Use of a vaccine strain of measles virus genetically engineered to produce carcinoembryonic antigen as a novel therapeutic agent against glioblastoma multiforme.
Despite the most aggressive medical and surgical treatments, glioblastoma multiforme remains incurable with a median survival of <1 year. We investigated the antitumor potential of a novel viral agent, an attenuated strain of measles virus (MV), derived from the Edmonston vaccine lineage, genetically engineered to produce carcinoembryonic antigen (CEA). CEA production as the virus replicates can serve as a marker of viral gene expression. Infection of a variety of glioblastoma cell lines including U87, U118, and U251 at MOIs 0.1, 1, and 10 resulted in significant cytopathic effect consisting of excessive syncycial formation and massive cell death at 72-96 h from infection. terminal deoxynucleotidyltransferase-mediated nick end labeling assays demonstrated the mechanism of cell death to be predominantly apoptotic. The efficacy of this approach in vivo was examined in BALB/c nude mice by using both s.c. and intracranial orthotopic U87 tumor models. In the s.c. U87 model, mice with established xenografts were treated with a total dose of 8 x 10(7) plaque forming units of MV-CEA, administered i.v. Mice treated with UV light inactivated MV, and untreated mice with established U87 tumors were used as controls. There was statistically significant regression of s.c. tumors (P < 0.001) and prolongation of survival (P = 0.007) in MV-CEA treated animals compared with the two control groups. In the intracranial orthotopic U87 model, there was significant regression of intracranial U87 tumors treated with intratumoral administration of MV-CEA at a total dose of 1.8 x 10(6) plaque forming units as assessed by magnetic resonance image (P = 0.002), and statistically significant prolongation of survival as compared with mice that received UV-inactivated virus and untreated mice (P = 0.02). Histological examination of brains of MV-CEA-treated animals revealed complete regression of the tumor with the presence of a residual glial scar and reactive changes, mainly presence of hemosiderin-laden macrophages. In addition, CEA levels in the peripheral blood in both the s.c. and orthotopic models increased before tumor regression, indicating viral gene expression, and returned to normal when the tumors regressed. Ifnar(ko) CD46 Ge transgenic mice, susceptible to MV infection, were used to assess central nervous system toxicity of MV-CEA. Intracranial administration of MV-CEA into the caudate nucleus of Ifnar(ko) CD46 Ge did not result in clinical neurotoxicity. Pathologic examination demonstrated limited microglial infiltration surrounding the injection site. In summary, MV-CEA has potent antitumor activity against gliomas in vitro, as well as in both s.c. and orthotopic U87 animal models. Monitoring CEA levels in the serum can serve as a low-risk method of detecting viral gene expression during treatment, and could allow dose optimization and individualization of treatment.
Department of Neurosurgery, Mayo Clinic, Rochester, Minnesota 55905, USA.
Loi K
LK
Phuong
Cory
C
Allen
Kah-Whye
KW
Peng
Caterina
C
Giannini
Suzanne
S
Greiner
Cynthia J
CJ
TenEyck
Prasanna K
PK
Mishra
Slobodan I
SI
Macura
Stephen J
SJ
Russell
Evanthia C
EC
Galanis
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D017209:Apoptosis / Q000502:physiology; D001932:Brain Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D019496:Cancer Vaccines / Q000009:adverse effects / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D002272:Carcinoembryonic Antigen / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics / Q000276:immunology; D002522:Chlorocebus aethiops; D005818:Genetic Engineering / Q000379:methods; D005909:Glioblastoma / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D006801:Humans; D008458:Measles Vaccine / Q000009:adverse effects / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D008459:Measles virus / Q000235:genetics / Q000276:immunology*; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008822:Mice, Transgenic; D014407:Tumor Cells, Cultured; D014709:Vero Cells; D023041:Xenograft Model Antitumor Assays
D015703:Antigens, CD; C497857:CD46 protein, human; D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; C497859:Mcp protein, mouse; D008458:Measles Vaccine; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins