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- W4313407907 abstract "Abstract A major challenge in T cell therapy against solid tumors is the heterogeneity of tumor antigen (TA) expression. Elimination of TA+ tumor cells often fails to suppress tumor growth due to the expansion of TA− tumor cells. To address this, we developed tumor-activated alloreactive T cells (TAATs) that display alloreactivities only in tumors. TAATs lack endogenous CD3ɛ expression and contain a tumor sensing mechanism that drives the expression of an exogenous copy of CD3ɛ in the presence of TA+ tumor cells. TAATs are therefore inactive in normal tissues due to retention of TCR/CD3 in the ER but become alloreactive in tumors. TAATs attack all HLA+ cells in tumors including tumor cells, stromal cells and cells that suppress immune functions. To generate TAATs, HLA-mismatched allogeneic T cells were stimulated with HLA class I+ breast cancer cells to expand alloreactive T cells. Endogenous CD3ɛ expression was then knocked out using CRISPR/Cas9. The T cells were also modified to express a Her2-specific synthetic Notch receptor that releases an intracellular domain containing a Gal4-VP64 transcription activator upon receptor engagement. In addition, an expression cassette with a CD3ɛ coding sequence driven by a promoter containing Gal4 binding sites was introduced to the T cells. When co-cultured with Her2+ cancer cells, TAATs restored TCR/CD3 expression and were able to degranulate and produce IFNγ in response to anti-CD3 stimulations. TAATs were also able to kill Her2+ cancer cells in co-cultures and kill Her2− cancer cells in the presence of Her2+ cancer cells. Compared with CAR T cells, TAATs may achieve superior tumor suppression through attacking a wider range of cells in tumors and by overcoming the immunosuppressive tumor microenvironment." @default.
- W4313407907 created "2023-01-06" @default.
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- W4313407907 date "2022-05-01" @default.
- W4313407907 modified "2023-09-23" @default.
- W4313407907 title "Directing T cell alloreactivity against solid tumors through tumor antigen dependent TCR expression" @default.
- W4313407907 doi "https://doi.org/10.4049/jimmunol.208.supp.122.12" @default.
- W4313407907 hasPublicationYear "2022" @default.
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