| RRC ID |
45467
|
| Author |
Fujiwara H, Ochi T, Ochi F, Miyazaki Y, Asai H, Narita M, Okamoto S, Mineno J, Kuzushima K, Shiku H, Yasukawa M.
|
| Title |
Antileukemia multifunctionality of CD4(+) T cells genetically engineered by HLA class I-restricted and WT1-specific T-cell receptor gene transfer.
|
| Journal |
Leukemia
|
| Abstract |
To develop gene-modified T-cell-based antileukemia adoptive immunotherapy, concomitant administration of CD4(+) and CD8(+) T cells that have been gene modified using identical HLA class I-restricted leukemia antigen-specific T-cell receptor (TCR) gene transfer has not yet been fully investigated. Here, using CD4(+) and CD8(+) T cells that had been gene modified with a retroviral vector expressing HLA-A*24:02-restricted and Wilms' tumor 1 (WT1)-specific TCR-α/β genes and siRNAs for endogenous TCRs (WT1-siTCR/CD4(+) T cells and WT1-siTCR/CD8(+) T cells), we examined the utility of this strategy. WT1-siTCR/CD4(+) T cells sufficiently recognized leukemia cells in an HLA class I-restricted manner and provided target-specific Th1 help for WT1-siTCR/CD8(+) T cells. By using a xenografted mouse model, we found that WT1-siTCR/CD4(+) T cells migrated to leukemia sites and subsequently attracted WT1-siTCR/CD8(+) T cells via chemotaxis. Therapy-oriented experiments revealed effective enhancement of leukemia suppression mediated by concomitant administration of WT1-siTCR/CD4(+) T cells and WT1-siTCR/CD8(+) T cells. Importantly, this augmented efficacy in the presence of WT1-siTCR/CD4(+) T cells was correlated with longer survival and enhanced formation of memory T cells by WT1-siTCR/CD8(+) T cells. Collectively, our experimental findings strongly suggest that this strategy would be clinically advantageous for the treatment of human leukemia.
|
| Volume |
29(12)
|
| Pages |
2393-401
|
| Published |
2015-12-1
|
| DOI |
10.1038/leu.2015.155
|
| PII |
leu2015155
|
| PMID |
26104661
|
| MeSH |
Animals
CD4-Positive T-Lymphocytes / immunology*
Cell Movement
Female
Genes, T-Cell Receptor*
Genetic Engineering
Histocompatibility Antigens Class I / physiology*
Humans
Immunotherapy, Adoptive*
Leukemia / immunology
Leukemia / therapy*
Lymphocyte Activation
Mice
T-Lymphocytes, Cytotoxic / immunology
WT1 Proteins / immunology*
|
| IF |
8.665
|
| Times Cited |
8
|
|
WOS Category
|
HEMATOLOGY
ONCOLOGY
|
| Resource |
| Human and Animal Cells |
293T(RCB2202) |
