Phase I Study of a Systemically Delivered p53 Nanoparticle in Advanced Solid Tumors

Abstract

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.

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

“…It is possible that the SGT-53 would not only improve outcomes in patients that already respond to checkpoint blockade, but also increase the percentage of patients who respond. SGT-53 has completed a first-in-man Phase I and Ib trials with favorable safety profiles 54,55 and is now being evaluated in multiple Phase Ib and II trials as combination therapy with currently approved chemotherapeutic agents. Our data here provide a strong mechanistic rationale for combining SGT-53 and PD1/PD-L1-based immune checkpoint blockade in a clinical trial setting.…”

Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy

“…The phase I liposomic formulation SGT-53 includes plasmidic DNA that expresses the tumor suppressor gene p53 to treat solid tumors [280,289].…”

Preparation and Characterization of Folate-Targeted Fe3O4 Nanoparticle Codelivering Cisplatin and TFPI-2 Plasmid DNA for Nasopharyngeal Carcinoma Therapy

“…However, the nonuniform treatment program and the lack of tissue targeting are problems that need to be addressed. Therefore, gene targeting therapy has come into the spotlight in team researches and clinical trials [19][20][21]. Our previous studies have, respectively, developed a cyclodextrin-poly derivative [22] and a folate-targeted cationic copolymer [23] to carry docetaxel and MMP siRNA plasmid for better anti-NPC treatment.…”