Immunotherapeutic potential of DISC-HSV and OX40L in cancer.
Several vectors, viral and bacterial, have been developed over the past few years for means of generating an effective antitumor immune response. We have developed and studied a "model for immunotherapy" using a viral vector disabled infectious single cycle-herpes simplex virus (DISC-HSV), which efficiently transduces various tumor cell lines and offers a useful vehicle for the further development of cell-based vaccines. The immunotherapeutic potential of DISC-HSV encoding granulocyte macrophage colony stimulating factor (GM-CSF) was demonstrated in a number of murine carcinoma models, leading to complete regression of well-established tumors in up to 70% of the mice. Moreover, the therapeutic potential of DISC-HSV-GM-CSF was significantly enhanced when used in combination therapy with either OX40L or dendritic cells (DC), even in a poorly immunogenic tumor model. The ability of this vector to accept large gene inserts, its good safety profile, its ability to undergo only a single round of infection, the inherent viral immunostimulatory properties and its ability to infect various tumor cell lines efficiently, make DISC-HSV an ideal candidate vector for immunotherapy. The DISC- CT-26 tumor model was used to investigate the mechanisms associated with immunotherapy induced tumor rejection. Although CTL induction, was positively correlated with regression, MHC class I down regulation and accumulation of immature Gr1+ myeloid cells were shown to be the main immuno-suppressor mechanisms operating against regression and associated with progressive tumor growth. The CTL response was associated with the immuno-dominant AH-1 peptide of the retroviral glycoprotein gp70. This model of immunotherapy has provided an opportunity to dissect further the immunological events associated with tumor-rejection and escape. Since other antigens may be important in initiating tumor rejection, we have investigated the expression of MTA-1, an antigen that appears to be expressed widely in human and murine tumors. The immunogenicity of MTA-1 was studied and its potential as a tumor rejection antigen is under investigation.
School of Biomedical and Natural Sciences, Nottingham Trent University, Clifton Lane, Nottingham, NG118NS, UK.
Deepak P
DP
Assudani
Murrium
M
Ahmad
Geng
G
Li
Robert C
RC
Rees
Selman A
SA
Ali
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D002277:Carcinoma; D003713:Dendritic Cells; D005822:Genetic Vectors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology; D006655:Histone Deacetylases / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D053278:OX40 Ligand; D012097:Repressor Proteins / Q000276:immunology*; D018139:Simplexvirus / Q000276:immunology* / Q000472:pathogenicity*; D015534:Trans-Activators; D019139:Tumor Escape; D048069:Tumor Necrosis Factors / Q000276:immunology*
D000951:Antigens, Neoplasm; D008562:Membrane Glycoproteins; C089320:MTA1 protein, human; D053278:OX40 Ligand; D012097:Repressor Proteins; C089251:TNFSF4 protein, human; D015534:Trans-Activators; D048069:Tumor Necrosis Factors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006655:Histone Deacetylases