Specific targeting of EGP-2+ tumor cells by primary lymphocytes modified with chimeric T cell receptors
| Autor: | K. T. Trevor, G. T. Hayman, L. Ren-Heidenreich |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Tumor targeting
T cell medicine.medical_treatment Genetic enhancement Recombinant Fusion Proteins Receptors Antigen T-Cell Tumor cells Biology Lymphocyte Activation law.invention law Antigens Neoplasm Transduction Genetic Genetics medicine Tumor Cells Cultured Humans Amino Acid Sequence Lymphocytes Molecular Biology DNA Primers Recombination Genetic Base Sequence T-cell receptor Immunotherapy T lymphocyte Epithelial Cell Adhesion Molecule Molecular biology medicine.anatomical_structure Cancer research Recombinant DNA Molecular Medicine Cell Adhesion Molecules |
| Zdroj: | Human gene therapy. 11(1) |
| ISSN: | 1043-0342 |
| Popis: | A promising strategy for cancer treatment is adoptive immunotherapy with gene-modified lymphocytes expressing a chimeric T cell receptor (cTCR) that directs tumor targeting and stimulates T cell effector functions. In this study, the activities of two novel cTCR molecules (GAgamma and GAHgamma) were investigated. Both encode a single-chain variable fragment (scFv) derived from the monoclonal antibody (MAb) GA733.2, which binds the epithelial glycoprotein 2 (EGP-2) overexpressed on a variety of human carcinomas. In the GAgamma cTCR, the scFv is directly fused to the transmembrane/cytoplasmic portions of the immunoglobulin Fc receptor (Ig FcRI) gamma subunit, which mediates T cell signaling. GAHgamma possesses an extracellular spacer composed of the CD8alpha immunoglobulin hingelike domain inserted between the scFv and gamma chain. Activated T cells (ATCs), stimulated ex vivo using anti-CD3 MAb, were derived from either healthy donors or patients and transduced with recombinant retrovirus encoding the respective GA cTCR molecules. After culture expansion for 14 days, GAgamma-modified ATCs demonstrated enhanced targeting and lysis of EGP-2+ colon cancer cells and increased cytokine secretion. Cells transduced with the GAHgamma cTCR displayed specific lytic activity that was about twofold greater than that of GAgamma-ATCs and produced significantly more cytokine. In addition, reactivation of GAHgamma-ATC with anti-CD3 MAb prior to addition to EGP-2+ tumor target induced a further increase in lytic activity. Because the activation status influences T cell antitumor functions, our data suggest that reactivation prior to adoptive transfer would improve the clinical efficacy of GAHgamma-modified ATCs. |
| Databáze: | OpenAIRE |
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