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Istvan Fodor, PhD, D.Sc.: Research Interests

Cancer gene therapy

Gene therapy provides a significant opportunity to design novel strategies for the control and cure of cancer. The use of vaccinia virus (VV) vectors has become a new promising method of gene delivery and cancer gene therapy. The ability of VV to lyse cancer cells suggests that the virus itself has potential as an oncolytic agent. We use recombinant VV 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, while 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 although the anti-tumor effect is significantly lower than that of replication-competent viruses. Recently, we showed that the virus was an effective agent for bladder tumor therapy in an orthotopic model of C57/Bl6 mice. Immunotherapy with low dose of vaccinia mediated interleukin-2 and interleukin-12 also induced significant antitumor effect in a glioma model (See Figure 1). Combination of tumor suppressor therapy with immunotherapy was found to be superior compared with a single modality treatment. Furthermore, sensitization of radiation treatment prior to VV-mediated tumor suppressor gene therapy could be also a promising strategy.

Molecular virology

Analyzing early gene expression of UV-inactivated VV, we found that inactivated viruses can effectively infect and express transgenes in mammalian cells and thus, can be utilized for gene therapy purposes. To monitor the 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 (Rluc) and jellyfish green fluorescent protein (gfp). Gene expression can be detected using two highly sensitive methods: low light video imaging and fluorescence microscopy. Using this virus in several murine tumor models, we found that VV can be an effective agent for non-invasive imaging of solid tumors and metastases. To improve the safety features of VV vaccines we constructed a Lister vaccine derivative (vVV-RG8) lacking genes for INFα/β and INFγ receptor homologs involved in evasion of immune response. The mutant is similar to the parental strain regarding gene expression and virus production, as well as immunogenicity in mice. However, it is less pathogenic and thus, safer for human vaccinations (see Figure 2). To facilitate our VV-related studies a convenient new method of construction of recombinant VV was developed. The list of VV constructed in our lab over last decade is shown in Table.

Figure 1: Survival of bladder tumor-bearing mice after recombinant vaccinia virus therapy. (PDF)
Figure 2: Virulence of a vaccinia virus mutant (VV-RG8) lacking interferon-gamma receptor homolog in mice. (PDF)

Collection of Lister-derived recombinant vaccinia viruses constructed and maintained in our laboratory.

Recent publications

B. Dénes, DS Gridley, N. Fodor, Z. Takátsy, TM Timiryasova, I. Fodor. Attenuation of a vaccine strain of vaccinia virus via inactivation of interferon viroceptor. J Gene Med (in press).

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.

GA Allen, B. Denes, I. Fodor, M. De Leon. Vaccinia virus infection and gene transduction in cultured neurons. Microbes & Infection 7: 1087–1096, 2005.

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.

X Luo, ML Andres, TM Timiryasova, I. Fodor, JM Slater. DS Gridley. Radiation-enhanced endostatin gene expression and effects of combination treatment. Technol Cancer Res Treat. 4: 193-202, 2005.

DS Gridley, GM Miller, X Luo, JD Cao, TM Timiryasova, I. Fodor, JM Slater. Proton radiation and TNF alpha/Bax gene therapy for orthotopic C6 brain tumor in Wistar rats. Technol Cancer Res Treat. 3:217-227, 2004.

S. Umphress, T. Timiryasova, T. Arakawa, S. Hilliker, I. Fodor, W. Langridge Vaccinia virus mediated expression of human APC induces apoptosis in colon cancer cells. Transgenics, 4: 19-33, 2003

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.

Z. Boldogkoi, A. Bratincsak, I. Fodor. Evaluation of pseudorabies virus as a gene transfer vector and an oncolytic agent for human tumor cells. Anticancer Res, 22:2153-9, 2002.

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.

T.M. Timiryasova, B. Chen, N. Fodor, I Fodor. New methods for construction of recombinant vaccinia viruses using PUV-inactivated virus as a helper. Biotechniques, 31:534-540, 2001.

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.

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.

I. Fodor, L. Kucsera, N. Fodor, V. Pálfi and V. I. Grabko. Gene immunization of mice with plasmid DNA expressing rabies glycoprotein. Acta Veter Hung, 48: 229-236, 2000.

T.M. Timiryasova, J. Li, B. Chen, D.Chong, W. H. R. Langridge, D. S. Gridley, I. Fodor. Antitumor activity of vaccinia virus in glioma model. Oncol Res, 11: 133-144, 1999.

T.M. Timiryasova, B. Chen, P. Haghighat, I. Fodor. Vaccinia virus-mediated expression of wild-type p53 suppresses glioma cell growth and induces apoptosis. Intern J Oncol, 14: 845-854, 1999.