A Phase l Study of a Tumor-targeted Systemic Nanodelivery System, SGT-94, in Genitourinary Cancers

Gene therapy development has been limited by our inability to target multifocal cancer with systemic delivery. We developed a systemically administered, tumor-targeted liposomal nanodelivery complex (SGT-94) carrying a plasmid encoding RB94, a truncated form of the RB gene. In preclinical studies, R...

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Bibliographic Details
Published in:Molecular therapy 2016-08, Vol.24 (8), p.1484-1491
Main Authors: Siefker-Radtke, Arlene, Zhang, Xin-qiao, Guo, Charles C, Shen, Yu, Pirollo, Kathleen F, Sabir, Sharjeel, Leung, Chris, Leong-Wu, Cindy, Ling, Chi-Ming, Chang, Esther H, Millikan, Randall E, Benedict, William F
Format: Article
Language:English
Subjects:
Aged
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Biological activity
Bladder cancer
Cancer therapies
Combined Modality Therapy
Cytomegalovirus
Cytotoxicity
Defective products
Drug dosages
Female
Gene therapy
Gene Transfer Techniques
Genetic Therapy - adverse effects
Genetic Therapy - methods
Humans
Liposomes
Male
Metastasis
Middle Aged
Molecular Targeted Therapy
Nanomedicine - methods
Neoplasm Metastasis
Neoplasm Staging
Neutropenia
Neutrophils
Oncology
Original
Patients
Plasmids
Plasmids - administration & dosage
Plasmids - adverse effects
Plasmids - genetics
Proteins
Receptors, Transferrin - immunology
Remission (Medicine)
Retinoblastoma Protein - genetics
Single-Chain Antibodies - genetics
Single-Chain Antibodies - immunology
Thrombocytopenia
Tomography, X-Ray Computed
Toxicity
Transgenes
Treatment Outcome
Tumors
Urogenital Neoplasms - diagnosis
Urogenital Neoplasms - genetics
Urogenital Neoplasms - mortality
Urogenital Neoplasms - therapy
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Summary:Gene therapy development has been limited by our inability to target multifocal cancer with systemic delivery. We developed a systemically administered, tumor-targeted liposomal nanodelivery complex (SGT-94) carrying a plasmid encoding RB94, a truncated form of the RB gene. In preclinical studies, RB94 showed marked cytotoxicity against tumor but not normal cells. SGT-94 was administered intravenously in a first-in-man study in metastatic genitourinary cancer. Minimal side effects were observed; dose-limiting toxicity (DLT) has not been reached in 11 evaluable patients. There was evidence of clinical activity at the 2.4 mg dose with one complete remission (CR) and one partial remission (PR). The patient in CR was retreated upon progression and had a second PR. Furthermore, there was tumor-specific targeting of the SGT-94 complex. One patient had wedge resections of two lung metastases which demonstrated RB94 expression at the DNA level by polymerase chain reaction (PCR) and at the protein level by Western blotting, with no RB94 present in normal contiguous lung. In conclusion, systemically delivered SGT-94 showed evidence of selective tumor targeting and was well tolerated with evidence of clinical activity. Additional studies are warranted to explore the activity of this drug as a single agent and in combination therapy.
ISSN:1525-0016
1525-0024
DOI:10.1038/mt.2016.118