Abstract 6644: aPD1 treatment of urothelial cancers is synergistically enhanced by activating anti tumor immunity using vascular targeted photodynamic therapy
Authors: Agemy Lilach , Sasson Keren , Yechezkel Tamar , Hamri Rachel , Robas Raz , Kain David , Scherz Avigdor 
Published: March 2024

Abstract
Background: Recurrence and progression rate following surgical treatment of locally advanced urothelial cancer is high, underscoring the unmet need to develop an effective, well tolerated treatment strategies, particularly for high grade upper tract urothelial cancer (HG-UTUC). The treatment success of low grade UTUC by vascular targeted photodynamic therapy (VTP) with WST11 (Padeliporfin) in phase I clinical trials led the FDA to approve Phase 3 trial in a fast track, orphan drug designation for low grade UTUC (ENLIGHT). Recently, treatment with immune checkpoint inhibitor (ICIs) of the PD1/PD-L1 axis has been approved for treatment of HG-UTUC. Yet, the failure rate of aPD1 therapy in HG-UTUC is high.We hypothesized that immune checkpoint inhibition needs to be complemented by the massive priming and accrual of newly activated anti-tumor immune cells through tumor immunogenic cell death. Early evidence indicated that WST11 VTP promotes anti-tumor immunity suggesting that VTP/aPD1 combinations may significantly improve the treatment success of HG-UTUC.
Methods: Mice bearing s.c. MB49-Luc, were subjected to WST11 VTP at 14d post implantation at suboptimal dose of drug or partial area of illumination. 4 or 5 doses of aPD1 were intraperitonealy administrated every 3 days starting at 1d post VTP (aPD1+1), or every 3 days till 10 days post-treatment starting at 2 days before VTP (aPD1-2). Tumor progression was followed up to 90 days post treatment using IVIS. Hematoxylin-eosin staining, and multiplex immunohistochemistry (mIHC) were performed on controls and treated animals.
Results: WST11 VTP with suboptimal drug dose, aPD1+1, and aPD1-2 resulted in 17%, 23% and 43% cure at day 90 post VTP. VTP at suboptimal drug dose combined with aPD1+1 or aPD1-2, resulted in 50% and 77% cure rate at 90 days, respectively. VTP with optimal drug dose (5mg/kg) but partial illumination resulted in 20% cure rate while combining this treatment modality with aPD1-2 resulted in 90% animal cure rate at day 90.At 24h post VTP mIHC showed a 2-3 fold increase of cytotoxic T cells, dendritic and NK cells, and a ~4 folds overexpression of PD1 and PD-L1 in the treated tumor tissue. At 2 days post aPD1-2 initiation, PD1 and PD-L1 apparent expression dropped to 0 and 2 folds higher than control, respectively. Following the combined VTP and aPD1-2 treatment, both PD1 and PDL-1 contents dropped down to zero and the CD8 content reached 3 folds enhancement compared to control.
Conclusions: These observations indicate that elevating the content of anti-tumor immune cells in the tumor microenvironment by VTP in combination with ICI synergistically enhances the therapeutic effect providing a much higher complete cure compared with the individual therapies. The cure rate extent strongly depends on the synchronization of the two modalities providing guidelines for the clinical management of HG-UTUC treatment.
Citation Format: Lilach Agemy, Keren Sasson, Tamar Yechezkel, Rachel Hamri, Raz Robas, David Kain, Avigdor Scherz. aPD1 treatment of urothelial cancers is synergistically enhanced by activating anti tumor immunity using vascular targeted photodynamic therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6644.