Abstract 1336: Combination of gemcitabine and local tumor ablation WST-11 vascular-targeted photodynamic therapy displays superior efficacy compared to either monotherapy in a urothelial cancer model
Authors: Kwanghee Kim, Sadna Budhu, Fengshen Kuo, Lilach Agemy, Stephen La Rosa, Sylvia Jebiwott, Karan Nagar, Chris Hughes, Jasmine Thomas, Laura Alvim, Rebecca Dubrovsky, Caoimhe Ryan, Daniel Rodriguez, Abraham Meyerson, Philip A. Watson, Natalia Kudinova, Andreas Aulitzky, Lucas M. Nogueira, Andrew Tracey, Wesley Yip, Phillip Wong, Taha Merghoub, Avigdor Scherz, Jonathan A. Coleman
Journal: Cancer Research (2025)

Abstract Vascular-targeted photodynamic therapy (VTP) with the photosensitizing agent padeliporfin (WST-11/TOOKAD Soluble) has demonstrated safety and efficacy for upper tract urothelial cancer (UTUC) in phase 1 (NCT03617003) and ongoing phase 3 clinical trials (NCT0420239). Here, we conducted a correlative study to assess immune modulatory activities of VTP using peripheral blood mononuclear cells (PBMCs) from 19 UTUC patients treated with VTP in the phase 1 trial. We complemented these findings with a preclinical assessment of a potential combination strategy with the chemotherapeutic agent gemcitabine. The frequency of CD8+ T cells among the CD3+ total T cells in patient PBMC was increased immediately after VTP in complete and partial responders (CR and PR), but the increase was more prominent and durable among CR than PR/non-responder (NR), suggesting an association of treatment response with CD8+ T cell driven immune modulation. An analysis of VTP induced effect in ovalbumin (OVA) expressing MB49 bladder tumor model showed an increase in OVA-specific CD8+ T cells in the blood and tumor samples, suggesting an association of treatment response with CD8+ T cell driven tumor antigen specific adaptive response that may be durable. We also observed an immediate increase in the population of myeloid derived suppressor cells (MDSCs) in patient PBMCs up to 24 hours post-VTP among all treated patients. The chemotherapy gemcitabine has been previously shown to reduce MDSCs in many cancer types, which makes it a rational strategy to combine with VTP. Combination of VTP with gemcitabine exhibited statistically significant local tumor control of MB49 and prevented lung metastasis, thereby improving overall survival compared to VTP or gemcitabine alone. Assessment of systemic anti-tumor responses using a bilateral tumor model, re-challenge in surviving mice and host immune effect in Rag1-/- (lacking T-cell and B-cell populations) mice bearing MB49 suggests that there is a long-term systemic immune modulation and antitumor activity enforced by the combination of VTP and gemcitabine. Additional analyses by flow cytometry and immunohistochemistry suggests that the combination of gemcitabine and VTP induces both innate and adaptive immune responses. Citation Format: Kwanghee Kim, Sadna Budhu, Fengshen Kuo, Lilach Agemy, Stephen La Rosa, Sylvia Jebiwott, Karan Nagar, Chris Hughes, Jasmine Thomas, Laura Alvim, Rebecca Dubrovsky, Caoimhe Ryan, Daniel Rodriguez, Abraham Meyerson, Philip A. Watson, Natalia Kudinova, Andreas Aulitzky, Lucas M. Nogueira, Andrew Tracey, Wesley Yip, Phillip Wong, Taha Merghoub, Avigdor Scherz, Jonathan A. Coleman. Combination of gemcitabine and local tumor ablation WST-11 vascular-targeted photodynamic therapy displays superior efficacy compared to either monotherapy in a urothelial cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1336.