Combination gene therapy using multiple immunomodulatory genes transferred by a defective infectious single-cycle herpes virus in squamous cell cancer Journal Article
| Authors: | Kim, S. H.; Carew, J. F.; Kooby, D. A.; Shields, J.; Entwisle, C.; Patel, S.; Shah, J. P.; Fong, Y. |
| Article Title: | Combination gene therapy using multiple immunomodulatory genes transferred by a defective infectious single-cycle herpes virus in squamous cell cancer |
| Abstract: | Herpes simplex type 2-defective infectious single-cycle (DISC) viruses are attenuated viruses that were originally produced as viral vaccines; however, these viruses are also efficient gene transfer vehicles. The main goals of this study were to examine determinants of the gene transfer by using DISC virus for squamous cancer and to evaluate the antitumoral efficacy of vaccination with tumor cells modified by DISC viruses carrying a combination of immunomodulatory genes (interleukin-2 (IL-2), granulocyte-macrophage colony-stimulating factor (GM-CSF), B7-1) in a model of squamous cell cancer (SCCVII) in C3H/HeJ mice. SCCVII cells transduced by DISC viruses (multiplicity of infection of 10) carrying the IL-2 or GM-CSF gene produced nanogram quantities of IL-2 or GM-CSF per 106 cells. Irradiated (5,000 cGy, 10,000 cGy) cells secreted levels of GM-CSF or IL-2 that were comparable with nonirradiated cells. In vivo vaccination using tumor cells transduced ex vivo with DISC-IL2 or DISC-GMCSF resulted in protection against subsequent tumor challenge (P < .01), with DISC-GMCSF-transduced, irradiated tumor cells showing the greatest effects (P < .001). Marked growth arrest also was noted in established tumors after direct injection of DISC-GMCSF (P < .001). These data demonstrate that (a) DISC virus is capable of efficient gene transfer, (b) GM-CSF-secreting genetically modified tumor vaccine protects against tumor cell challenge and suppresses tumor growth, and (c) intratumoral injection of DISC-GMCSF significantly suppresses the growth of established tumors. These results not only confirm clinically relevant gene transfer but also demonstrate that the gene transfer is an effective anti-cancer therapy. |
| Keywords: | controlled study; disease-free survival; squamous cell carcinoma; nonhuman; flow cytometry; cd8-positive t-lymphocytes; animal cell; mouse; animals; mice; interleukin 2; granulocyte macrophage colony stimulating factor; animal model; tumor cells, cultured; cancer therapy; gene transfer; animalia; genetic vectors; cancer inhibition; cancer vaccines; cd4-positive t-lymphocytes; tumor cell; gene therapy; herpes virus; herpesviridae; immunomodulation; virus replication; tumor growth; tumor vaccine; herpes; interleukin-2; gene transfer techniques; mice, inbred c3h; neoplasms, squamous cell; granulocyte-macrophage colony-stimulating factor; defective viruses; squamous cell cancer; humans; female; priority journal; article; herpesvirus 2, human; defective infectious single-cycle virus; defective virus; papovaviridae |
| Journal Title: | Cancer Gene Therapy |
| Volume: | 7 |
| Issue: | 9 |
| ISSN: | 0929-1903 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2000-09-01 |
| Start Page: | 1279 |
| End Page: | 1285 |
| Language: | English |
| PUBMED: | 11023201 |
| PROVIDER: | scopus |
| DOI: | 10.1038/sj.cgt.7700231 |
| DOI/URL: | |
| Notes: | Export Date: 18 November 2015 -- Source: Scopus |
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