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

Area of Science:

• Immunology
• Oncology
• Gene Therapy

Background:

• Adoptive T cell therapy using gene-modified T cells targeting tumor antigens is a promising strategy for metastatic melanoma.
• Tumor-specific T cell receptors (TCRs) are engineered into autologous T cells to enhance anti-tumor immune responses.

Purpose of the Study:

• To investigate the dynamics of transgene expression in T cells modified with a tyrosinase-reactive TCR (TIL 1383I) in metastatic melanoma patients.
• To identify factors influencing the maintenance of transgene expression in gene-modified T cells post-infusion.

Main Methods:

• A clinical trial involving seven metastatic melanoma patients treated with autologous T cells engineered to express TIL 1383I TCR and a CD34 selection marker.
• Monitoring of transgene expression in TCR-transduced T cells after infusion.
• In vitro studies assessing transgene expression under different culture conditions, including stimulation with anti-CD3/anti-CD28 beads, cytokines (IL-15), and histone deacetylase (HDAC) inhibitors.

Main Results:

• Both lentiviral and retroviral transduction resulted in loss of transgene expression by 4 weeks post-transfer.
• Transgene expression could be reactivated by stimulation with anti-CD3/anti-CD28 beads and cytokines.
• In vitro culture without cytokines led to transgene downregulation, while culture with IL-15 maintained expression.
• Histone deacetylase (HDAC) inhibitors maintained transgene expression and functional T cell responses to tumor.

Conclusions:

• Epigenetic mechanisms likely contribute to the loss of transgene expression in lentiviral- and retroviral-transduced T cells.
• Interleukin-15 and HDAC inhibitors show potential for maintaining transgene expression and function in gene-modified T cell therapies.
• Further research into epigenetic regulation is crucial for optimizing T cell receptor-based immunotherapies for melanoma.