Expression of FMS-like tyrosine kinase 3 ligand by oncolytic herpes simplex virus type I prolongs survival in mice bearing established syngeneic intracranial malignant glioma.
BACKGROUND
Glioblastoma is a fatal brain tumor in needing urgent effective therapy. Treatments with both oncolytic viruses and immunotherapy have shown preclinical efficacy and clinical promise. We sought to exploit possible synergies between oncolytic herpes simplex virus type 1 (oHSV-1) infection of intracranial gliomas and delivery of immune-stimulating fms-like tyrosine kinase 3 ligand (Flt3L) by engineering a herpes vector to express the cytokine.


OBJECTIVE
To construct an oHSV-1 vector that expresses high levels of Flt3L and examine its antiglioma efficacy in an immunocompetent murine model.


METHODS
G47Δ and a bacterial artificial chromosome system were used to generate a novel oHSV-1, termed G47Δ-Flt3L, expressing Flt3L. Cytokine expression was confirmed, and G47Δ-Flt3L was injected intratumorally into established intracranial CT-2A gliomas in syngeneic C57/Bl6 mice. Animals were followed for survival and assessed by the Kaplan-Meier method.


RESULTS
G47Δ-Flt3L expressed high levels of Flt3L in culture. Expression of Flt3L affected neither viral replication nor had a cytotoxic effect on CT2A glioma cells. Direct inoculation into intracerebral CT2A glioma cells resulted in high levels of detectable Flt3L in mouse blood and was superior to parental G47Δ in prolonging survival in glioma-bearing animals.


CONCLUSIONS
Treatment with G47Δ-Flt3L improves survival of glioma-bearing mice.
Simches Brain Tumor Research Laboratories, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Zachary
Z
Barnard
Hiroaki
H
Wakimoto
Cecile
C
Zaupa
Anoop P
AP
Patel
Jacquelyn
J
Klehm
Robert L
RL
Martuza
Samuel D
SD
Rabkin
William T
WT
Curry
D000818:Animals; D001932:Brain Neoplasms / Q000628:therapy*; D022202:Chromosomes, Artificial, Bacterial; D004195:Disease Models, Animal; D005910:Glioma / Q000628:therapy*; D018259:Herpesvirus 1, Human; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D050130:Oncolytic Virotherapy / Q000379:methods*; D014185:Transplantation, Isogeneic; D051941:fms-Like Tyrosine Kinase 3 / Q000096:biosynthesis*
D051941:fms-Like Tyrosine Kinase 3