Abstract PR012: Targeting Chronic Inflammation in Ovarian Cancer Through Immune Engineering

Abstract Background: Chronic inflammatory disorders contribute to over 30% of global mortality and underlie major diseases such as cancer, fibrosis, and autoimmunity. Fibrosis is a hallmark of chronic inflammation following tissue injury that drives progressive organ dysfunction and cancer progression. Existing anti-fibrotic therapies are limited by modest efficacy and systemic toxicity. We hypothesize that the selective elimination of fibrogenic and inflammatory effector cells can disrupt self-perpetuating cycles of injury and inflammation, providing a targeted therapeutic avenue for chronic disease. Methods: Using proximity-based surface proteomics, we identified the urokinase plasminogen activator receptor (uPAR) as broadly upregulated in senescent and chronically injured tissues across cancer and fibrotic contexts. This was corroborated by a meta-analysis of eight senescence-focused and sixteen cancer transcriptomic datasets, as well as immunohistochemical validation on patient tissue microarrays. uPAR, a GPI-anchored membrane protein central to wound healing and tissue remodeling, is consistently elevated during chronic inflammation in cancer and fibrosis. In a somatic tissue-engineered syngeneic mouse model of ovarian cancer, we demonstrated the anti-tumor efficacy of murine uPAR-targeted CAR T cells. We then generated clinical-grade human uPAR-targeting single-chain variable fragments (scFvs) through phage display and hybridoma screening and validated their ability to eradicate both orthotopic and metastatic xenograft tumors. Results: uPAR-targeted CAR T cells selectively eliminated senescent cells and attenuated fibrosis in preclinical models of liver and lung injury. In cancer, uPAR expression marks aggressive tumor cells undergoing epithelial-to-mesenchymal transition (EMT) and senescent stromal cells embedded in immunosuppressive niches. In multiple solid tumor models, including immune-excluded settings, human uPAR CAR T cells exhibited potent and durable anti-tumor activity. In an ovarian cancer model, adjuvant administration of uPAR CAR T cells post-surgical debulking effectively prevented metastatic recurrence. Therapeutic efficacy was tracked via noninvasive biomarkers, including circulating soluble uPAR and uPAR-targeted PET imaging. Despite detectable expression in subsets of myeloid cells, treatment with uPAR CAR T cells did not induce sustained myelodepletion in mice with a humanized immune system. Conclusions: These findings establish uPAR-targeted CAR T cells as a promising therapeutic strategy across cancer, fibrosis, and degenerative diseases by eliminating shared pathological cell states that sustain chronic inflammation and tissue dysfunction. Citation Format: Zeda Zhang, Yu-jui Ho, Xin Fang, Clemens Hinterleitner, Sascha Haubner, Friederike Rieke, Edwin Pratt, Marguerite Li, Wei Luan, Minseo Kim, Elif Ozcelik, Kevin Chen, Amanda Kulick, Eric Chan, Eric Rosiek, Elisa de Stanchina, Britta Weigelt, Judith Feucht, Ignacio Vazquez-Garcia, Dmitriy Zamarin, Sohrab Shah, Jason Lewis, Corina Amor, Jorge Mansilla-Soto, Aveline Filliol, Michel Sadelain, Scott Lowe. Targeting Chronic Inflammation in Ovarian Cancer Through Immune Engineering [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr PR012.