A. H. Choi1, M. P. O’Leary1, J. Lu1, S. Kim1, N. G. Chen1,2, Y. Fong1,2 1City Of Hope National Medical Center,Department Of Surgery,Duarte, CA, USA 2Beckman Research Institute,Center For Gene Therapy, Department Of Hematology And Hematopoetic Cell Transplantation,Duarte, CA, USA
Introduction: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a higher recurrence rate and poor prognosis. Oncolytic viruses possess a natural selectively for replication and destruction of cancer cells, making oncolytic immunotherapy an attractive treatment modality for a disease such as TNBC that lacks effective targeted therapy. Here we describe a novel chimeric parapoxvirus that efficiently kills TNBC in vitro and in vivo.
Methods: A novel chimeric parapoxvirus (HOV-189) was generated in our lab and selected as a candidate virus through high-throughput screening. Cytotoxicity of HOV-189 was assayed in vitro in the TNBC cell line MDA-MB-468. Viral replication was examined through standard plaque assay. Orthotopic TNBC xenografts were generated by MDA-MB-468 implantation into the second and fourth mammary fat pads of athymic nude mice. Xenografts were treated with a single intratumoral injection of HOV-189 at 1×103 plaque-forming units (PFU), 1×104 PFU, or 1×105 PFU per tumor. Treatment response was assessed by measuring tumor size every 3 days.
Results: HOV-189 demonstrated dose-dependent cytotoxicity at low multiplicity of infection (MOI), with >90% cell death 6 days after treatment. Interestingly, the virus did not replicate efficiently in this cell line at low MOI. In vivo, statistically significant reductions in tumor size were observed two weeks after intratumoral injection of HOV-189 at doses as low as 1×103 PFU compared to saline-injected control tumors (P<0.01). This reduction in tumor size was sustained six weeks post-treatment without significant signs of viral toxicity.
Conclusion: HOV-189 demonstrated efficient cytotoxicity in vitro and potent anti-tumor effect in vivo at doses as low as 103 PFU. Taken together with its relatively poor in vitro replication, the anti-tumor effect observed in vivo may be secondary to HOV-189’s ability to prime the innate immune system against tumor rather than through direct oncolysis.