Results of a completed phase I clinical trial of CYT-6091: A pegylated colloidal gold-TNF nanomedicine

Abstract

3586 Background: CYT-6091 is the first tumor-targeted nanomedicine formulation designed to safely deliver an API that itself is not approved for systemic administration due to unacceptable toxicity. CYT-6091, consisting of tumor necrosis factor-α (TNF) covalently linked to pegylated colloidal gold nanoparticles, has been safely administered in preclinical models, demonstrating an increased T1/2 compared to native TNF, a documented trafficking of nanoparticles to tumor, and no hypotension, the known DLT for TNF. Methods: CYT-6091 was tested in a phase I open label trial in solid tumor, advanced stage patients. Patients (n = 3/dose), admitted to the NIH Clinical Center ICU, received two IV injections of CYT-6091 on day 0 and 14. Dosing started at 50 μg/m2 of TNF, up to 600 μg/m2. Vital signs were monitored and blood samples were drawn over 48 h. The primary endpoint of the study was to determine the MTD for CYT-6091. Secondary endpoints included PK, disease response (staged 45 days post treatment by RECIST), and the detection of gold nanoparticles in tumors and in adjacent healthy tissue. Results: Twenty-nine patients were treated. Even at the lowest dose (50 μg/m2), patients exhibited a febrile response, which was mitigated by acetaminophen and indomethacin pretreatment. None of the 29 patients treated with doses of 50–600 μg/m2 showed a DLT hypotensive response, and in fact, no DLT was seen. T1/2 estimates for TNF, administered as CYT-6091, are 120, 131, 127, 146, 112, 113, 266, 371, and 160 minutes for 50, 100, 150, 200, 250, 300, 400, 500, 600 μg/m2, respectively (published T1/2 for native TNF is ∼27 minutes). In the 28 patients eligible for response assessment, there was 1 PR (100 μg/m2 dose, 7 months duration) and 3 SD (2, 2, and 3 months duration). Electron micrographs show gold nanoparticles in tumor biopsies. Conclusions: CYT-6091 is well tolerated at doses up to 600 μg/m2 of TNF, levels 3-times greater than the published MTD for native TNF. CYT-6091 targets tumors in humans. Efficacy studies in combination with chemotherapy are planned. [Table: see text]

Biocompatibility and Cytotoxicity of Gold Nanoparticles: Recent Advances in Methodologies and Regulations

“…However, only a few examples of AuNPs currently are under investigation in clinical trials [161,162]. According to the literature, Aurimune CYT-6091 (Cytimmune) is the first tumor-targeted nanomedicine consisting of tumor necrosis factor-α (TNF) covalently linked to pegylated colloidal gold [163,164]. The conclusion after finishing the phase I clinical trial was that CYT-6091 targeted tumors in humans and was well tolerated at doses greater than maximum tolerated dose for native TNF.…”

Novel bio-friendly and non-toxic thiocarbohydrate stabilizers of gold nanoparticles

“…A large number of gold compounds have been studied as anticancer and anti-HIV agents [1][2][3][4][5][6][7][8][9][10] and as drug delivery vehicles in the form of gold nanoparticles in therapeutics because of their bio-inertness and cellular imaging ability. 11 However, development of gold compounds and gold nanoparticles as therapeutics 12 are hampered by their unstable nature and lack of biocompatibility. 11,13 It has, therefore, become necessary to find both non-toxic and biocompatible ligands in order to produce gold compounds that would help overcome the above shortcomings.…”

Tumor necrosis factor interaction with gold nanoparticles

“…The protein tumor necrosis factor-a (TNF) is the prototypical member of a pro-apoptotic ligand family with substantial significance for cancer therapy. [1][2][3][4][5][6][7][8][9][10][11] Studies show that after binding with specific cytokine receptors (TNFR) on the tumor endothelial vascular lining, TNF is able to induce hemorrhagic necrosis of several types of tumors. 8,10 However, TNF is also a known pro-inflammatory cytokine that regulates immune response.…”