Abstract CT059: Systemic administration using targeted gene delivery with SGT-RB94 shows evidence of tumor targeting and anticancer activity: a phase I first-in-man trial
Authors: Siefker-Radtke Arlene , Zhang Xin-qiao , Pirollo Kathleen F. , Chang Esther H. , Leung Chris P. , Guo Charles , Millikan Randall E. , Benedict William F. 
Published: July 2016

Abstract
Background: Development of gene therapy has been limited by our inability to systemically administer treatment which selectively targets tumor tissue. We developed an SGT-RB94 nanocomplex composed of cationic liposome encapsulating plasmid DNA encoding the RB94 gene which had previously been shown to selectively kill cancer cells but not non-transformed human cells. The surface of the liposome is decorated with a single chain antibody fragment to the transferrin receptor to target the nanocomplex to cancer cells.
Methods: We performed a phase I trial of single agent SGT-RB94 in patients with previously treated metastatic cancer. Treatment with SGT-RB94 was administered twice a week for 3 weeks out of four using a fixed at a fixed DNA dose of 0.6, 1.2, or 2.4 mg pDNA. Radiographic imaging was performed every 2 cycles to evaluate for response. When possible, a biopsy of a metastatic site was performed, after beginning treatment to evaluate for targeting of the gene product. PCR was performed to show expression of SGT-94 in RB+ tumors, RB94 protein production was confirmed using Western blotting.
Results: Thirteen patients were treated with 11 clinically evaluable for response. Dose-limiting toxicity was not observed at the 2.4 mg dose. A total of 181 doses of SGT-94 were administered. The treatment was well tolerated with the most frequent treatment related toxicities being Grade 1-2 fever and chills (27%), thrombocytopenia (45%), neutropenia (18%), and hypotension (18%). The only grade 3-4 toxicity were lymphopenia (9%), and neutropenia (9%). The fever/chills and hypotension most typically occurred after the first dose, and responding with steroids. The neutropenia and thrombocytopenia were also transient and improved with continued dosing.
There was evidence of clinical activity with a complete response in a lung metastases; this patient was retreated upon progression, and had a partial response in his peritoneal implants. Two patients continued to have stable disease after 4-5 cycles of treatment. Two patients had RB- tumors by immunohistochemistry. One had a post-treatment biopsy showing evidence of cytoplasmic staining for the RB protein with extensive tumor necrosis following treatment, but this tumor ultimately progressed. One patient with stable disease had surgical consolidation with wedge resection of his lung metastases which showed RB94 expression by PCR, and protein production by Western blot in two separate tumors, but not in his normal lung tissue.
Conclusions: Systemic delivery of SGT-RB94 was well tolerated with evidence of clinical activity and selective targeting of tumor tissue, overcoming a major limitation to current gene therapy strategies. Further development of SGT-RB94 as a treatment modality is warranted.
Citation Format: Arlene Siefker-Radtke, Xin-qiao Zhang, Kathleen F. Pirollo, Esther H. Chang, Chris P. Leung, Charles Guo, Randall E. Millikan, William F. Benedict. Systemic administration using targeted gene delivery with SGT-RB94 shows evidence of tumor targeting and anticancer activity: a phase I first-in-man trial. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT059.