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

Meeuwsen, M.H.

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...Show moreIn 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.
Show less

Leiden University Scholarly Publications

View statistics

Documents

In Collections

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

Funding