用于多抗原 T 细胞治疗的 B 细胞恶性肿瘤靶向 TCR 的广泛系统鉴定方法

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.