|Istvan Fodor, PhD|
|Professor, Biochemistry and Microbiology|
|School of Medicine|
|University Faculty Profile|
Cancer. We have used recombinant vaccinia virus expressing tumor suppressors, cytokines and suicide genes to examine the biological effects in human and murine glioma cells. We found that glioma cells infected with rVV-p53 exhibited growth inhibition and apoptosis. In an ex vivo experiment, mice implanted with vaccinia virus-infected rat glioma cells remained tumor free until the end of the observation period. Animals implanted with non-infected cells rapidly died from cancer. The oncolytic effect was greater with the virus expressing tumor suppressor p53. Local treatment of glioma with VV vector, and especially rVV-p53, greatly reduced the tumor growth in mice. The high dose virus treatment did not induce disease symptoms in immuno-deficient athymic mice. Replication-deficient VV vectors for gene delivery are also capable of prolonged expression of transgenes in cultured cells and animals. Furthermore, we showed that the recombinant virus was an effective agent for bladder tumor therapy in an orthotopic model of C57/Bl6 mice, and for immunotherapy of glioma in combination with a low dose of vaccinia expressing interleukin-2 and interleukin-12. Combination of tumor suppressor therapy with immunotherapy was found to be superior compared with a single modality treatment, and sensitization of radiation treatment prior to VV-mediated tumor suppressor gene therapy could be a promising alternative strategy to control the cancer development.
Cancer imaging. To monitor the tumor infection and dissemination of vaccinia virus in real time in vivo, we constructed a recombinant vaccinia virus VV-RG expressing fused reporter genes of Renilla luciferase and jellyfish green fluorescent protein. Gene expression can be detected using two highly sensitive methods: low light video imaging and fluorescence microscopy. Using this virus we found that VV can be an effective agent for non-invasive imaging of solid tumors and metastases. These studies, combined with searches of reliable tumor markers, will be extended to elucidation of mechanisms associated with the development of health disparities in cancer.
Vaccines. To improve the safety features of vaccinia virus vaccines, we constructed a Lister vaccine derivative lacking the genes for INF ?/? and INF? receptor homologs involved in evasion of immune response. The mutant is similar to the parental strain regarding gene expression, virus production, and immunogenicity in mice, but it is less pathogenic and thus, safer for human vaccinations. In collaborative studies with Dr. W. Langridge, we demonstrated that vaccinia virus is a safe and feasible system for delivery of islet autoantigens and IL-10 for both prevention and therapy of autoimmune diabetes in prediabetic NOD mice. In future studies we will explore the possible mechanisms of developing health disparities in diabetic patients.
1. C-F Hung, Y-C Tsai1,LHe, G Coukos, I Fodor, L Qin, H Levitsky and T-C Wu. Vaccinia virus preferentially infects and controls human and murine ovarian tumors in mice. Gene Therapy, 2009 (in press).
2. W. Langridge, B. Denes and I. Fodor. Cholera toxin B subunit enhancement of vaccines for infectious and autoimmune diseases (review). Key Opinions, 2009 (submitted).
3. J.R. Tysome, A. Briat1, T. Timiryasova, I. Fodor, et al., Lister strain of vaccinia virus armed with endostatin-angiostatin fusion gene as a novel therapeutic agent for human pancreatic cancer. Gene Therapy, 2009 (accepted).
4. B. Denes, N. Fodor, A Obenaus, and I. Fodor. Engineering oncolytic vaccinia viruses for non-invasive optical imaging of tumors. Open Biotechnol. J 2: 252-261, 2008.
5. C-F. Hung, Y-C Tsai, L. He, G Coukos, I Fodor, L Qin, H Levitsky and T-C Wu. Vaccinia virus preferentially infects and controls human and murine ovarian tumors in mice. Gene Therapy 14: 20?29, 2007
6. B. Denes, DS Gridley, N. Fodor, Z. Takatsy, TM Timiryasova, I. Fodor. Attenuation of a vaccine strain of vaccinia virus via inactivation of interferon viroceptor. J Gene Med 8: 814-823, 2006.
7. B. Denes, V. Krausova, N. Fodor, T. Timiryasova, D. Henderson, J. Hough, J. Yu, I. Fodor, WHR Langridge. Protection of NOD mice from Type 1 diabetes after oral inoculation with vaccinia viruses expressing adjuvanted islet autoantigens. J Immunother 28: 438?448, 2005.
8. GA Allen, B. Denes, I. Fodor, M. De Leon. Vaccinia virus infection and gene transduction in cultured neurons. Microbes and Infection 7: 1087?1096, 2005.
9. I. Fodor, T. Timiryasova, B. Denes, J. Yoshida, H. Ruckle, M. Lilly. Vaccinia virus-mediated p53 gene therapy of bladder cancer in an orthotopic murine model. J Urol 173, 604-609, 2005.
10. S. Umphress, T. Timiryasova, T. Arakawa, S. Hilliker, I. Fodor, W. LangridgeVaccinia virus mediated expression of human APC induces apoptosis in colon cancer cells. Transgenics, 4: 19-33, 2003.
11. T. Timiryasova, D.S. Gridley, B. Chen, M.L. Andres, R. Dutta-Roy, G. Miller, E.J.M. Bayeta, I. Fodor. Radiation enhances the anti-tumor effects of vaccinia-p53 gene therapy in glioma. Technol Cancer Res Treat, 2, 223-235, 2003.
12. B. Chen, T.M. Timiryasova, P. Haghighat, M.L. Andres, E.H. Kajioka, R. Dutta-Roy, D.S. Gridley, I. Fodor. Low-dose vaccinia virus-mediated cytokine gene therapy of glioma. J. Immunother, 24: 46-57, 2001. 13. T.M. Timiryasova,B. Chen, I. Fodor.Replication-deficient vaccinia virus gene therapy vector: evaluation of exogenous gene expression mediated by PUV-inactivated virus in glioma cells. J Gene Med, 3: 468-477, 2001.
14. B. Chen, T.M. Timiryasova, M.L. Andres, E.H. Kajioka, R. Dutta-Roy, D.S. Gridley, I. Fodor. Evaluation of combined vaccinia virus-mediated antitumor gene therapy with wild-type p53, IL-2 and IL-12 in a glioma model. Cancer Gene Ther, 7: 1437-1447, 2000.