WST-11 vascular-targeted photodynamic therapy induced immune modulation in upper tract urothelial cancer

Abstract Introduction: Vascular-targeted photodynamic therapy (VTP) with the photosensitizing agent padeliporfin (WST-11/TOOKAD Soluble; STEBA Biotech) has been approved for treating men with low-risk prostate cancer. A phase 1 trial of VTP evaluating treatment of upper tract urothelial carcinoma (UTUC) showed an acceptable safety profile with strong potential as an effective, kidney-sparing endoscopic management option. These results support a recently initiated multi-center Phase 3 trial (ENLIGHTED). Here we conducted a correlative study to assess immune modulatory activities of VTP and its potential association with treatment response. Methods: 19 patients with UTUC received up to two endoscopic VTP treatments in a phase I trial evaluating the safety of VTP. Treatment was applied by endoscopic illumination for 10 minutes at the involved site in the upper tract with three light fluence doses at 100 mW/cm, 150 mW/cm, or 200 mW/cm after intravenous injection of 4 mg/kg WST-11. Complete response was defined by absence of visible tumor and negative urine cytology at 30 days post treatment. To investigate the impact of VTP on the immune system, patient blood samples were collected and banked at 6 time points (base line, 4-6 hrs, 1 day, 1 week, 2 weeks, and 4 weeks post-treatment). Peripheral blood mononuclear cells (PBMCs) were subjected to flow cytometry analyses for T cell activation status and the abundance of myeloid derived suppressive cell (MDSC). Patient analyses were further stratified by complete responders (CR) and partial responders (PR). Mice bearing a murine bladder cell line MB49 or MB49 expressing ovalbumin (MB49-ova) was utilized for the assessment of efficacy and immune modulation by VTP. Results and Conclusions: An increase of the MDSC population in PBMC was observed immediately after VTP treatment (up to 24 hrs) in both CR and PR. However, the MDSC level returned close to pretreatment level in the majority of cases. The frequency of CD8 T cells among the total (CD3 positive) T cells in PBMC was increased immediately after VTP in both CR and PR. However, this increase was more prominent and durable among CR than PR, suggesting an association of treatment response with CD8 T cell driven immune modulation. Analysis of VTP induced antigen-specific immune responses using ovalbumin (ova) tetramers on MB49-ova model showed an increase in ova specific CD8 T cells in the blood and tumor samples at day 7 post VTP, indicating that VTP might induce tumor antigen specific adaptive response. Future analysis will be focused on the analysis of T cell receptor repertoire and immune correlation with clinical benefit. In summary, our pre-clinical and clinical data suggests that VTP induces antigen-specific CD8 T cell responses that may be durable. Citation Format: Kwanghee Kim, Sadna Budhu, Wesley Yip, Andrew Tracey, Andreas Aulitzky, Jasmine Thomas, Karan Nagar, Laura Alvim, Rebecca Dubrovsky, Caoimhe Ryan, Natalia Kudinova, Phillip Wong, Taha Merghoub, Avigdor Scherz, Jonathan Coleman. WST-11 vascular-targeted photodynamic therapy induced immune modulation in upper tract urothelial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2421.