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- W4313356543 abstract "Abstract Clinical trials utilizing the adoptive transfer of autologous tumor antigen specific lymphocytes have demonstrated superior clinical efficacy compared to standard-of-care. However, the majority of patients do not achieve a durable complete response requiring further optimization of the therapy. The rapid expansion of therapeutic T cells increases susceptibility to Activation Induced Cell Death (AICD) following TCR restimulation in vitro. Our investigations demonstrate that TCR restimulation enhances phosphorylation of γH2AX and pSMC-1, which are markers of double-strand DNA breaks. Onset of DNA damage was accompanied by the autophosphorylation of ATM, activation of the cell-death regulator p53 via phosphorylation on Ser15, and its accumulation in the nucleus. Directed inhibition of ATM with Caffeine or KU55933 protected cells from AICD. The anti-oxidant N-acetylcysteine (NAC) prevented the onset of DNA damage and subsequent ATM/p53 activation as well as cell death. Expansion of TIL1383I transduced human T cells in NAC reduced levels of γH2AX, PD-1 and CD57 while enhancing killing of MEL624 melanoma cells in vitro. In the Pmel model, expansion of T cells in NAC increased their persistence in blood and spleen and decreased γH2AX expression. NAC treatment also increased the presence of Pmel cells in the tumor, reduced tumor growth and significantly increased survival of B16-F10 challenged mice. Taken together, these data suggest the addition of NAC to current therapeutic T cell expansion protocols has the potential to improve the quality and therapeutic efficacy of the cell product infused into patients." @default.
- W4313356543 created "2023-01-06" @default.
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- W4313356543 date "2016-05-01" @default.
- W4313356543 modified "2023-09-23" @default.
- W4313356543 title "N-acetylcysteine protects melanoma specific cytotoxic T cells from TCR restimulation induced DNA damage and enhances tumor control in vitro and in vivo." @default.
- W4313356543 doi "https://doi.org/10.4049/jimmunol.196.supp.144.14" @default.
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