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Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Hammer, K; Kazcorowski, A; Liu, L; Behr, M; Schemmer, P; Herr, I; Nettelbeck, DM.
Engineered adenoviruses combine enhanced oncolysis with improved virus production by mesenchymal stromal carrier cells.
Int J Cancer. 2015; 137(4):978-990
Doi: 10.1002/ijc.29442
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- Co-authors Med Uni Graz
- Schemmer Peter
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- 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. © 2015 UICC.
- Find related publications in this database (using NLM MeSH Indexing)
- Adenoviridae - genetics
- Adenoviridae - metabolism
- Cell Line, Tumor -
- Genetic Vectors -
- Humans -
- Mesenchymal Stromal Cells - metabolism
- Oncolytic Virotherapy -
- Oncolytic Viruses - genetics
- Oncolytic Viruses - metabolism
- Pancreatic Neoplasms - genetics
- Pancreatic Neoplasms - pathology
- Pancreatic Neoplasms - therapy
- Precision Medicine -
- Virus Replication - genetics
- Xenograft Model Antitumor Assays -
- Find related publications in this database (Keywords)
- oncolytic adenovirus
- pancreatic cancer
- carrier cells
- prodrug activation
- TRAIL