Integrating padeliporfin vascular-targeted photodynamic therapy with enfortumab vedotin and immune checkpoint blockade in urothelial cancer models

Vascular-targeted photodynamic therapy (VTP) has demonstrated efficacy in the ongoing phase III trial for low-grade upper tract urothelial carcinoma (UTUC), achieving a 78% complete response rate (NCT0420239). VTP is a local ablation therapy where light activated padeliporfin occludes tumor blood vessels, causing tumor necrosis while sparing healthy urothelium. VTP induces systemic antitumor immunity and was reported to potentiate PD-1/PD-L1 immune checkpoint blockade (ICB) while preventing lung metastases in kidney and bladder cancer models. Enfortumab vedotin (EV), an antibody-drug conjugate targeting Nectin-4, with pembrolizumab (Pembro), improved overall and progression-free survival versus chemotherapy in locally advanced or metastatic urothelial carcinoma, with a 30.4% complete response rate (Phase III EV-302/KEYNOTE-A39, NCT04223856). Given the local ablation and immune activities of VTP, its combination with EV+Pembro may improve UTUC responses. To better understand how patients with UTUC might benefit from such combination strategies, we investigated antibody drug conjugate (ADC) and ICB target expression using bulk RNA-seq from a UTUC patient cohort at MSKCC (n=100). A correlative study of patient PBMC samples from the VTP Phase-1 trial (NCT03617003) was performed to assess immune-modulatory activities. The effects of VTP on ADC and ICB expression were assessed using preclinical and patient tissue. Therapeutic activities of VTP in combination with ICB or EV in urothelial cancer were evaluated using both syngeneic and patient-derived xenograft (PDX) models. ADC targets (Nectin-4, Trop2, and ERBB2) were expressed higher in patients with luminal papillary compared to variant histology such as basal and squamous subtypes. ICB targets (PD1, PDL-1, CTLA-4) were higher in aggressive UTUC cases. A PDX model (UCC14) with luminal papillary characteristics and high Nectin-4 demonstrated tumor regression with 3 doses of EV. Flow cytometric analyses of patient PBMCs and preclinical data using the MB49 bladder cancer model demonstrated CD8⁺ T cell-driven immune modulation, leading us to hypothesize that VTP may complement EV and anti-PD1 by converting immune-desert tumors into more inflamed, treatment-responsive phenotypes. UCC14 and an MB49 high-Nectin-4 model are currently being evaluated to determine whether combining VTP with EV and/or Pembro enhances immune infiltration and response durability, providing translational rationale for integrating VTP with EV+Pembro in UTUC.