title: Oncolytic virotherapy for treatment of breast cancer, including triple-negative breast cancer.
abstract: Breast cancer is a heterogeneous disease, characterized by several distinct biological subtypes, among which triple-negative breast cancer (TNBC) is one associated with a poor prognosis. Oncolytic virus replication is an immunogenic phenomenon, and viruses can be armed with immunostimulatory molecules to boost virus triggered antitumoral immune responses. Cyclophosphamide (CP) is a chemotherapy drug that is associated with cytotoxicity and immunosuppression at higher doses, whereas immunostimulatory and anti-angiogenic properties are observed at low continuous dosage. Therefore, the combination of oncolytic immuno-virotherapy with low-dose CP is an appealing approach. We investigated the potency of oncolytic adenovirus Ad5/3-D24-GMCSF on a TNBC cell line andin vivoin an orthotopic xenograft mouse model, in combination with low-dose CP or its main active metabolite 4-hydroperoxycyclophosphamide (4-HP-CP). Furthermore, we summarized the breast cancer-specific human data on this virus from the Advanced Therapy Access Program (ATAP). Low-dose CP increased the efficacy of Ad5/3-D24-GMCSFin vitroand in a TNBC mouse model. In ATAP, treatments appeared safe and well-tolerated. Thirteen out of 16 breast cancer patients treated were evaluable for possible benefits with modified RECIST 1.1 criteria: 1 patient had a minor response, 2 had stable disease (SD), and 10 had progressive disease (PD). One patient is alive at 1,771 d 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.
authors.affiliation: University of Helsinki, Faculty of Medicine, Department of Pathology, Cancer Gene Therapy Group , Helsinki, Finland.
authors.forename: Simona
authors.initials: S
authors.lastname: Bramante
authors.affiliation: University of Helsinki, Faculty of Medicine, Department of Pathology, Cancer Gene Therapy Group , Helsinki, Finland.
authors.forename: Anniina
authors.initials: A
authors.lastname: Koski
authors.affiliation: University of Helsinki, Faculty of Medicine, Department of Pathology, Cancer Gene Therapy Group , Helsinki, Finland.
authors.forename: Ilkka
authors.initials: I
authors.lastname: Liikanen
authors.affiliation: Oncos Therapeutics Ltd. , Helsinki, Finland.
authors.forename: Lotta
authors.initials: L
authors.lastname: Vassilev
authors.affiliation: University of Helsinki, Faculty of Medicine, Department of Pathology, Cancer Gene Therapy Group , Helsinki, Finland.
authors.forename: Minna
authors.initials: M
authors.lastname: Oksanen
authors.affiliation: University of Helsinki, Faculty of Medicine, Department of Pathology, Cancer Gene Therapy Group, Helsinki, Finland; TILT Biotherapeutics Ltd., Helsinki, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Siurala
authors.affiliation: Oncos Therapeutics Ltd. , Helsinki, Finland.
authors.forename: Raita
authors.initials: R
authors.lastname: Heiskanen
authors.affiliation: Oncos Therapeutics Ltd. , Helsinki, Finland.
authors.forename: Tiina
authors.initials: T
authors.lastname: Hakonen
authors.affiliation: Docrates Cancer Center , Helsinki, Finland.
authors.forename: Timo
authors.initials: T
authors.lastname: Joensuu
authors.affiliation: University of Helsinki, Faculty of Medicine, Department of Pathology, Cancer Gene Therapy Group, Helsinki, Finland; Helsinki University Central Hospital, Department of Obstetrics and Gynecology, Helsinki, Finland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kanerva
authors.affiliation: University of Helsinki, Faculty of Medicine, Department of Pathology, Cancer Gene Therapy Group, Helsinki, Finland; Oncos Therapeutics Ltd., Helsinki, Finland.
authors.forename: Sari
authors.initials: S
authors.lastname: Pesonen
authors.affiliation: University of Helsinki, Faculty of Medicine, Department of Pathology, Cancer Gene Therapy Group, Helsinki, Finland; TILT Biotherapeutics Ltd., Helsinki, Finland; Helsinki University Central Hospital, Department of Oncology, Helsinki, Finland.
authors.forename: Akseli
authors.initials: A
authors.lastname: Hemminki
keywords: Breast cancer; GM-CSF; combination therapies; cyclophosphamide; oncolytic adenovirus; oncolytic virotherapy; triple-negative breast cancer