Neoadjuvant vascular-targeted photodynamic therapy improves survival and reduces recurrence and progression in a mouse model of urothelial cancer

Abstract

Locally advanced urothelial cancer has high recurrence and progression rates following surgical treatment. This highlights the need to develop neoadjuvant strategies that are both effective and well-tolerated. We hypothesized that neoadjuvant sub-ablative vascular-targeted photodynamic therapy (sbVTP), through its immunotherapeutic mechanism, would improve survival and reduce recurrence and progression in a murine model of urothelial cancer. After urothelial tumor implantation and 17 days before surgical resection, mice received neoadjuvant sbVTP (WST11; Tookad Soluble, Steba Biotech, France). Local and systemic response and survival served as measures of therapeutic efficacy, while immunohistochemistry and flow cytometry elucidated the immunotherapeutic mechanism. Data analysis included two-sided Kaplan–Meier, Mann–Whitney, and Fischer exact tests. Tumor volume was significantly smaller in sbVTP-treated animals than in controls (135 mm3 vs. 1222 mm3, P < 0.0001) on the day of surgery. Systemic progression was significantly lower in sbVTP-treated animals (l7% vs. 30%, P < 0.01). Both median progression-free survival and overall survival were significantly greater among animals that received sbVTP and surgery than among animals that received surgery alone (P < 0.05). Neoadjuvant-treated animals also demonstrated significantly lower local recurrence. Neoadjuvant sbVTP was associated with increased early antigen-presenting cells, and subsequent improvements in long-term memory and increases in effector and active T-cells in the spleen, lungs, and blood. In summary, neoadjuvant sbVTP delayed local and systemic progression, prolonged progression-free and overall survival, and reduced local recurrence, thereby demonstrating therapeutic efficacy through an immune-mediated response. These findings strongly support its evaluation in clinical trials.

Medical gas plasma augments bladder cancer cell toxicity in preclinical models and patient-derived tumor tissues

“…This innovative treatment approach's principle relies on generating a versatile mix of ROS/RNS species capable of eliciting oxidative distress and thereby lethal damage in tumor cells. This concept is comparable to photodynamic therapy (PDT) that has already been implemented for many types of cancer therapies in clinical oncology [26] and is also under investigation for its usage in the treatment of urinary bladder cancer [27] , [28] . However, knowledge of the efficacy of the multi-ROS/RNS mixtures of medical gas plasma technology against this disease is rare.…”

Preclinical Studies on the Safety and Toxicity of Photoditazine in the Antibacterial Photodynamic Therapy of Uropathogenic Bacteria

“…The traditional PDT is based on intravenous infusion of a photosensitizer followed by light illumination [ 26 , 27 ]. This causes a localized ischemia-reperfusion injury [ 28 , 29 ] or a direct tissue injury [ 30 , 31 ] depending on photosensitizer localization. In contrast to traditional PDT, the developed technique involves a local infusion of the photosensitizer into the renal pelvis.…”

Photodynamic Therapy: Current Trends and Potential Future Role in the Treatment of Bladder Cancer

“…Several recent studies have examined combinations of vascular-targeted PDT with WST11 [42][43][44]. Corradi et al showed very interesting results for the combination with anti-CTLA4 immunotherapy in a heterotopic urothelial carcinoma mouse model: significantly reduced tumor growth, reduced development of lung metastases, prolonged survival, and no tumor growth after tumor re-irradiation in pretreated mice [42].…”

“…Alvim et al recently published further data on vascular-targeted PDT (WST 11) in combination with a PD1 inhibitor and OX40 in a mouse model with allografted MB-49 upper tract urothelial carcinoma cells. The above combination therapy showed the best efficacy in inhibiting tumor growth and prolonging survival compared to the combination with only one of the above agents [44]. Poly(caprolactone) based biodegradable and nontoxic polymeric matrix was used to formulate an in situ thermo-responsive hydrogel to deliver doxorubicin [45].…”