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October 19, 2020
The Chen Lab has identified a promising target for chimeric antigen receptor T (CAR-T) cell-based therapies for acute myeloid leukemia. CAR-T cell-based therapies have produced remarkable responses in patients with certain blood cancers, but translating that success to the treatment of other cancers has proven challenging. CAR-T cells are immune cells that have been engineered to home in on cancer cells by targeting antigens—fragments of proteins displayed on a cell’s surface—that are associated with tumors. However, since healthy tissues can also express some tumor-associated antigens, they may be targeted by CAR-T cells, leading to toxic effects in patients. Additionally, cancer cells can gain resistance to the therapy, if they stop expressing the targeted tumor-associated antigens.
In a study appearing in Nature Biomedical Engineering, Chen Lab researchers circumvented both of these outcomes in cell lines and mouse models of acute myeloid leukemia (AML) by targeting a mutant form of the gene encoding for the protein nucleophosmin, NPM1c. NPM1 mutation is a key step in the transformation of healthy cells into leukaemic cells, with the NPM1c variant occurring in about a third of AML patients. Researchers used a yeast surface display approach to identify a binder for antigens resulting from NPM1c, and then used the binder to develop CAR-T cells that were highly effective against AML cells. Because NPM1c is present only in cancer cells, the CAR-T cells are likely to produce no or minimal toxicity in healthy tissues. Resistance is unlikely to develop, since cancer cells depend on expression of mutant NPM1 for survival. The Chen Lab will adapt this approach to target NPM1c using natural killer cells (CAR-NK), with support from the Koch Institute Frontier Research Program through the Michael (1957) and Inara Erdei Fund and the Kathy and Curt Marble Cancer Research Fund.