uPAR-Directed CAR-T Cells Show Promise in Solid Tumor Therapy

Chimeric antigen receptor (CAR) T-cell therapy has shown strong success in treating blood cancers, but tackling solid tumors has proven much harder. These tumors lack consistent surface targets and are protected by fibrous tissue and immune-suppressive cells that block immune attack. Researchers at Memorial Sloan Kettering Cancer Center (MSK) and collaborators have now engineered a different kind of CAR T cell that recognizes cancer cells and the tumor’s supportive network, both marked by a surface protein called uPAR.

Their study, published in Cell, describes how uPAR-targeting CAR T cells reduced or cleared multiple tumor types in laboratory models, including lung, ovarian, and pancreatic cancers. “In our laboratory models, these engineered cells selectively eliminated not only solid tumor cells, but also the uPAR-positive fibroblasts and immunosuppressive myeloid cells that provide a protective environment for the tumor to grow in,” says co-senior author Scott Lowe. In mouse models, the therapy wiped out metastases and produced durable remissions, with resistant mice rejecting tumor reintroduction later. Post-surgical treatment with a single dose of the engineered cells also prevented relapse.

uPAR, or urokinase plasminogen activator receptor, is a protein found on the outside of cells. In healthy tissue, very few cells have uPAR on their surface; it’s primarily found on myeloid immune cells, and helps with processes associated with wound healing. By focusing on a marker of this “wound-like” cell state, the new approach targets not just tumor cells but also cancer-supportive cells.

The study linked high uPAR expression to mutations in p53, KRAS, and RAS-pathway genes—hallmarks of aggressive cancer—and to increased cell plasticity and fibrosis. Enhanced sensitivity to the therapy was observed when CAR T treatment was combined with chemotherapy that induced cellular senescence, which raised uPAR levels. The engineered T cells were most effective on cells displaying at least 1,500 uPAR molecules on their surface.

Importantly, uPAR-directed CAR T cells could attack tumors from multiple angles, Sadelain says. “We’re not just targeting uPAR on the surface of tumor cells, but also the uPAR-expressing fibroblasts and myeloid cells in a tumor’s supporting ‘niche,” he adds. “That is something unique.”

Targeting uPAR could also apply to fibrotic and inflammatory disorders. The team suggests that monitoring uPAR-linked disease might one day be possible through blood tests measuring soluble uPAR or through imaging with uPAR-directed PET scans.