title: Hexon modification to improve the activity of oncolytic adenovirus vectors against neoplastic and stromal cells in pancreatic cancer.
abstract: Primary pancreatic carcinoma has an unfavourable prognosis and standard treatment strategies mostly fail in advanced cases. Virotherapy might overcome this resistance to current treatment modalities. However, data from clinical studies with oncolytic viruses, including replicating adenoviral (Ad) vectors, have shown only limited activity against pancreatic cancer and other carcinomas. Since pancreatic carcinomas have a complex tumor architecture and frequently a strong stromal compartment consisting of non-neoplastic cell types (mainly pancreatic stellate cells = hPSCs) and extracellular matrix, it is not surprising that Ad vectors replicating in neoplastic cells will likely fail to eradicate this aggressive tumor type. Because the TGFβ receptor (TGFBR) is expressed on both neoplastic cells and hPSCs we inserted the TGFBR targeting peptide CKS17 into the hypervariable region 5 (HVR5) of the capsid protein hexon with the aim to generate a replicating Ad vector with improved activity in complex tumors. We demonstrated increased transduction of both pancreatic cancer cell lines and of hPSCs and enhanced cytotoxicity in co-cultures of both cell types. Surface plasmon resonance analysis demonstrated decreased binding of coagulation factor X to CKS17-modified Ad particles and in vivo biodistribution studies performed in mice indicated decreased transduction of hepatocytes. Thus, to increase activity of replicating Ad vectors we propose to relax tumor cell selectivity by genetic hexon-mediated targeting to the TGFBR (or other receptors present on both neoplastic and non-neoplastic cells within the tumor) to enable replication also in the stromal cell compartment of tumors, while abolishing hepatocyte transduction, and thereby increasing safety.
authors.affiliation: Department of Gene Therapy, Ulm University, Ulm, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Lucas
authors.affiliation: Univ. Paris-Sud, Orsay Cedex, France and CNRS UMR 8203, Institut Gustave Roussy, Villejuif Cedex, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Benihoud
authors.affiliation: Univ. Paris-Sud, Orsay Cedex, France and CNRS UMR 8203, Institut Gustave Roussy, Villejuif Cedex, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Vigant
authors.affiliation: Institute of Pharmacology of Natural Products & Clinical Pharmacology, Ulm University.
authors.forename: Christoph Q
authors.initials: CQ
authors.lastname: Schmidt
authors.affiliation: Institute of Pharmacology of Natural Products & Clinical Pharmacology, Ulm University, Ulm, Germany; Tierforschungszentrum, Ulm University, Ulm, Germany.
authors.forename: Christoph Q Andreas
authors.initials: CQ
authors.lastname: Schmidt
authors.affiliation: Tierforschungszentrum, Ulm University, Ulm, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Wortmann
authors.affiliation: Department of Clinical Chemistry, Ulm University, Ulm, Germany.
authors.forename: Max G
authors.initials: MG
authors.lastname: Bachem
authors.affiliation: Institute of Pharmacology of Natural Products & Clinical Pharmacology, Ulm University, Ulm, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Simmet
authors.affiliation: Department of Gene Therapy, Ulm University, Ulm, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kochanek
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D036022:Capsid Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein / Q000378:metabolism; D005170:Factor X / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics* / Q000378:metabolism; D022781:Hepatocytes / Q000473:pathology / Q000821:virology; D006801:Humans; D007075:Immunoglobulin M / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D050504:Oncolytic Viruses / Q000235:genetics* / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology* / Q000628:therapy / Q000821:virology; D058954:Pancreatic Stellate Cells / Q000378:metabolism; D015202:Protein Engineering; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D017154:Stromal Cells / Q000821:virology; D014161:Transduction, Genetic; D056189:Viral Tropism; D014779:Virus Replication
chemical_list: D036022:Capsid Proteins; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D007075:Immunoglobulin M; D018125:Receptors, Transforming Growth Factor beta; C018315:hexon capsid protein, Adenovirus; D005170:Factor X; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II