438. Oncolytic Immunotherapy for Treatment of Breast Cancer, Including Triple-Negative Breast Cancer

Abstract

Breast cancer is a heterogeneous disease, characterized by several distinct biological subtypes associated with specifical biological behavior and different clinical outcomes. Triple-negative breast cancer (TNBC) is defined as estrogen receptor (ER)-negative, progesterone receptor (PR)-negative and lacking overexpression of human epidermal growth factor receptor 2 (HER2). Among all the breast cancer subtypes, TNBC (10-15% of breast cancers) is associated with a worse prognosis.Oncolytic virus replication is an immunogenic phenomenon, and viruses can be armed with immunostimulatory molecules. Cyclophosphamide (CP) is a chemotherapy drug that works by slowing or stopping cell growth. At higher doses, CP is associated with increased cytotoxicity and immunosuppression, while at low continuous dosage it shows immunostimulatory and antiangiogenic properties. Therefore, the combination of oncolytic immunovirotherapy with low-dose CP is an appealing approach.We investigated the potency of oncolytic adenovirus Ad5/3-D24-GMCSF on a TNBC cell line and animal models, in combination with low-dose CP or its main active metabolite 4-hydroxycyclophosphamide (4-HP-CP). Furthermore, we summarized the breast cancer-specific human data from the Advanced Therapy Access Program (ATAP).Low-dose CP effectively increased the efficacy of Ad5/3-D24-GMCSF in vitro and in a TNBC xenograft mouse model. In ATAP, treatments appeared safe and well-tolerated. Fourteen out of sixteen breast cancer patients treated were evaluable for possible therapy benefit with modified RECIST criteria: one patient had minor response, four had stable disease, and nine had progressive disease. One patient was alive at 941 days after treatment.Ad5/3-D24-GMCSF in combination with low-dose CP showed promising efficacy in preclinical studies and possible antitumor activity in breast cancer patients refractory to other forms of therapy. This preliminary data supports continuing the clinical development of oncolytic adenoviruses for treatment of breast cancer, including TNBC.