Pirollo Kathleen F, Nemunaitis John, Leung Po Ki, Nunan Robert, Adams Jana, Chang Esther H
Department of Oncology, Experimental Therapeutics Division, Georgetown University Medical Center, Washington, District of Columbia, USA.
Mary Crowley Cancer Research Centers, Dallas, Texas, USA.
Mol Ther. 2016 Sep;24(9):1697-706. doi: 10.1038/mt.2016.135. Epub 2016 Jun 30.
Loss of p53 suppressor function, through mutations or inactivation of the p53 pathway, occurs in most human cancers. SGT-53 is a liposomal nanocomplex designed for systemic, tumor-targeting delivery of the wt p53 gene. In this nanodelivery system, an anti-transferrin receptor single-chain antibody fragment serves as the targeting moiety. In an initial phase 1 trial in patients with advanced solid tumors, SGT-53 demonstrated tumor-specific targeting, was shown to be well tolerated, and was associated with an antitumor effect in several patients. Our preclinical studies have also demonstrated enhanced antitumor activity with the combination of SGT-53 and docetaxel. Thus, this dose-escalation trial was undertaken to assess the combination of SGT-53 and docetaxel for safety and potential efficacy in 14 advanced cancer patients. Results reveal that the combination of SGT-53 (maximum dose, 3.6 mg DNA/infusion) and docetaxel (75 mg/m(2)/infusion) was well tolerated. Moreover, clinical activity involving 12 evaluable patients was observed. Three of these patients achieved RECIST-verified partial responses with tumor reductions of -47%, -51%, and -79%. Two others had stable disease with significant shrinkage (-25% and -16%). These results support phase 2 testing of SGT-53 in combination with docetaxel.
通过p53途径的突变或失活导致p53抑制功能丧失，这在大多数人类癌症中都会发生。SGT-53是一种脂质体纳米复合物，设计用于野生型p53基因的全身肿瘤靶向递送。在这个纳米递送系统中，抗转铁蛋白受体单链抗体片段作为靶向部分。在一项针对晚期实体瘤患者的初始1期试验中，SGT-53显示出肿瘤特异性靶向性，耐受性良好，并且在一些患者中具有抗肿瘤作用。我们的临床前研究还表明，SGT-53与多西他赛联合使用可增强抗肿瘤活性。因此，进行了这项剂量递增试验，以评估SGT-53和多西他赛联合使用对14例晚期癌症患者的安全性和潜在疗效。结果显示，SGT-53（最大剂量，3.6mg DNA/输注）和多西他赛（75mg/m²/输注）联合使用耐受性良好。此外，观察到12例可评估患者的临床活性。其中3例患者达到了RECIST验证的部分缓解，肿瘤缩小率分别为-47%、-51%和-79%。另外2例患者病情稳定，肿瘤显著缩小（-25%和-16%）。这些结果支持SGT-53与多西他赛联合进行2期试验。
