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• W2034608303 abstract "Immune-mediated tumor eradication requires the adequate expansion, trafficking and intra-tumoral activation of tumor antigen- specific T cells. Suboptimal T cell activation results in anergy and apoptosis, thereby aborting effective tumor immunity. To avoid these pitfalls, tumor-specific T cells must be given optimal activating signals at the time of antigen priming and restimulation. It is not clear, however, what costimulatory ligands or combinations thereof are best suited to achieve tumor eradication, what activating mechanisms are redundant, antagonistic or additive, nor how to most effectively provide T cell costimulation in a clinically relevant fashion. Chimeric molecules are a useful means to probe the ligand binding and signaling functions of costumulatory receptors. In the context of CARs, we and others have shown that the addition of CD28 sequences to CD3_ chain-based receptors increases in vitro antigen-induced T cell expansion and improves the response rate in tumor-bearing mice treated with CD3_-based CARs.To provide combined CD28 and 4-1BB signals in antigen-dependent fashion, we generated tandem chimeric receptors and investigated their effect on human primary CD8+ T cell proliferation, cytokine secretion, survival and eradication of established prostate-specific membrane antigen (PSMA)-positive tumor cells in xenogeneic chimeras. We have successfully generated a tumor antigen-specific receptor that signals through serial endodomains derived from CD3_, CD28 and 4-1BB. We analyzed its function in human primary CD8+ T lymphocytes in vitro and in vivo, comparing it to other PSMA- specific receptors that only contain 1 or 2 of these domains. All chimeric receptors effectively killed PSMA-positive tumor cell lines in vitro, underscoring their antigen-specificity and sufficient signaling strength to trigger cytolysis. In proliferative assays, the z chain receptor was not able to offset T cell apoptosis, unless it was complemented with either CD28 (P28z) or 4-1BB (PBBz) cytoplasmic domains. Both dual-fusion receptors increased secretion of IFN-g, GM-CSF, and TNF-a upon restimulation of rested T cells with cell-bound PSMA and decreased T cell death following exposure to antigen, albeit to a lesser extent for the 4-1BB–based receptor than for P28z. The poor in vivo performance of the PBBz receptor suggests that enhanced cytokine secretion is not sufficient to increase tumor rejection. In summary, several mechanisms may have contributed to the increased anti-tumor activity of the P28BBz+ CD8 T cells, including the enhanced cytokine production, CTL activity, tumor antigen- induced proliferation and T cell survival. This receptor should be useful to sustain the function of CD8+ T cells targeting prostate cancer in patents with hormone refractory disease." @default.
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• W2034608303 date "2006-01-01" @default.
• W2034608303 modified "2023-09-28" @default.
• W2034608303 title "269. Integrated CD28 and 4-1BB Signals Strongly Potentiate CD8+ T Cell Mediated radication of Metastatic Prostate Cancer" @default.
• W2034608303 doi "https://doi.org/10.1016/j.ymthe.2006.08.323" @default.
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