Zhang, Zeda, Ho, Yu-jui, Fang, Xin, Hinterleitner, Clemens, Haubner, Sascha, Rieke, Friederike, Pratt, Edwin, Li, Marguerite, Luan, Wei, Kim, Minseo, Ozcelik, Elif, Chen, Kevin, Kulick, Amanda, Chan, Eric, Rosiek, Eric, de Stanchina, Elisa, Weigelt, Britta, Feucht, Judith, Vazquez-Garcia, Ignacio, Zamarin, Dmitriy, Shah, Sohrab, Lewis, Jason, Amor, Corina, Mansilla-Soto, Jorge, Filliol, Aveline, Sadelain, Michel, Lowe, Scott (September 2025) Targeting Chronic Inflammation in Ovarian Cancer Through Immune Engineering. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research, 2025 Sep 19-21, Denver, CO.
Abstract
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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>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.</jats:p> <jats:p>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.
| Item Type: | Conference or Workshop Item (Paper) |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > ovarian cancer diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL labs > Amor lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 19 September 2025 |
| Date Deposited: | 29 Oct 2025 12:32 |
| Last Modified: | 29 Oct 2025 12:32 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/41992 |
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