Safety Study: Intraventricular Injection of a Modified Oncolytic Measles Virus into Measles-Immune, hCD46-Transgenic, IFNαRko Mice.
The modified Edmonston vaccine strain of measles virus (MV) has shown potent oncolytic efficacy against various tumor types and is being investigated in clinical trials. Our laboratory showed that MV effectively kills medulloblastoma tumor cells in both localized disease and when tumor cells are disseminated through cerebrospinal fluid (CSF). Although the safety of repeated intracerebral injection of modified MV in rhesus macaques has been established, the safety of administering MV into CSF has not been adequately investigated. In this study, we assessed the safety of MV-NIS (MV modified to express the human sodium iodide symporter protein) injected into the CSF of measles-immunized and measles virus-susceptible transgenic (CD46, IFNαRko) mice. Treated animals were administered a single intraventricular injection of 1 × 105or 1 × 106TCID50(50% tissue culture infective dose) of MV-NIS. Detailed clinical observation was performed over a 90-day period. Clinically, we did not observe any measles-related toxic effects or behavioral abnormality in animals of any treated cohort. The complete blood count and blood chemistry analysis results were found to be within normal range for all the cohorts. Histologic examination of brains and spinal cords revealed inflammatory changes, mostly related to the needle track; these resolved by day 21 postinjection. To assess viral biodistribution, quantitative RT-PCR to detect the measles virus N-protein was performed on blood and brain samples. Viral RNA was not detectable in the blood as soon as 2 days after injection, and virus cleared from the brain by 45 days postadministration in all treatment cohorts. In conclusion, our data suggest that a single injection of modified MV into the CSF is safe and can be used in future therapeutic applications.
1 Department of Neurological Surgery, Helen Diller Family Comprehensive Cancer Center, University of California , San Francisco, San Francisco, California.
Sangeet
S
Lal
2 Department of Molecular Medicine, Toxicology and Pharmacology Laboratory, Mayo Clinic, Rochester, Minnesota.
Kah-Whye
KW
Peng
2 Department of Molecular Medicine, Toxicology and Pharmacology Laboratory, Mayo Clinic, Rochester, Minnesota.
Michael B
MB
Steele
2 Department of Molecular Medicine, Toxicology and Pharmacology Laboratory, Mayo Clinic, Rochester, Minnesota.
Nathan
N
Jenks
1 Department of Neurological Surgery, Helen Diller Family Comprehensive Cancer Center, University of California , San Francisco, San Francisco, California.
Hong
H
Ma
1 Department of Neurological Surgery, Helen Diller Family Comprehensive Cancer Center, University of California , San Francisco, San Francisco, California.
Gary
G
Kohanbash
1 Department of Neurological Surgery, Helen Diller Family Comprehensive Cancer Center, University of California , San Francisco, San Francisco, California.
Joanna J
JJ
Phillips
1 Department of Neurological Surgery, Helen Diller Family Comprehensive Cancer Center, University of California , San Francisco, San Francisco, California.
Corey
C
Raffel
D000818:Animals; D005260:Female; D006801:Humans; D007276:Injections, Intraventricular; D008297:Male; D008457:Measles / Q000276:immunology / Q000628:therapy* / Q000821:virology; D008459:Measles virus / Q000472:pathogenicity*; D051916:Membrane Cofactor Protein / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000502:physiology*; D053633:Receptor, Interferon alpha-beta / Q000502:physiology*; D027981:Symporters / Q000502:physiology*; D000099209:Sodium-Iodide Symporters
D051916:Membrane Cofactor Protein; D053633:Receptor, Interferon alpha-beta; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C497859:Mcp protein, mouse
CSF injection of MV-NIS; biodistribution; measles virus; safety study