Treatment Effects of WST11 Vascular Targeted Photodynamic Therapy for Urothelial Cell Carcinoma in Swine

Abstract

Purpose Surgical management of upper tract urothelial carcinoma requires removal of kidney and ureter, compromising renal function. Non-surgical alternatives have potentially prohibitive safety concerns. We examine the feasibility and safety of ablation of the ureter and renal pelvis using endoluminal vascular-targeted photodynamic therapy in a porcine model and report efficacy of WST11 vascular-targeted photodynamic therapy in a murine model. Materials and Methods Following approval, we performed 28 endoluminal ablations in the ureters and renal pelvis of 18 swine. Intravenous infusion of WST11 (4mg/kg) followed by laser illumination (10 minutes) was performed via percutaneous access or retrograde ureteroscopic approach. Animals were followed clinically with laboratory testing, imaging and histology was evaluated at several post-ablation time points. A murine xenograft was created with the 5637 human urothelial cell carcinoma line to determine sensitivity to this therapy. Results At 24 hours, 50 mW/cm laser fluence produced superficial necrosis of the ureter and deeper necrosis (penetrating the muscularis propria or adventitia) was produced by treatment with 200 mW/cm in the ureter and renal pelvis. At 4 weeks, superficial urothelium had regenerated over the treatment site. No symptomatic obstruction, clinically relevant hydronephrosis, or abnormality of lab testing was noted up to 4 weeks. In mice, 80% had no evidence of tumor at 19 days after WST11 vascular-targeted photodynamic therapy. Conclusions Urothelial cell carcinoma appears to be sensitive to WST11 vascular-targeted photodynamic therapy. Depth of WST11 vascular-targeted photodynamic therapy treatment effects can be modulated in a dose-dependent manner by titration of light intensity. Moreover, this treatment modality, applied to the porcine upper urinary tract, is feasible via antegrade and retrograde access.

Detection of Treatment Success after Photodynamic Therapy Using Dynamic Contrast-Enhanced Magnetic Resonance Imaging

“…In a phase III clinical trial, the treatment was found to be a promising alternative to active surveillance of early stage prostate tumors 6 . PDT with padeliporfin has also proven successful in preclinical in vivo studies with application to renal and urethral tumors 7 , 8 . Furthermore, other photosensitizers were tested for treatment of, amongst others, pancreatic cancer 9 and brain gliomas 10 .…”

Developments in Vascular-Targeted Photodynamic Therapy for Urologic Malignancies

“…Finally, the authors determined optimal laser fiber distribution, specifically spaced 1 cm apart, and the relationship between laser fluence and the radius of tissue ablation. A companion study similarly confirmed the safety of endoluminal ablation in the ureter and renal pelvis and the intensity dependence of the depth of tissue necrosis [ 24 ]. This investigation further showed that tissue in the irradiated area, in this case, the urothelium, regenerates within 4 weeks with no functional changes.…”

PD‐1/PD‐L1 inhibitors‐based treatment for advanced renal cell carcinoma: Mechanisms affecting efficacy and combination therapies

“…It could promote the recruitment of CD8+ T cells in the TME, and the activation of CD8+ T cells could be enhanced by increasing the proportion of DCs in the tumor and upregulating the expression of the costimulatory ligand CD86 on them. 122 Vascular‐targeted photodynamic therapy, which rapidly blocks the associated blood vessels that supply tumor nutrients and leads to tumor necrosis and eradication, 123 also improved cellular immunity in an in‐situ RENCA mouse model of lung metastatic RCC through promoting the infiltration of T cells in the metastatic site and increasing the proportion of CD8+ T cells and CD4+FOXP3‐T cells. 124 Furthermore, cryoablation could improve T cell activity by upregulating IFN‐γ, IL‐10, and GZMB expression and promoting the infiltration of CD8+ T cells at the early stage of RCC, indicating that the combination of cryoablation and anti‐PD‐1 exhibited strong efficacy.…”