ABSTRACT
The fibroblast growth factor receptor 4 (FGFR4) is overexpressed in rhabdomyosarcoma (RMS) and represents a promising target for treatments based on specific and efficient antibodies. Despite progress, there is an urgent need for targeted treatment options to improve survival rates, and to limit long-term side effects. From phage display libraries we selected FGFR4-specific single-domain antibodies (sdAb) binding to recombinant FGFR4 and validated them by flow cytometry, surface plasmon resonance, and fluorescence microscopy. The specificity of the selected sdAb was verified on FGFR4-wild type and FGFR4-knock out cells. FGFR4-sdAb were used to decorate vincristine-loaded liposomes and to generate chimeric antigen receptor (CAR) T cells. First, incubation of RMS cells with FGFR4-sdAb revealed that FGFR4-sdAb can block FGF19-FGFR4 signaling via the MAPK pathway and could therefore serve as therapeutics for FGFR4-dependent cancers. Second, FGFR4-targeted vincristine-loaded liposomes bound specifically to RMS cells and were internalized by the receptor, demonstrating the potential for active drug delivery to the tumor. Third, FGFR4-CAR T cells, generated with one sdAb candidate, demonstrated strong and specific cytotoxicity against FGFR4 expressing RMS cells. We selected novel FGFR4-sdAb with high specificity and nano- to picomolar affinities for FGFR4 which have the potential to enable multiple FGFR4-targeted cancer therapy approaches.
ABSTRACT
PURPOSE: To study the efficacy and safety of a new sclerosing gel of absolute ethanol in the percutaneous treatment of venous malformations (VM). MATERIALS AND METHODS: In this prospective, non-randomized multicenter study patients with clinically and by magnetic resonance imaging diagnosed VM were treated. Efficacy and safety of the gel was evaluated. Therapeutic outcome was judged at day 56 after the last sclerosing therapy. Blood ethanol levels of ethanol were measured after each infusion. Local and systemic adverse events were recorded. RESULTS: Seventy-five (75) patients (age 4-46 y, mean 26 y) were treated in 172 sessions. Compared to no treatment, ethanol gel showed a complete cure rate of about 15% per session (p<0.00001). At the end of the last session, therapeutic outcome was complete (score 2) and partial (score 1) in 28 (37%) and 42 patients (56%), respectively, whereas treatment failure (score 0) was observed in 5 patients (7%). The plasmatic ethanol levels were very low (mean±SEM 0.03±0.06 g L(-1)), with only one patient above the legal 0.5 g L(-1) intoxication limit (0.6 g L(-1)). Forty-six (46) product-related adverse events (all local, none systemic) were reported. They included temporary mild isolated pain (N=21), inflammatory reactions (N=4), and local complications (7 skin necroses, 7 compressive neuropathies, 4 product leakage/fistula, 2 intralesional fibrous or granulomatous tissue, 1 dense node; 12.2% of the infusions). All local complications resolved spontaneously, except for 2 skin necroses requesting surgical paring. CONCLUSION: Ethanol gel is an embosclerosing substance that provides high efficiency and improves safety of ethanol in the treatment of VM lesions.
