Gene therapy of malignant solid tumors by targeting erbB2 receptors and by activating T cells

Area of Science:

• Immunotherapy
• Oncology
• Molecular Biology

Background:

• Anti-erbB2 antibodies are used in immunotherapy.
• Combining antibody and T-cell therapies can improve outcomes.
• Engineering T cells to express anti-erbB2 single-chain variable fragments (scFv) targets erbB2-positive cells.

Purpose of the Study:

• To investigate the effect of CD28 signaling on T-cell activation and anti-tumor efficacy.
• To construct a recombinant gene encoding anti-erbB2 scFv fused with CD28 and CD3ζ signaling domains.
• To evaluate the anti-tumor activity of T cells engineered with this construct.

Main Methods:

• Constructed a retroviral vector expressing anti-erbB2 scFv/Fc/CD28/CD3ζ.
• Transduced T cells with the retroviral vector.
• Assessed T cell activation and cytotoxicity against erbB2-positive tumor cells.
• Measured cytokine secretion (IFN-γ and IL-2).

Main Results:

• Engineered T cells specifically lysed erbB2-positive tumor cells.
• T cells secreted interferon-γ (IFN-γ) and IL-2 upon target cell binding.
• A single molecule delivering both CD3 and CD28 signals was sufficient for T cell activation.
• Exogenous B7/CD28 co-stimulation was not required.

Conclusions:

• The anti-erbB2 scFv/Fc/CD28/CD3ζ construct enables T cells to effectively target and lyse erbB2-positive tumor cells.
• Combined CD3 and CD28 signaling via a single fusion molecule promotes complete T cell activation.
• This approach offers a potential strategy for enhanced adoptive T-cell immunotherapy against erbB2-expressing cancers.