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 and in 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-GMCSF and 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.

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

“…41,199 Along the lines of our Trial Watch series, here we discuss recent preclinical and clinical advances in the development of ICD-inducing chemotherapeutic regimens. 200 Several other interventions that trigger bona fide ICD, such as radiation therapy administered according to specific regimens, 94,[201][202][203] high hydrostatic pressure, 3,4 oncolytic virotherapy [204][205][206][207][208] and photodynamic therapy, 44,86,98,99 are not discussed here in further detail.…”

Temozolomide Enhances Triple-Negative Breast Cancer Virotherapy In Vitro

“…Previously, it was reported that the MDA-MB-436 human TNBC cell line, when treated with a triple combination of TMZ; 4-hydroperoxycyclophosphamide (4-HPCP); an active metabolite of the prodrug cyclophosphamide (CP); and Ad5/3-D24-GMCSF, a 5/3-capsid chimeric OAd coding for GM-CSF, had increased immunogenic cell killing and autophagy [ 31 ]. In another study, it was reported that CP at low doses increased the efficacy of Ad5/3-DM4-GMCSF in MDA-MB-436 cells, and similar effects were observed in an orthotopic TNBC xenograft mouse model [ 35 ].…”

Potent antitumor effect of tumor microenvironment‐targeted oncolytic adenovirus against desmoplastic pancreatic cancer

“…Current trends of oncolytic Ad development for clinical applications have focused on armed oncolytic Ads expressing anticancer therapeutic genes. Several clinical studies have evaluated the efficacy of these Ads against various types of cancers . In the context of this strategy, we generated oncolytic Ad expressing DCN, a potent inducer of tumor cell apoptosis and ECM degradation, as a potential candidate for the treatment of desmoplastic pancreatic cancer.…”