Safety and Efficacy in Advanced Solid Tumors of a Targeted Nanocomplex Carrying the p53 Gene Used in Combination with Docetaxel: A Phase 1b Study

Abstract

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.

Effect of docetaxel‑loaded lipid microbubble in combination with ultrasound‑triggered microbubble destruction on the growth of a gastric cancer cell line

“…Another study demonstrated that the p53 pathway was responsible for mediating tumor cell cycle arrest and cell apoptosis in response to combination treatment with DOC and resveratrol (42). In addition, a recent clinical study demonstrated that the nanocomplex carrying the p53 gene in combination with DOC could significantly block solid tumor development (43). The present study identified that DLLD combined with UTMD induced the highest expression level of p53 and its downstream effector, p21, in the BGC-823 cell line.…”

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.…”

Nanotherapeutics for Gene Modulation that Prevents Apoptosis in the Brain and Fatal Neuroinflammation

“…We have previously shown that the encapsulation of either antisense ODN or siRNA forming scL-based nanocomplexes greatly increased its serum stability and bioavailability in mice. 31 The safety of scL-based nanocomplex has been established in the completed phase I clinical trial using scL delivering the tumor suppressor gene wtp53 (in an experimental anti-cancer agent termed SGT-53) 32 and in a second phase I trial using nanocomplexes carrying the gene encoding RB94 (in a second experimental anti-cancer agent termed SGT-94). 33 Thus, this method of combining liposomal encapsulation of payload with targeting the TfR may provide a safe and useful method to enhance CNS drug delivery to achieve effective gene modulation in treating acute as well as chronic neurological disorders that require longer-term interventions.…”