Treatment of Human Breast Cancer in a Brain Metastatic Model by G207,a Replication-Competent Multimutated Herpes Simplex Virus 1

Abstract

We investigated the therapeutic efficacy of G207, a replication-competent multimutated herpes simplex virus type 1, for the treatment of human malignant mammary tumors metastatic to the brain. In vitro studies demonstrated that G207 efficiently destroyed three of four human malignant breast cancer cell lines. MDA-MB-435 was most susceptible and MDA-MB-231 was least susceptible to G207. In athymic mice harboring subcutaneous or intracerebral MDA-MB-435 cells, intraneoplastic inoculation of G207 caused growth inhibition and/or prolonged survival. In contrast, G207 had minimal effects on MDA-MB-231 subcutaneous tumor growth or survival in the intracerebral tumor model. The efficacy of G207 therapy in vivo correlated well with the susceptibility of the human cancer cells to G207 in vitro. Histological studies indicate that G207 replication is restricted to tumor cells in vivo and does not occur in the surrounding brain tissue. These results suggest that G207 shows particular promise for use as a novel antineoplastic agent for metastatic brain tumors and that in vitro testing may predict which tumors will be most responsive in vivo.

Overview summary

We have created a replication-competent herpes simplex virus type 1 (HSV-1) vector, termed G207, which we have demonstrated to be efficacious in the treatment of primary human brain tumors. In this article we have extended the spectrum of use of G207 to the treatment of human breast cancer, including a brain metastatic model. In addition, we have provided experimental evidence for one of the underlying hypotheses, that replication and consequent spread of the virus within tumor cells are responsible for the inhibition of tumor growth seen in vivo. The efficacy of G207 therapy in vivo correlated well with the susceptibility of the human cancer cells to G207 in vitro. These data constitute the first reported use of a second-generation vector of genetically engineered replication-competent HSV-1 in the treatment of human tumors other than primary brain tumors.