| Autor: |
Tamson V. Moore, Gina M. Scurti, Matthew DeJong, Siao-Yi Wang, Annika V. Dalheim, Courtney R. Wagner, Kelli A. Hutchens, Jodi J. Speiser, Constantine V. Godellas, Chris Fountain, Jessica Fleser, Tarsem Moudgil, Mallory Thomas, David Murray, Brendan D. Curti, Joseph I. Clark, Bernard A. Fox, Michael I. Nishimura |
| Jazyk: |
angličtina |
| Rok vydání: |
2021 |
| Předmět: |
|
| Zdroj: |
Molecular Therapy: Oncolytics, Vol 20, Iss , Pp 352-363 (2021) |
| Druh dokumentu: |
article |
| ISSN: |
2372-7705 |
| DOI: |
10.1016/j.omto.2021.01.014 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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