VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents

Speaker: 林子華

Commentator: 陳舜華 老師

Time: Dec.17, 2003, 14:00~15:00

Place: Room 601

Abstract:

      Oncolytic virus has been developed for cancer therapy, which would replicate preferentially in malignant cells, has the ability to treat disseminated metastasis, and ultimately be cleared by the patients. Previous approaches consist of altering virus tropism by modifying viral surface antigens or by expressing toxic gene product with tissue-specific promoter, or using selected viruses for their ability to replicate preferentially in functional-deficiency tumor cells (1). Vesicular stomatitis virus (VSV), an enveloped, negative-sense RNA virus exquisitely sensitive to treatment with interferon (IFN), has been used as a replication-competent oncolytic virus for the treatment of IFN non-responsive tumors (2). The attenuated VSV strains, AV1 and AV2, which were found to induce IFN-alpha 20~50-fold more than wild-type (WT) VSV, differed from the WT strain in their M protein’s sequence. The authors present evidence that the WT VSV M protein can block the nuclear transport of IFN mRNA, thus the cellular anti-viral activity is inhibited. Since the mutant M protein has lost this function, these attenuated strains are selectively attenuated in IFN responsive cells, but highly lytic in 80% of human tumor cell lines tested. In a xenograft model of human ovarian cancer and in an immune competent mouse model of metastatic colon cancer, both AV1 and AV2 effected completely and durable cures in the majority of treated animals when delivered systematically (3). These results suggest that these attenuated VSV strains that trigger antiviral responses will have a significantly improved therapeutic potential for the treatment of IFN non-responsive cancer.  

References:

1.        Norman, K.L., Farassati, F., and Lee P.W. 2001. Oncolytic virus and cancer therapy. Cytokine Growth Factor Rev. 12, 271-282.

2.        Stojdl, D.F., Lighty, B., Knowles S., Marius R., Atkins H., Sonenberg N., Bell J.C. 2000 Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus. Nat. Med. 6, 821–825.

3.        Stojdi, D.F., Lichty, B.D., tenOever, B.R., Paterson, J.M., Power, A.T., Knowles, S., Marious, R., Reynard, J., Atkins, H., Brown, E.G., Dulbin, R.K., Durbin, J.E., Hiscott, J., and Bell, C. 2003. VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents. Cancer cell 4, 263-275