CAR T
Published on May 07, 2024
CAR-TEAM cells used to target PDAC cells and CAFs within the TME
by Clinical Cancer Research
Wehrli M, Guinn S, Birocchi F, et al. Mesothelin CAR T-Cells Secreting Anti-FAP/Anti-CD3 Molecules Efficiently Target Pancreatic Adenocarcinoma and Its Stroma. Clinical Cancer Research. 2024; (doi: 10.1158/1078-0432.CCR-23-3841).
Mesothelin-directed chimeric antigen receptor (CAR) T-cells have had only limited success in treating pancreatic ductal adenocarcinoma (PDAC), but researchers have uncovered a strategy to overcome thick stroma in PDAC that contributes to a challenging tumor microenvironment (TME). To address the stroma, which is generated by cancer-associated fibroblasts (CAFs), investigators designed T-cells with an anti-mesothelin CAR and a secreted T-cell engaging molecule (TEAM) that targets CAFs through fibroblast activation protein (FAP) and engages T-cells through CD3. The capacity for mesoFAP CAR-TEAM cells to target PDAC cells and CAFs within the TME was observed in a series of patient-derived models and also mouse models of PDAC with primary or metastatic liver tumors. When released from mesothelin-targeting CAR T cells, the TEAM sought out and bound to CD3 and FAP, stimulating T cell activation and cytotoxicity of the target cell. The results demonstrate that mesoFAP CAR-TEAM cells support modification of tumor stroma, allowing them to more efficiently eliminate PDAC and CAFs than T-cells engineered to target either antigen individually.
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