Oncolytic virotherapy for treatment of breast cancer, including triple-negative breast cancer
Oncolytic virotherapy for treatment of breast cancer, including triple-negative breast cancer
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DOI：
10.1080/2162402x.2015.1078057
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发表时间：
2016-01-01
期刊：
影响因子：
7.2
通讯作者：
Hemminki, Akseli
中科院分区：
文献类型：
--
作者：
Bramante, Simona;Koski, Anniina;Hemminki, Akseli
乳腺癌是一种异质性疾病，其特征在于几种不同的生物学亚型，其中三阴性乳腺癌（TNBC）是与不良预后相关的一种。溶瘤病毒复制是一种免疫原性现象，并且病毒可以用免疫刺激分子武装以增强病毒触发的抗肿瘤免疫应答。环磷酰胺（CP）是一种化疗药物，在较高剂量下与细胞毒性和免疫抑制相关，而在低连续剂量下观察到免疫刺激和抗血管生成特性。我们研究了溶瘤腺病毒Ad 5/3-D24-GMCSF与低剂量CP或其主要活性代谢物4-羟过氧环磷酰胺（4-HP-CP）联合应用对TNBC细胞系和原位异种移植小鼠模型的效力。此外，我们总结了来自高级治疗访问计划（ATAP）的关于该病毒的乳腺癌特异性人类数据。低剂量CP在体外和TNBC小鼠模型中增加了Ad 5/3-D24-GMCSF的功效。在ATAP中，治疗似乎安全且耐受性良好。16例接受治疗的乳腺癌患者中有13例可根据改良的RECIST 1.1标准评价可能的获益：1例患者有轻微缓解，2例患者病情稳定（SD），10例患者病情进展（PD）。Ad 5/3-D24-GMCSF联合低剂量CP在临床前研究中显示出良好的疗效，并可能对其他形式治疗无效的乳腺癌患者具有抗肿瘤活性。这些初步数据支持继续临床开发溶瘤腺病毒用于治疗乳腺癌，包括TNBC。
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 vivo 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 in vitro 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.