A phage display selected fab fragment with MHC class I-restricted specificity for MAGE-A1 allows for retargeting of primary human T lymphocytes.
The clinical benefit of adoptive transfer of MHC-restricted cytotoxic T lymphocytes(CTL) for the treatment of cancer is hampered by the low success rate to generate antitumor CTLs. To bypass the need for tumor-specific CTL, we developed a strategy that allows for grafting of human T lymphocytes with MHC-restricted antigen specificity using in vitro selected human Fab fragments fused to the Fc(epsilon)RI-gamma signaling molecule. Retroviral introduction of a Fab-based chimeric receptor specific for MAGE-A1/HLA-A1 into primary human T lymphocytes resulted in binding of relevant peptide/MHC complexes. Transduced T lymphocytes responded to native MAGE-A1/HLA-A1POS target cells by specific cytokine production and cytolysis. Therefore, peptide/MHC-specific Fab fragments represent new alternatives to TCR to confer human T lymphocytes with tumor specificity, which provides a promising rationale for developing immunogene therapies.
Willemsen
R A
RA
Department of Clinical and Tumor Immunology, Academic Hospital Rotterdam/Daniel den Hoed Cancer Center, The Netherlands.
Debets
R
R
Hart
E
E
Hoogenboom
H R
HR
Bolhuis
R L
RL
Chames
P
P
D000951:Antigens, Neoplasm; D000939:Epitopes; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D015788:HLA-A1 Antigen / Q000276:immunology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000235:genetics* / Q000378:metabolism; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins / Q000276:immunology; D019151:Peptide Library; D011971:Receptors, Immunologic / Q000235:genetics*; D012190:Retroviridae / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D000939:Epitopes; D015788:HLA-A1 Antigen; D007140:Immunoglobulin Fab Fragments; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D019151:Peptide Library; D011971:Receptors, Immunologic