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

Abstract

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

• Authors: Qian Sun, Xiying Zhang, Limei Wang, Xujie Gao, Yanjuan Xiong, Liang Liu, Feng Wei, Lili Yang, Xiubao Ren
• Journal: Cell death & disease (Cell Death Dis) Vol. 10 Issue 7 Pg. 475 (06 17 2019) ISSN: 2041-4889 [Electronic] England
• PMID: 31209257 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• HLA-A Antigens
• MAGEA4 protein, human
• Neoplasm Proteins
• Receptors, Antigen, T-Cell
• Interferon-gamma

Topics

• Adoptive Transfer
• Animals
• Antigens, Neoplasm (genetics, therapeutic use)
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Female
• Gene Silencing
• Genetic Therapy
• HLA-A Antigens (metabolism)
• Humans
• Interferon-gamma (metabolism)
• Leiomyosarcoma (genetics, therapy)
• Lymphocytes (metabolism)
• Melanoma (genetics, pathology, therapy)
• Mice, Inbred NOD
• Mice, SCID
• Neoplasm Proteins (genetics, therapeutic use)
• Receptors, Antigen, T-Cell (genetics)
• Uterine Neoplasms (genetics, therapy)