Abstract
Adoptive immunotherapy with antigen-specific T cells can be effective for treating melanoma and chronic myeloid leukemia (CML). However, to obtain sufficient antigen-specific T cells for treatment, the T cells have to be cultured for several weeks in vitro, but in vitro T cell expansion is difficult to control. Alternatively, the transfer of T cell receptors (TCRs) with defined antigen specificity into recipient T cells may be a simple solution for generating antigen-specific T cells. The objective of this study was to identify CML-associated, antigen-specific TCR genes and generate CML-associated, antigen-specific T cells with T cell receptor (TCR) gene transfer. Our previous study has screened an oligoclonal Vβ21 with a different oligoclonal Vα partner in peripheral blood mononuclear cells (PBMCs) derived from patients with CML. In this study, oligoclonally expanded TCR α genes, which pair with TCR Vβ21, were cloned into the pIRES eukaryotic expression vector (TCR Vα-IRES-Vβ21). Next, two recombinant plasmids, TCR Vα13-IRES-Vβ21 and TCR Vα18-IRES-Vβ21, were successfully transferred into T cells, and the TCR gene-modified T cells acquired CML-specific cytotoxicity with the best cytotoxic effects for HLA-A11+ K562 cells observed for the TCR Vα13/Vβ21 gene redirected T cells. In summary, our data confirmed TCRVα13/Vβ21 as a CML-associated, antigen-specific TCR. This study provided new evidence that genetically engineered antigen-specific TCR may become a druggable approach for gene therapy of CML.
Highlights
Chronic myelogenous leukemia (CML) is a common hematological malignancy in adult
Several studies have demonstrated that p210 protein fusion region-derived peptides bind to different major histocompatibility complex (MHC) class-I molecules (A11,A0201,A3 and B8) and induce chronic myeloid leukemia (CML)-specific cytotoxic T lymphocytes (CTL), which can kill CML cells in vitro [20, 22,23,24,25,26]
In vivo, bcr-abl fusion protein-specific CTLs were detected in peripheral blood mononuclear cells (PBMCs) from CML patients using bcr-abl peptide/MHC tetramer technology [23]
Summary
Chronic myelogenous leukemia (CML) is a common hematological malignancy in adult. The typical genetic alteration is the Philadelphia chromosome resulting from,t(9;22) (q34;q11), which forms a bcr-abl fusion gene encoding BCR-ABL fusion proteins with unusual tyrosine kinase activity [1]. Approximately 30% of patients interrupt imatinib therapy because of suboptimal response or intolerance, in the case, the second-generation TKIs are the choice for the patients [3, 4]. It is well known, allogenic hematopoietic stem cell transplantation (alloHSCT) is currently the only curative therapeutic approach for CML. The ideal strategy for adoptive T cell immunotherapy is to infuse leukemic antigenspecific cytotoxic T lymphocytes (CTLs). Application of this mode of leukemic antigen-specific T cell adoptive transfer is often limiting because the isolation and in vitro expansion of leukemic antigen-specific T cells is labor-intensive and time-consuming [9]. A recently developed T cell receptor (TCR)-mediated gene therapy may facilitate overcoming this limitation
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