A capsid-modified, conditionally replicating oncolytic adenovirus vector expressing TRAIL Leads to enhanced cancer cell killing in human glioblastoma models.
Glioblastoma multiforme (GBM) is the most aggressive brain tumor, and patients rarely survive for more than 2 years. Gene therapy may offer new treatment options and improve the prognosis for patients with GBM. Adenovirus-mediated gene therapy strategies for brain tumors have been limited by inefficient gene transfer due to low expression of the adenovirus serotype 5 (Ad5) receptor. We have used an adenovirus vector that specifically replicates in tumor cells and uses an Ad5 capsid and the adenovirus serotype (Ad35) fiber for efficient infection of malignant tumor cells. This vector also expresses adenovirus E1A and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in a tumor-specific manner. Here, we show that this oncolytic vector (Ad5/Ad35.IR-E1A/TRAIL) efficiently infects the GBM tumor cell lines SF767, T98G, and U-87 MG. Tumor cell killing was markedly enhanced with Ad5/Ad35.IR-E1A/TRAIL compared with wild-type Ad5 and Ad35 virus or Ad5/Ad35.IR-E1A- vectors without TRAIL expression in vitro. In vivo experiments using s.c. xenografted U-87 MG cells in NOD/SCID mice showed a significant growth delay of tumors after i.t. injection of Ad5/Ad35.IR-E1A/TRAIL, whereas adenovirus wild-type injections showed only marginal or no effect. Our findings indicate that the use of a capsid-modified adenoviral vector, in combination with TRAIL expression, is a promising novel approach for gene therapy of glioblastoma.
Wohlfahrt
Martin E
ME
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA.
Beard
Brian C
BC
Lieber
André
A
Kiem
Hans-Peter
HP
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity / Q000502:physiology*; D000257:Adenoviridae Infections / Q000378:metabolism / Q000473:pathology / Q000821:virology; D017500:Adenovirus E1A Proteins / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002213:Capsid / Q000378:metabolism*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology / Q000628:therapy* / Q000821:virology*; D006801:Humans; D051916:Membrane Cofactor Protein / Q000096:biosynthesis / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D050130:Oncolytic Virotherapy / Q000379:methods*; D011991:Receptors, Virus / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis / Q000235:genetics*; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D017500:Adenovirus E1A Proteins; C568771:CLMP protein, human; C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D051916:Membrane Cofactor Protein; D011991:Receptors, Virus; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human