Effect of HSV-IL12 Loaded Tumor Cell-Based Vaccination in a Mouse Model of High-Grade Neuroblastoma.
We designed multimodal tumor vaccine that consists of irradiated tumor cells infected with the oncolytic IL-12-expressing HSV-1 virus, M002. This vaccine was tested against the syngeneic neuroblastoma mouse model Neuro 2a injected into the right caudate nucleus of the immunocompetent A/J mice. Mice were vaccinated via intramuscular injection of multimodal vaccine or uninfected irradiated tumor cells at seven and 14 days after tumor establishment. While there was no survival difference between groups vaccinated with cell-based vaccine applied following tumor injection, a premunition prime/boost vaccination strategy produced a significant survival advantage in both groups and sustained immune response to an intracranial rechallenge of the same tumor. The syngeneic but unrelated H6 hepatocellular tumor cell line grew unrestricted in vaccinated mice, indicative of vaccine-mediated specific immunity to Neuro 2a tumors. Longitudinal analyses of tumor-infiltrating lymphocytes revealed a primary adaptive T cell response involving both CD4+ and CD8+ T cell subsets. Spleen cell mononuclear preparations from vaccinated mice were significantly more cytotoxic to Neuro 2a tumor cells than spleen cells from control mice as demonstrated in a four-hour in vitro cytotoxicity assay. These results strongly suggest that an irradiated whole cell tumor vaccine incorporating IL-12-expressing M002 HSV can produce a durable, specific immunization in a murine model of intracranial tumor.
Department of Surgery, The University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA.
David F
http://orcid.org/0000-0003-3548-0887
DF
Bauer
Department of Medicine, The University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA.
Larisa
L
Pereboeva
Department of Surgery, The University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA.
G Yancey
GY
Gillespie
Department of Biostatistics and Preventive Medicine, The University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA.
Gretchen A
GA
Cloud
Department of Medicine, The University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA.
Osama
http://orcid.org/0000-0003-3842-9825
O
Elzafarany
Department of Medicine, The University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA.
Catherine
C
Langford
Department of Surgery, The University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA.
James M
http://orcid.org/0000-0001-7457-7329
JM
Markert
Department of Medicine, The University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA.
Lawrence S
http://orcid.org/0000-0001-7180-0994
LS
Lamb
D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D005822:Genetic Vectors / Q000235:genetics; D018259:Herpesvirus 1, Human / Q000235:genetics*; D007111:Immunity, Cellular / Q000276:immunology; D016130:Immunophenotyping; D018664:Interleukin-12 / Q000235:genetics*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D060787:Neoplasm Grading; D009447:Neuroblastoma / Q000235:genetics* / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D050504:Oncolytic Viruses / Q000235:genetics; D010641:Phenotype; D016019:Survival Analysis; D016896:Treatment Outcome; D014611:Vaccination
D019496:Cancer Vaccines; D018664:Interleukin-12