title: Engineered adenoviruses combine enhanced oncolysis with improved virus production by mesenchymal stromal carrier cells.
abstract: Oncolytic viruses have demonstrated in pre-clinical and clinical studies safety and a unique pleiotropic activity profile of tumor destruction. Yet, their delivery suffers from virus inactivation by blood components and sequestration to healthy tissues. Therefore, mesenchymal stromal cells (MSCs) have been applied as carrier cells for shielded virus delivery to tumors after ex vivo infection with oncolytic viruses. However, infection and particle production by MSCs have remained unsatisfying. Here, we report engineered oncolytic adenoviruses (OAds) for improved virus production and delivery by MSCs. OAds are uniquely amenable to molecular engineering, which has facilitated improved tumor cell destruction. But for MSC-mediated regimens, OAd engineering needs to achieve efficient infection and replication in both MSCs and tumor cells. We show that an Ad5/3 chimeric OAd capsid, containing the adenovirus serotype 3 cell-binding domain, strongly increases the entry into human bone marrow-derived MSCs and into established and primary pancreatic cancer cells. Further, we reveal that OAd with engineered post-entry functions-by deletion of the anti-apoptotic viral gene E1B19K or expression of the death ligand TRAIL--markedly increased virus titers released from MSCs, while MSC migration was not hampered. Finally, these virus modifications, or viral expression of FCU1 for local 5-FC prodrug activation, improved tumor cell killing implementing complementary cytotoxicity profiles in a panel of pancreatic cancer cell cultures. Together, our study establishes post-entry modification of OAd replication for improving virus delivery by carrier cells and suggests a panel of optimized OAds for future clinical development in personalized treatment of pancreatic cancer.
authors.affiliation: Oncolytic Adenovirus Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Hammer
authors.affiliation: Molecular OncoSurgery, German Cancer Research Center (DKFZ) and Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Adam
authors.initials: A
authors.lastname: Kazcorowski
authors.affiliation: Molecular OncoSurgery, German Cancer Research Center (DKFZ) and Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Oncolytic Adenovirus Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Behr
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schemmer
authors.affiliation: Molecular OncoSurgery, German Cancer Research Center (DKFZ) and Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Herr
authors.affiliation: Oncolytic Adenovirus Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Nettelbeck
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D005822:Genetic Vectors; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D057285:Precision Medicine; D014779:Virus Replication / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
keywords: TRAIL; carrier cells; oncolytic adenovirus; pancreatic cancer; prodrug activation