Targeting the epidermal growth factor receptor (HER) family by T cell receptor gene-modified T lymphocytes

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Human epidermal growth factor receptor 2 (HER2) is a validated target antigen in breast and other cancers.
• HER2 overexpression is also observed in stomach cancer and acute lymphoblastic leukemia.
• Targeting HER2 is a key strategy in developing novel cancer therapies.

Purpose of the Study:

• To investigate the potential of T cell receptor (TCR)-based immunotherapy for HER2-positive malignancies.
• To engineer primary human T cells to express a HER2-specific TCR.
• To evaluate the efficacy and specificity of these modified T cells in recognizing HER2-expressing tumor cells.

Main Methods:

• Isolation of HER2-reactive TCR genes from an allo-human leukocyte antigen-A2-restricted CTL clone.
• Introduction of TCRα- and β-chain genes into a retroviral vector (MP71).
• Murinization and codon optimization of TCR genes for enhanced expression in primary human T cells.

Main Results:

• Engineered T cells demonstrated efficient tumor recognition, comparable to the parental CTL clone.
• The HER2-reactive TCR retained its known cross-reactivity with HER3 and HER4 after transduction.
• Successful expression of the HER2-specific TCR in primary human T cells was achieved.

Conclusions:

• TCR gene transfer is a viable strategy for developing HER2-targeted T cell therapies.
• This approach holds promise for treating HER2-positive breast cancer and other HER2-expressing solid tumors and hematological malignancies.
• The retained cross-reactivity with HER3 and HER4 broadens the potential application of this therapy.