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In situ expression of soluble B7-1 in the context of oncolytic herpes simplex virus induces potent antitumor immunity.
- Source :
-
Cancer research [Cancer Res] 2001 Jan 01; Vol. 61 (1), pp. 153-61. - Publication Year :
- 2001
-
Abstract
- In vivo delivery of immunomodulatory genes is a promising strategy for solid tumor vaccination. A drawback is that it necessitates induction of a large effect from transgene expression in a small percentage of tumor cells. Although the B7 family is known to be the most potent of the costimulatory molecules, gene transduction of B7 alone has not been effective in inducing antitumor immunity in nonimmunogenic tumors by ex vivo methods, much less in vivo. We have developed a novel approach where a gene encoding soluble B7-1, a fusion protein of the extracellular domain of murine B7-1 and the Fc portion of human IgG1, is delivered to tumor cells in vivo in the context of an oncolytic replication-competent herpes simplex virus, and the gene product is secreted by tumor cells rather than expressed on the cell surface. Defective herpes simplex virus vectors containing the B7-1-immunoglobulin (B7-1-Ig) fusion transgene (dvB7Ig) were generated using G207 as a helper virus and tested in the poorly immunogenic murine neuroblastoma, Neuro2a, in syngeneic A/J mice. Intraneoplastic inoculation of dvB7Ig/G207 at a low titer successfully inhibited the growth of established s.c. tumors, despite the expression of B7-1-Ig being detected in only 1% or fewer of tumor cells at the inoculation site, and prolonged the survival of mice bearing intracerebral tumors. Immunohistochemistry of dvB7Ig/G207-inoculated tumors revealed a significant increase in CD4+ and CD8+ T-cell infiltration compared with control tumors inoculated with defective vector expressing alkaline phosphatase (dvAP/G207). The antitumor effect of dvB7Ig/G207 was not manifested in athymic mice. In vivo depletion of immune cell subsets in A/J mice further revealed that CD8+ T cells, but not CD4+ T cells, were required. Animals cured of their tumors by dvB7Ig/G207 treatment were protected against rechallenge with a lethal dose of Neuro2a cells but not SaI/N cells. The results demonstrate that the use of soluble B7-1 for immune gene therapy is a potent and clinically applicable means of in situ cancer vaccination.
- Subjects :
- Animals
Antigens, Differentiation immunology
B7-1 Antigen biosynthesis
Brain Neoplasms genetics
Brain Neoplasms immunology
Brain Neoplasms therapy
CD4-Positive T-Lymphocytes immunology
CD8-Positive T-Lymphocytes immunology
Cancer Vaccines genetics
Cancer Vaccines immunology
Cell Division immunology
Chlorocebus aethiops
Female
Genetic Therapy methods
Genetic Vectors genetics
Herpesvirus 1, Human genetics
Immunoconjugates genetics
Immunoconjugates immunology
Immunoglobulin Fc Fragments biosynthesis
Immunoglobulin Fc Fragments genetics
Immunoglobulin Fc Fragments immunology
Immunoglobulin G biosynthesis
Immunotherapy, Active methods
Macrophages immunology
Mice
Mice, Inbred A
Mice, Inbred BALB C
Mice, Nude
Neuroblastoma immunology
Neuroblastoma pathology
Neuroblastoma therapy
Recombinant Fusion Proteins biosynthesis
Skin Neoplasms immunology
Skin Neoplasms pathology
Skin Neoplasms therapy
Solubility
Transgenes
Vero Cells
B7-1 Antigen genetics
B7-1 Antigen immunology
Immunoglobulin G genetics
Immunoglobulin G immunology
Recombinant Fusion Proteins genetics
Recombinant Fusion Proteins immunology
Subjects
Details
- Language :
- English
- ISSN :
- 0008-5472
- Volume :
- 61
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 11196154