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

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.
Competing Interests: T.V.M. G.M.S., M.D., S.Y.W., A.V.D, C.R.W., K.A.H., J.J.S., C.V.G., C.F., J.F., T.M., M.T., D.M., B.D.C. B.A.F., and M.I.N. have no conflicts of interest to disclose. J.I.C. is on the speakers’ bureau for Bristol Meyers Squibb (BMS) and Merck; is a consultant for Clinigen; receives research support (to institution) from BMS, Prometheus, AVEO, and Roche/Genentech; and has a family member employed full time by BMS.
(© 2021 The Authors.)