TCRs as precision tools against B-cell and plasma cell malignancies

Abstract

In this thesis we identified TCRs for the treatment of B-cell and plasma cell malignancies. In our approach we identified TCRs specific to peptides from B-cell lineage antigens, that are expressed in B-cell malignancies, presented in various HLA alleles. These epitopes, being self-peptides, are not immunogenic in an HLA-matched setting. To overcome this, we isolated T-cell clones across HLA-barriers using donors lacking the target HLA-alleles. We used peptide-HLA multimers for isolation, followed by comprehensive potency and safety tests to select T cells with precise antigen recognition. The TCRs of selected T-cell clones were sequenced, inserted into retroviral vectors, and introduced into third-party T cells. These T cells were then evaluated for their specificity and ability to target and eliminate B-cell malignancies expressing the antigen in vitro and in in vivo xenograft models. Throughout the thesis we described multiple TCRs with potential clinical applicability for B-cell and plasma cell malignancies. In chapter 2, TCRs are described that target peptides from FCRL5 in HLA-A1, VPREB3 in HLA-A24, and BOB1 in HLA-B35. In chapter 3, TCRs target peptides from the Jchain presented in HLA-A1, -A3, -A11 and -A24. In chapter 4, TCRs target peptides from IgA in HLA-B7 and IgG in HLA-A2.