Disease indication: Glioblastoma, Lung Cancer, Breast Cancer and other Cancers with Cancer Stem Cells
Drug format: Oncolytic Virus
Drug class: First-in class
Research stage and Preliminary data:
1st Generation – Zika Virus (ZIKV)
- In vivo: In mouse models of glioma, ZIKV treatment prolongs median survival by up to 18 days and cures 40-50% of mice (see data below).
- Human: Studies in cell lines and cancer stem cells are ongoing.
2nd Generation – Attenuated ZIKV (E218A)
- In vitro studies in Glioblastoma Stem Cells (GSCs): ZIKV-E218A alone killed GSCs and had greater antitumor efficacy in combination with the standard-of-care temozolomide. ZIKV-∆3’UTR, based on a live attenuated vaccine candidate, is also highly effective in GSCs.
Figure: Mouse models of glioma treated with ZIKV show greater survival compared to control.
Glioblastoma Multiforme (GBM) is a lethal form of brain cancer that is currently treated by surgical resection followed by chemotherapy and radiation. These treatments are ineffective and inevitably GBM recurs because glioblastoma stem cells (GSCs) repopulate the tumor. Local treatments with oncolytic viruses can kill GSCs. However, the current oncolytic virus approaches also kill neighboring non-tumor brain cells.
Keywords: Oncolytic virus, Glioblastoma Multiforme (GBM), Zika Virus, Cancer Stem Cells
Mode of action:
The Diamond and Chheda labs have devised a Zika-based oncolytic virus technology that targets GSCs with minimal off-target effects in the adult brain. Zika infects and kills the neural progenitor cells that make up GSCs. The invention leverages this specific cytotoxic action to kill GSCs in glioblastoma. To improve on safety further, the inventors also devised immune sensitized versions of Zika (ZIKV-E218A and ZIKV-∆3’UTR), which should reduce the chance of systemic infection. Also, ZIKV-E218A has synergistic effects with the standard-of-care temozolomide and has potent antitumor activity. In addition, Zika treatment could potentially be applied to other solid tumors that are renewed by cancer stem cells.
Greater safety –
- Zika has limited effects on healthy brain cells making it potentially safer than the current oncolytic virus approaches.
- The attenuated Zika variant has similar efficacy in killing GSCs with lower potential for toxicity to surrounding healthy neural cells.
Unmet medical need – Current glioblastoma treatments are ineffective and only extend life by 1-2 years. This technology could potentially improve survival for GBM patients.
Synergy with current standard-of-care chemotherapy – A combination of Zika and temozolomide effectively kills GSCs and could potentially prevent recurrence.
Patent status – Provisional patent application filed
Publications – Zhu, Z., Gorman, M. J., McKenzie, L. D., Chai, J. N., Hubert, C. G., Prager, B. C., … & Tycksen, E. (2017). Zika virus has oncolytic activity against glioblastoma stem cells. Journal of Experimental Medicine, 214(10), 2843-2857.
Figure: Survival curves showing 40-50% survival in glioma mouse models treated with ZIKV.