uPAR Targeting to Enable CAR T Cell Therapies to Treat Solid Cancers
uPAR is expressed as a surface marker on senescent cells, and researchers have published the results of targeting chimeric antigen receptor (CAR) T cell therapies to uPAR in the context of clearing senescent cells from aged tissues. Absent an enormous reduction in cost, it is unlikely that CAR T therapies will see much use in this context, but they continue to be used in cancer therapy. Here, researchers show that targeting uPAR-expressing cells in and around solid tumors enables CAR T therapy to work in this context. CAR T therapy was developed for leukemia and has so far struggled to make the jump to the more complex environment of solid tumors; different approaches are needed, and this one seems to be producing positive results so far.
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. 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.
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. 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.