Preclinical evaluation of VAX-IP, a novel bacterial minicell-based biopharmaceutical for nonmuscle invasive bladder cancer.
Preclinical evaluation of VAX-IP, a novel bacterial minicell-based biopharmaceutical for nonmuscle invasive bladder cancer.
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DOI：
10.1038/mto.2016.4
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Godbey WT
中科院分区：
文献类型：
--
作者：
Tsuji S;Chen X;Hancock B;Hernandez V;Visentin B;Reil K;Sabbadini R;Giacalone M;Godbey WT
开发能够预防非肌层浸润性膀胱癌复发和进展的新疗法仍然是一个未满足的临床需求。监测和治疗复发性疾病的持续成本以及其高患病率和发病率沿着是全球医疗保健经济的压力。目前的工作描述了VAX-IP作为一种新型细菌小细胞为基础的生物药剂正在开发用于治疗非肌肉浸润性膀胱癌和其他肿瘤适应症的表征和药理学评价。VAX-IP小细胞选择性地靶向两种肿瘤学相关的整联蛋白异二聚体亚型，以特异性地向癌细胞递送独特的细菌溶细胞素蛋白毒素，产气荚膜梭菌溶素O，从而以独特的肿瘤溶解机制快速杀死表达整联蛋白的鼠和人尿路上皮细胞癌细胞。在浅表性膀胱癌的同基因原位模型的两种临床相关变体中，VAX-IP小细胞作为膀胱内施用的单一药剂的体内药理学评价导致显著的存活优势，在早期或晚期治疗开始后分别有28.6%（P = 0.001）和16.7%（P = 0.003）的动物存活。这些临床前研究的结果保证了在服务不足的非肌肉浸润性膀胱癌患者人群中进行进一步的非临床和最终的临床研究，其中完全治愈是可以实现的。
The development of new therapies that can prevent recurrence and progression of nonmuscle invasive bladder cancer remains an unmet clinical need. The continued cost of monitoring and treatment of recurrent disease, along with its high prevalence and incidence rate, is a strain on healthcare economics worldwide. The current work describes the characterization and pharmacological evaluation of VAX-IP as a novel bacterial minicell-based biopharmaceutical agent undergoing development for the treatment of nonmuscle invasive bladder cancer and other oncology indications. VAX-IP minicells selectively target two oncology-associated integrin heterodimer subtypes to deliver a unique bacterial cytolysin protein toxin, perfringolysin O, specifically to cancer cells, rapidly killing integrin-expressing murine and human urothelial cell carcinoma cells with a unique tumorlytic mechanism. The in vivo pharmacological evaluation of VAX-IP minicells as a single agent administered intravesically in two clinically relevant variations of a syngeneic orthotopic model of superficial bladder cancer results in a significant survival advantage with 28.6% (P = 0.001) and 16.7% (P = 0.003) of animals surviving after early or late treatment initiation, respectively. The results of these preclinical studies warrant further nonclinical and eventual clinical investigation in underserved nonmuscle invasive bladder cancer patient populations where complete cures are achievable.