HDAC inhibition prevents transgene expression downregulation and loss-of-function in T-cell-receptor-transduced T cells.
Mol Ther Oncolytics
oregon; portland; chiles
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 in vitro 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.
Keywords: HDAC inhibitors; TCR-transduced T cells; cancer immunotherapy; cell therapy; functional responses; gene silencing; gene-modified T cells; sodium butyrate; transgene silencing; vorinostat.
Earle A. Chiles Research Institute
Moore, Tamson V; Scurti, Gina M; DeJong, Matthew; Wang, Siao-Yi; Dalheim, Annika V; Wagner, Courtney R; Hutchens, Kelli A; Speiser, Jodi J; Godellas, Constantine V; Fountain, Chris; Fleser, Jessica; Moudgil, Tarsem; Thomas, Mallory; Murray, David; Curti, Brendan D; Clark, Joseph I; Fox, Bernard A; and Nishimura, Michael I, "HDAC inhibition prevents transgene expression downregulation and loss-of-function in T-cell-receptor-transduced T cells." (2021). Articles, Abstracts, and Reports. 4486.