T-cell receptor gene therapy targeting melanoma-associated antigen-A4 by silencing of endogenous TCR inhibits tumor growth in mice and human

摘要: Genetically engineered T cells expressing a T-cell receptor (TCR) are powerful tools for cancer treatment and have shown significant clinical effects in sarcoma patients. However, mismatch of the introduced TCR α/β chains with endogenous may impair expression transduced TCR, resulting an insufficient antitumor capacity modified cells. Here, we report development immunotherapy using human lymphocytes codon-optimized melanoma-associated antigen (MAGE)-A4 HLA-A*2402-restricted which specifically downregulate by small interfering RNA (si-TCR). We evaluated efficacy this both NOD-SCID mice uterine leiomyosarcoma Our results revealed that exhibited high surface tumor-specific enhanced cytotoxic activity against antigen-expressing tumor cells, increased interferon-γ production specific MAGE-A4 peptide stimulation. Retarded growth was also observed inoculated cell lines HLA-A*2402. Furthermore, successful management case treated si-TCR/HLA-A*2402 gene-modified indicate TCR-modified therapy is promising novel strategy treatment.