Targeting cell surface protein uPAR with car t cell therapy to treat solid tumors and surroundings
Chimeric antigen receptor T-cell therapy — CAR T for short — has been a major advance in treating blood cancers like leukemia and lymphoma. But the immunotherapy has struggled against solid tumors for two main reasons: tumor cells often don’t share one consistent surface target, and many solid tumors are protected by a dense network of scar tissue and immune-suppressive cells that blocks T cells.
Now, researchers have developed a new type of CAR T cell designed to address both problems at once — by attacking cancer cells as well as supportive cells in the tumor microenvironment that bear a surface protein called uPAR.
The preclinical findings, published in Cell, still need to be tested for safety and efficacy in people.
“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,” says co-senior study author.
“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,” the author adds.
The team tested the effectiveness of the uPAR-targeted CAR T cells in a range of preclinical systems, including cancer cells, human tumors grown in mice, and mouse models that mimic metastatic disease.
Overall, the new approach shows significant power to fight cancer with limited impact on other healthy tissues and cells, the researchers report.
In a mouse model of ovarian cancer, for example, uPAR-targeting CAR T cells were able to wipe out metastases, leading to durable remissions. And mice whose tumors had been eliminated also resisted developing new tumors when researchers tried to introduce cancer again later, indicating the CAR T cells remained active.
Additionally, a single, adjuvant dose of the engineered cells after surgery eliminated residual disease in mice, while surgery alone helped only temporarily.
The urokinase plasminogen activator receptor — or uPAR — 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.
But in cancer, which co-opts the body’s normal wound healing programs, both tumor cells and cells in the fibrous “niche” that support the tumor produce a lot more uPAR.
By focusing on uPAR, the new approach allows researchers to target cells in a particular state rather than a specific type of cell.
The CAR T cells that target CD19 in leukemia and lymphoma, for example, primarily target B cells — including cancer cells that develop from B cells. uPAR, on the other hand, tends to show up on the most dangerous, identity-shifting cancer cells — as well as on nearby support cells that are stuck in a constant wound-healing mode, building scar tissue and suppressing the immune response.
“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,” the author says.
The researchers became interested in uPAR through studies of “cellular senescence” — a brake the body imposes on damaged or stressed cells, which stops them from dividing.
Some standard cancer treatments like chemotherapy can also push cells into senescence — raising uPAR levels in tumor cells.
In the study, researchers found uPAR was elevated in 12 of the 14 human cancer types they analyzed, with especially high levels in some types of ovarian, pancreatic, colon, lung, and brain cancers.
“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,” the author says. “We also found high uPAR was associated with the activation of genes that are important for cellular plasticity, inflammation, and fibrosis, which are all hallmarks of aggressive cancer.”
In preclinical experiments, uPAR-targeted CAR T cells were effective at killing cancer cells across multiple cancer models. And their effect could be further enhanced by combining them with senescence-inducing treatments such as the chemotherapy agent cisplatin, which raised uPAR levels and made tumor cells easier for the engineered T cells to attack.
Testing showed that the engineered cells worked most effectively when there were at least 1,500 uPAR molecules on the surface of each cell.
And to make the engineered cells even more effective, the team developed the new CAR T cells using new uPAR-binding molecules designed to recognize a form of uPAR that is less likely to be shed from the cell surface due to inflammation.
Importantly, uPAR-directed CAR T cells could attack tumors from multiple angles, the author 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,” the author says. “That is something unique.”
The researchers believe targeting uPAR also holds promise for diseases beyond cancer.
“The same types of cells and tissues that we find around tumors are important in other fibrotic, degenerative, and inflammatory disorders,” the author says.
Beyond CAR T cells, uPAR might also be targeted with antibody drug conjugates, antibody-delivered radiation, and CAR-based natural killer cell treatments, the study authors note.
The researchers also showed two potential ways to monitor uPAR-high disease without a biopsy: measuring suPAR (a soluble fragment of uPAR) in blood, and using uPAR-targeted PET scans to spot tumors and metastases and track the cancer’s response to treatment over time.
