Journal
MOLECULAR THERAPY
Volume 30, Issue 2, Pages 564-578Publisher
CELL PRESS
DOI: 10.1016/j.ymthe.2021.08.010
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Funding
- Dutch Cancer Society (KWF kankerbestrijding, Amsterdam, the Netherlands) [KWF UL-2014-6831]
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CAR T cell therapy shows potential for the treatment of B cell malignancies, but antigen-negative escape variants limit its efficacy. This study identifies promising TCRs targeting multiple antigens for the treatment of B cell malignancies through a systematic approach.
CAR T cell therapy has shown great promise for the treatment of B cell malignancies. However, antigen-negative escape variants often cause disease relapse, necessitating the development of multi-antigen-targeting approaches. We propose that a T cell receptor (TCR)-based strategy would increase the number of potential antigenic targets, as peptides from both intracellular and extracellular proteins can be recognized. Here, we aimed to isolate a broad range of promising TCRs targeting multiple antigens for treatment of B cell malignancies. As a first step, 28 target genes for B cell malignancies were selected based on gene expression profiles. Twenty target peptides presented in human leukocyte antigen (HLA)-A*01:01, -A*24:02, -B*08:01, or -B*35:01 were identified from the immunopeptidome of B cell malignancies and used to form peptide-HLA (pHLA)-tetramers for T cell isolation. Target-peptide-specific CD8 T cells were isolated from HLA-mismatched healthy donors and subjected to a stringent stepwise selection procedure to ensure potency and eliminate cross-reactivity. In total, five T cell clones specific for FCRL5 in HLA-A*01:01, VPREB3 in HLA-A*24:02, and BOB1 in HLA-B*35:01 recognized B cell malignancies. For all three specificities, TCR gene transfer into CD8 T cells resulted in cytokine production and efficient killing of multiple B cell malignancies. In conclusion, using this systematic approach we successfully identified three promising TCRs for T cell therapy against B cell malignancies.
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