HDAC inhibition prevents transgene expression downregulation and loss-of-function in T-cell-receptor-transduced T cells. Journal Article

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Authors: Moore, TV; Scurti, GM; DeJong, M; Wang, SY; Dalheim, AV; Wagner, CR; Hutchens, KA; Speiser, JJ; Godellas, CV; Fountain, C; Fleser, J; Moudgil, T; Thomas, M; Murray, D; Curti, BD; Clark, JI; Fox, BA; Nishimura, MI
Article Title: HDAC inhibition prevents transgene expression downregulation and loss-of-function in T-cell-receptor-transduced T cells.
Abstract: T cells that are gene-modified with tumor-specific T cell receptors are a promising treatment for metastatic melanoma patients. In a clinical trial, we treated seven metastatic melanoma patients with autologous T cells transduced to express a tyrosinase-reactive T cell receptor (TCR) (TIL 1383I) and a truncated CD34 molecule as a selection marker. We followed transgene expression in the TCR-transduced T cells after infusion and observed that both lentiviral- and retroviral-transduced T cells lost transgene expression over time, so that by 4 weeks post-transfer, few T cells expressed either lentiviral or retroviral transgenes. Transgene expression was reactivated by stimulation with anti-CD3/anti-CD28 beads and cytokines. TCR-transduced T cell lentiviral and retroviral transgene expression was also downregulated when T cells were cultured without cytokines. Transduced T cells cultured with interleukin (IL)-15 maintained transgene expression. Culturing gene-modified T cells in the presence of histone deacetylase (HDAC) inhibitors maintained transgene expression and functional TCR-transduced T cell responses to tumor. These results implicate epigenetic processes in the loss of transgene expression in lentiviral- and retroviral-transduced T cells.
Journal Title: Molecular therapy oncolytics
ISSN: 2372-7705; 2372-7705
Publisher: Unknown  
Date Published: 2021