remaining out of the range of viral infection, and tumor eradication cannot be achieved. Matrix modification with bacterial collagenase coinjection results in a significant improvement in the initial range of viral distribution within the tumor. This results in an extended range of infected tumor cells and improved virus propagation, ultimately leading to enhanced therapeutic outcome. Thus, fibrillar collagen can be a formidable barrier to viral distribution and matrix-modifying treatments can significantly enhance the therapeutic response.
authors.affiliation: Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachussetts 02114, USA.
authors.forename: Trevor D
authors.initials: TD
authors.lastname: McKee
authors.forename: Paola
authors.initials: P
authors.lastname: Grandi
authors.forename: Wilson
authors.initials: W
authors.lastname: Mok
authors.forename: George
authors.initials: G
authors.lastname: Alexandrakis
authors.forename: Numpon
authors.initials: N
authors.lastname: Insin
authors.forename: John P
authors.initials: JP
authors.lastname: Zimmer
authors.forename: Moungi G
authors.initials: MG
authors.lastname: Bawendi
authors.forename: Yves
authors.initials: Y
authors.lastname: Boucher
authors.forename: Xandra O
authors.initials: XO
authors.lastname: Breakefield
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D000818:Animals; D017364:Collagenases / Q000378:metabolism / Q000494:pharmacology; D024022:Fibrillar Collagens / Q000378:metabolism*; D015870:Gene Expression; D005822:Genetic Vectors / Q000493:pharmacokinetics; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000628:therapy / Q000821:virology*; D051379:Mice; D016513:Mice, SCID; D050130:Oncolytic Virotherapy / Q000379:methods*; D014018:Tissue Distribution; D014771:Virion / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D024022:Fibrillar Collagens; D049452:Green Fluorescent Proteins; D017364:Collagenases