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Targeting of T lymphocytes to Neu/HER2-expressing cells using chimeric single chain Fv receptors
I Stancovski1, D G Schindler, T Waks
1Department of Chemical Immunology, Weizmann Institute of Science, Rehovot, Israel.
Abstract:
Cell surface molecules essential for the transformed phenotype or growth of malignant cells are attractive targets for anticancer immunotherapy. Antibodies specific to Neu/HER2, a human adenocarcinoma-associated growth factor receptor, were demonstrated to have tumor-inhibitory capacity. Yet, the inefficient accessibility of antibodies to solid tumors limits their clinical use. To redirect effector lymphocytes to adenocarcinomas, we constructed and functionally expressed in T cells chimeric single chain receptor genes incorporating both the Ag-binding domain of anti-Neu/HER2 antibodies and the zeta-signal-transducing subunit of the TCR/CD3 complex or the gamma-signal-transducing subunit of the Ig Fc receptor complex. Surface expression of the anti-Neu/HER2 chimeric genes in cytotoxic T cell hybridomas endowed them with specific Neu/HER2 recognition enabling their activation for IL-2 production and lysis of transformed cells overexpressing Neu/HER2. These chimeric genes hold promise for the immunotherapy of cancer.
Insights
Researchers engineered chimeric receptors in T cells to target Neu/HER2-positive adenocarcinomas. This immunotherapy approach enhances T cell activation for targeted cancer cell lysis, showing promise for cancer treatment.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Cell surface molecules are key targets for anticancer immunotherapy.
- Antibodies against Neu/HER2 show tumor-inhibitory potential but face accessibility challenges in solid tumors.
Purpose of the Study:
- To develop a novel immunotherapy strategy by redirecting effector lymphocytes to adenocarcinomas.
- To construct and express chimeric single-chain receptors in T cells for targeted cancer recognition.
Main Methods:
- Engineered chimeric single-chain receptor genes combining anti-Neu/HER2 antibody binding domains with T cell receptor/Fc receptor signaling subunits.
- Expressed these chimeric genes in cytotoxic T cell hybridomas.
- Assessed T cell activation via IL-2 production and tumor cell lysis.
Main Results:
- Surface expression of chimeric genes conferred specific Neu/HER2 recognition on T cells.
- Activated T cells demonstrated enhanced IL-2 production and lysis of Neu/HER2-overexpressing cancer cells.
- Chimeric receptors effectively redirected T cell-mediated cytotoxicity.
Conclusions:
- Chimeric single-chain receptors are a promising tool for enhancing T cell-based immunotherapy against Neu/HER2-positive adenocarcinomas.
- This approach overcomes antibody accessibility limitations by engineering T cells for direct tumor targeting.
- Further development holds potential for effective cancer immunotherapy strategies.