Selection of human antibody fragments directed against tumor T‐cell epitopes for adoptive T‐cell therapy

Abstract

Adoptive transfer of antigen-specific T-cells has shown therapeutic successes in the treatment of tumors in patients with metastatic melanoma. Tumor antigen-specific Tlymphocytes, 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. '

T Cell Receptor-Like Recognition of Tumor In Vivo by Synthetic Antibody Fragment

“…Even though up to 50% of patients treated with ex vivo expanded tumor-infiltrating lymphocytes show clinical responses [70], [98], it is not possible to produce significant quantities of tumor infiltrating T cells from all cancer patients due to the inability to either isolate or expand them in vitro . There is promise in the field of genetically modified T-lymphocytes, where TCR-like antibodies are transferred to T lymphocytes via retroviral infection for their expression on the T cell surface [99]. T cells expressing tumor-specific receptors, chimeric antigen receptors and modified TCRs specifically killed tumor cells and had antitumor effects in vivo [100]–[103].…”

In VitroSelection of Cancer Cell-Specific Molecular Recognition Elements from Amino Acid Libraries

“…Other studies have selected scFv MREs specific for melanoma cells [ 100 ], hepatocarcinoma [ 101 ], and ex vivo breast cancer tissue [ 102 ]. Additionally, Fab MREs have been selected that bind to T-cell malignancies [ 103 ] and ovarian carcinoma cells [ 104 ], among others.…”

Measuring Antigen‐Specific Immune Responses, 2008 update

“…Willemsen et al (16) made use of the selection power of phage display technology allowing the screening of tens of billions of individual clones by high‐throughput selection for antigen receptors with binding capacity for the peptide‐MHC complex. This strategy was used to select antibody‐type receptors for a panel of class I and II‐restricted tumor‐specific epitopes to be used for immuno‐gene therapy of cancer.…”