Breast cancer is the leading cause of death in women under 40, with triple negative breast cancer (TNBC) being the most aggressive form of the disease with the poorest overall survival rates of all breast cancer types. TNBC represents 15-20% of all breast cancers, and the treatment options for advanced stage breast cancers including TNBC are limited, with survival rates hovering around 25% over the past two decades. Hence, there is an urgent need for development of therapeutic strategies to combat this deadly disease. Here, we have proposed the use of oncolytic herpes simplex virus 1 (oHSV-1) for treatment of advanced stage TNBC. The large genome of oHSV-1 allows for flexibility in engineering transgenes in the oncolytic virus (OV), such as the 15-hydroxyprostaglandin dehydrogenase, which degrades tumor-promoting prostaglandin E2. The oHSV-1 can be further modified to specifically target TNBC cells by engineering of the gD glycoprotein to target the androgen receptor, which is overexpressed in TNBC cells. oHSV-1 facilitates killing of TNBC cells both by oncolysis and by inducing an antitumor immune response that increases infiltration of CD8+ T-lymphocytes for cytotoxic killing of tumor cells. While TNBC cells may develop immune resistance by expressing the immune checkpoint molecule programmed cell death ligand 1 (PD-L1), this resistance can be mitigated by using oHSV-1 in combination with an immune checkpoint blockade such as anti-PD-1 antibodies. Finally, to improve the effectiveness of oHSV-1 as a therapeutic agent post intratumoral administration, we propose using mesenchymal stem cells (MSCs) as cell carriers of the OV to improve its systemic delivery, in addition to modifying the oHSV-1 surface proteins to express polyethylene glycol to reduce sequestration by the mononuclear phagocytic system in the liver and spleen. Therapeutics for TNBC are most effective early in the disease, highlighting the importance of future work to explore strategies for early diagnosis of TNBC, which will allow for increased effectiveness of our proposed oHSV-1 treatment, ultimately leading to improved overall prognosis and outcomes of individuals with TNBC.
Herpes simplex virus 1 in oncolytic virotherapy for treatment of triple negative breast cancer
Fall 2019 / Winter 2020