Phase I Study of a Systemically Delivered p53 Nanoparticle in Advanced Solid Tumors
Phase I Study of a Systemically Delivered p53 Nanoparticle in Advanced Solid Tumors
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DOI：
10.1038/mt.2013.32
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发表时间：
2013-05-01
影响因子：
12.4
通讯作者：
Chang, Esther H.
中科院分区：
文献类型：
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作者：
Senzer, Neil;Nemunaitis, John;Chang, Esther H.
将治疗分子选择性递送至原发性和转移性肿瘤对于有效的癌症治疗是最佳的。已经开发了用于抗癌治疗剂的全身性肿瘤靶向递送的脂质体纳米递送复合物（scL）。scL采用抗转铁蛋白受体（TfR）scFv作为靶向分子。通过p53途径的突变或失活，p53抑制功能的丧失存在于大多数人类癌症中。p53功能障碍的持续存在不是暂时允许肿瘤发生，而是维持肿瘤生长的持续需要。在此，我们报告了使用scL纳米复合物（SGT-53）恢复正常人类肿瘤抑制基因p53的首次人体I期临床试验的结果。本试验在晚期实体瘤患者中观察到最小的副作用。此外，大多数患者病情稳定。1例腺样囊性癌患者在1个治疗周期后由不可切除变为可切除。更重要的是，我们观察到转基因在转移性肿瘤中的积累，而不是在正常皮肤组织中，以剂量相关的方式。这些结果不仅表明全身递送的SGT-53具有良好的耐受性和抗癌活性，而且还提供了SGT-53靶向肿瘤递送至转移性病变的证据。
Selective delivery of therapeutic molecules to primary and metastatic tumors is optimal for effective cancer therapy. A liposomal nanodelivery complex (scL) for systemic, tumor-targeting delivery of anticancer therapeutics has been developed. scL employs an anti-transferrin receptor (TfR), scFv as the targeting molecule. Loss of p53 suppressor function, through mutations or inactivation of the p53 pathway, is present in most human cancers. Rather than being transiently permissive for tumor initiation, persistence of p53 dysfunction is a continuing requirement for maintaining tumor growth. Herein, we report results of a first-in-man Phase I clinical trial of restoration of the normal human tumor suppressor gene p53 using the scL nanocomplex (SGT-53). Minimal side effects were observed in this trial in patients with advanced solid tumors. Furthermore, the majority of patients demonstrated stable disease. One patient with adenoid cystic carcinoma had his status changed from unresectable to resectable after one treatment cycle. More significantly, we observed an accumulation of the transgene in metastatic tumors, but not in normal skin tissue, in a dose-related manner. These results show not only that systemically delivered SGT-53 is well tolerated and exhibits anticancer activity, but also supply evidence of targeted tumor delivery of SGT-53 to metastatic lesions.