Researchers at Memorial Sloan Kettering Cancer Center and collaborators announced on March 30 the development of a new type of chimeric antigen receptor T-cell (CAR T) therapy aimed at treating hard-to-treat solid tumors. The findings, published in Cell, show that the engineered CAR T cells can attack both cancer cells and supportive cells in the tumor microenvironment that display a protein called uPAR.
This approach is significant because traditional CAR T therapies have been successful against blood cancers but have struggled with solid tumors due to inconsistent surface targets and protective barriers formed by scar tissue and immune-suppressive cells. The new strategy aims to overcome these obstacles by targeting uPAR-positive fibroblasts and myeloid cells as well as tumor cells.
"This new approach shrank several types of solid tumor in the lab, including lung, pancreatic, and ovarian cancers - and even cleared metastases in some experiments," said Scott Lowe, PhD, co-senior study author and Chair of the Cancer Biology and Genetics Program at Sloan Kettering Institute. "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," he said.
The preclinical tests involved human cancer cell lines grown in mice as well as mouse models simulating metastatic disease. Results showed significant anti-cancer activity with limited effects on healthy tissues. In one experiment involving ovarian cancer models, mice treated with uPAR-targeted CAR T cells achieved durable remissions after their metastases were eliminated. Additional experiments indicated that combining this therapy with senescence-inducing treatments like cisplatin could further enhance its effectiveness.
Zeda Zhang, PhD, first author of the study from the Lowe Lab at MSK, explained: "Our work shows uPAR marks not only malignancy, but also the broader ecosystem that supports cancer - a feature that sets uPAR apart from other cell-surface targets." Senior authors include Michel Sadelain MD PhD (now at Columbia University) and Aveline Filliol PhD from MSK.
The researchers found high levels of uPAR expression across many human cancer types analyzed—especially those with mutations affecting p53 or genes within the RAS pathway—suggesting potential broad applicability for this therapeutic approach. According to Dr. Filliol: "High uPAR expression was most strongly associated with mutations that compromise p53 - the tumor-suppressor often called the 'guardian of the genome' - and activating mutations in KRAS and other genes in the RAS pathway... We also found high uPAR was associated with activation of genes important for cellular plasticity, inflammation, and fibrosis..."
Looking ahead, researchers are considering additional ways to target or monitor diseases characterized by elevated uPAR levels beyond oncology—including fibrotic or inflammatory disorders—and exploring alternative treatment modalities such as antibody drug conjugates or natural killer cell-based therapies. The next steps will involve further testing for safety and efficacy before advancing toward clinical trials.
