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

Document Type

Article

Publication Date

3-26-2021

Publication Title

Mol Ther Oncolytics

Keywords

oregon; portland; chiles

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 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.

Clinical Institute

Cancer

Department

Earle A. Chiles Research Institute

Department

Oncology

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