Effective treatment of an orthotopic xenograft model of human glioblastoma using an EGFR-retargeted oncolytic herpes simplex virus.
Glioblastoma multiforme (GBM) remains an untreatable human brain malignancy. Despite promising preclinical studies using oncolytic herpes simplex virus (oHSV) vectors, efficacy in patients has been limited by inefficient virus replication in tumor cells. This disappointing outcome can be attributed in part to attenuating mutations engineered into these viruses to prevent replication in normal cells. Alternatively, retargeting of fully replication-competent HSV to tumor-associated receptors has the potential to achieve tumor specificity without impairment of oncolytic activity. Here, we report the establishment of an HSV retargeting system that relies on the combination of two engineered viral glycoproteins, gD and gB, to mediate highly efficient HSV infection exclusively through recognition of the abundantly expressed epidermal growth factor receptor (EGFR) on glioblastoma cells. We demonstrate efficacy in vitro and in a heterotopic tumor model in mice. Evidence for systemically administered virus homing to the tumor mass is presented. Treatment of orthotopic primary human GBM xenografts demonstrated prolonged survival with up to 73% of animals showing a complete response as confirmed by magnetic resonance imaging. Our study describes an approach to HSV retargeting that is effective in a glioma model and may be applicable to the treatment of a broad range of tumor types.
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Hiroaki
H
Uchida
Marco
M
Marzulli
Kenji
K
Nakano
William F
WF
Goins
Janet
J
Chan
Chang-Sook
CS
Hong
Lucia
L
Mazzacurati
Ji Young
JY
Yoo
Amy
A
Haseley
Hiroshi
H
Nakashima
Hyunjung
H
Baek
Heechung
H
Kwon
Izumi
I
Kumagai
Masahide
M
Kuroki
Balveen
B
Kaur
E Antonio
EA
Chiocca
Paola
P
Grandi
Justus B
JB
Cohen
Joseph C
JC
Glorioso
D000818:Animals; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D006224:Cricetinae; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D005822:Genetic Vectors; D005909:Glioblastoma / Q000628:therapy*; D019073:HT29 Cells; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D010957:Plasmids; D011995:Recombination, Genetic; D018139:Simplexvirus / Q000235:genetics* / Q000502:physiology; D016896:Treatment Outcome; D014709:Vero Cells; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D066246:ErbB Receptors