Cancer agnostic potential of CAR T cells targeting the urokinase plasminogen activator receptor

We previously identified the urokinase plasminogen activator receptor (uPAR) as a cell-surface protein expressed on subsets of myeloid cells and broadly upregulated in senescent states. Murine uPAR-targeting CAR T cells can ameliorate fibrosis and prophylactically prevent metabolic syndrome in aged mice, paving the way for their use in senescence-driven pathologies. uPAR can also be expressed at high levels in cancer and, by performing a pan-cancer analysis, we now show that subsets of most tumor types display strong uPAR expression, which correlates with an epithelial-mesenchymal transition (EMT)-like state, increased fibrosis, metastasis, and poor patient outcomes.

Single-cell and spatial analyses revealed that tumors with high uPAR expression in tumor cells often harbor senescent-like, uPAR-positive stromal cells, typically subsets of fibroblasts and macrophages. In mouse models, CAR T cells with uPAR-targeting single-chain variable fragments (scFvs) showed potent and persistent efficacy against multiple tumor types. In the context of high-grade serous ovarian cancer, adjuvant CAR T cell treatment following primary tumor debulking surgery cured mice by eliminating distal organ metastases. uPAR CAR T cells were well-tolerated, demonstrating efficacy in syngeneic and humanized immune system models without significant disruption of the myeloid compartment.