Abstract P2-18-01: Treatment of Human Breast Tumors by Oncolytic Herpes Simplex Virus

Abstract

Abstract Background: Breast cancer is the most common cancer for women in the world, although current therapies have improve the outcome, the breast cancer deaths are still the second highest among cancers in women. Metastasis to the lung frequently results in severe complications, and currently, there are no curative treatment options available for patients with metastetic breast cancer. Oncolytic viral therapy is a new strategy for treating cancers. Replication-competent herpes simplex virus (HSV) can infect, replicate and kill tumor cells by a direct cytopathic effect and then spread within the tumor cells. In this study, the cytotoxicity of HSV vectors, G47Δ were examined on different human breast cancer cell lines, immortalized human breast cell lines, and primary culture normal human breast cells. Pulmonary metastasis model of breast cancer was constructed and the treatment effect of G47D was evaluated. Methods: Human BC cell lines SK-BR-3, MDA-MB-453, and MCF-7, immortalized breast cells MCF-10A and 76N-tert, and cultured primary normal breast cells HMEC1 and HMEC2 were cultured in vitro and infected with G47Δ at different multiplicities of infection (MOIs). The viability of infected cells was measured. G47Δ-infected cells were identified using X-gal histochemistry for LacZ expression. A pulmonary metastatic BC model was established with Balb-c nude mice by tail vein injection of MDA-MB-435 cells. Treatment was initiated 21 days after injection of tumor cells, with the virus group treated twice weekly with four total i.v. administrations of G47Δ (2*107pfu/100ul) and on day 60 mice were sacrificed and tumor nodules on the surface of the lung counted after Indian ink staining. Results: G47Δ was highly cytotoxic to BC cells and 76N-tert in vitro at very low MOI (0.01). For all of these cell lines, more than 85% and 95% cells were killed at MOI=0.01 and MOI=0.1 respectively on the fifth day after infection. However, both HMEC1 and HMEC2 cells were viable even 5 days after infection. A slight effect was found with MCF-10A, of which only 7% and 24.5% were killed at MOI=0.01 and MOI=0.1 respectively on day 5. In the pulmonary metastatic model, the average number of surface lung tumor nodules in the G47Δ group was one, but ten in the control group. X-gal staining illustrated viral replication and spread in the tumor cells in vitro and in vivo. Conclusions: Recently constructed oncolytic HSV vector G47Δ was effective at killing human breast cancer cells and immortalized breast cells, but didn't infect the normal breast cells. The i.v. administrations of G47Δ could effectively cure metastatic breast cancer. Our studies demonstrated that as a novel therapeutic agents, G47Δ was safe and exhibited superior antitumor effects, thereby making it appropriate for human clinical trials. It is worth noting that G47Δ was effective for lung metastatic breast cancer, which could assure the long survival rate of patients with advance breast cancer. The efficiency of G47Δ warrants consideration of clinical application. (Key words) breast cancer; cancer therapy; herpes simplex virus; oncolytic virus; gene therapy; Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-18-01.