Evaluation Of A Novel Oncolytic Vaccinia Viruses Armed With MIL-21 For Treatment Of Breast Cancer

Background Breast cancer is the most common cancer in women of the world.Although the advanced surgery,chemotherapy,radiotherapy,hormonal and targeted therapy,has improved relapse-free survival in the adjuvant setting,30-40% of patients with breast cancer still die from a recurrence and metastasis of their breast cancer and make breast cancer the second leading cause of death from cancer among women in China.Therefore,new therapeutic agents for this disease are urgently needed.The new therapy should have a better selectivity for the tumor cells and multiple functional mechanisms.Moreover,it won’t have the antagonism to the existing conventional treatments.Replication selective oncolytic virus(RSOV)provides a new therapeutic approach for cancer therapy.RSOV can selectively kill cancer cells and replicate in tumor cells but not in normal cells.We created a new generation of oncolytic vaccinia virus,named VV△TK△N1L-RFP.This virus might have enhanced antitumour efficacy and a better safety.In the present study we aimed to evalute its oncolytic effect and biological safety in vitro and vivo.Objective To evaluate the efficacy of tumor-targeted oncolytic vaccinia virus(VV)vectors,VVΔTKΔN1L-RFP and VVΔTKΔN1L-m IL-21 for murine breast cancer,JC,TUBO and 4T1 in vitro and in vivo.Methods The effect of cytotoxicity of the viruses on JC,TUBO and 4T1 cells at different MOI(multiplicity of infection)were compared by MTS assay.The replication of the two viruses in the three cell lines was tested by TCID50.ELISA assay was performed to detect m IL-21 expression in the supernatants of the three cell lines culture after the virus infection.Orthotopic 4T1 and TUBO breast cancer models in the BALB/c mice were established to investigate the antitumor efficacy of the different VVs.Results: The two viruses were able to replicate in mouse breast cancer cells,and low dose of VV caused significant cytotoxicity.High level of m IL-21 protein was expressed in the supernatants of all the tumour cells after VVΔTKΔN1L-m IL-21 infection.In the orthotopic 4T1 breast cancer model,all the viruses did not show significant anti-tumour effect(P>0.05).In the orthotopic TUBO breast cancer model,tumor growth was inhibited(t=2.396,P<0.05;t=4.008,P <0.01)and survival time(χ2 =16.94,P<0.01)of mouse was prolonged by both of VVΔTKΔN1L-RFP and VVΔTKΔN1L-m IL-21 treatment group.Conclusion: The two viruses have the ability to kill tumor cells and replicate in breast cancer cells.In vivo,the two viruses have different therapeutic effects on Her-2 gene amplification and triple negative breast cancer.