Selection of human antibody fragments directed against tumor T-cell epitopes for adoptive T-cell therapy.
Adoptive transfer of antigen-specific T-cells has shown therapeutic successes in the treatment of tumors in patients with metastatic melanoma. Tumor antigen-specific T-lymphocytes, however, occur only at low frequencies in a small proportion of patients. This low T-lymphocyte frequency together with the difficulties associated with in vitro generation of T-lymphocytes specific for cancers other than melanoma hampers adoptive T cell therapy. To make adoptive T-cell therapy more uniformly applicable, strategies were developed at transferring tumor-specificity to primary human T-lymphocytes via antibody (Ig) or T-cell receptor (TCR) molecules. We exploited the selection power of phage display that allows for the testing of tens of billions of individual clones with a high-throughput selection of Fabs with peptide/MHC complex binding capacity. Following in vitro selection, human "TCR-like" Fab fragments have been functionally expressed on human T-lymphocytes, resulting in MHC-restricted, tumor-specific lysis and cytokine production. Currently, we have extended our selections to a panel of class I and II MHC-restricted MAGE and other tumor-specific epitopes, and would like to propose that phage display represents a technology able to expand T-cell therapy to numerous tumor types.
Willemsen
Ralph
R
Department of Medical Oncology, Unit Clinical and Tumor Immunology, Tumor Immunology Group, Erasmus MC-Daniel den Hoed Cancer Center, 3075 EA Rotterdam, The Netherlands. r.a.willemsen@erasmusmc.nl
Chames
Patrick
P
Schooten
Erik
E
Gratama
Jan Willem
JW
Debets
Reno
R
D000912:Antibodies, Neoplasm / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006801:Humans; D007128:Immunoglobulin Fragments / Q000276:immunology*; D016219:Immunotherapy, Adoptive; D009369:Neoplasms / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology
D000912:Antibodies, Neoplasm; D018984:Epitopes, T-Lymphocyte; D007128:Immunoglobulin Fragments; D011948:Receptors, Antigen, T-Cell