Immunotherapy

Antileukemia multifunctionality of CD4+ T cells genetically engineered by HLA class I-restricted and WT1-specific T-cell receptor gene transfer

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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.

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Acknowledgements

We thank Dr Kenji Kameda, Ehime University for technical assistance. We also thank Dr Yoshiki Akatsuka, Department of Hematology, Fujita Health University for supplying the K562-A24 and Dr Hiroo Saji, HLA Laboratory, Japan for HLA typing. This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (HF and MY); a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare (MY); a grant from Takeda Science Foundation (MY); a grant from the Uehara Memorial Foundation (MY); and a grant from the Princess Takamatsu Cancer Research Fund (MY).

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Correspondence to H Fujiwara or M Yasukawa.

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SO and JM are employees of Takara Bio. All other authors declare no conflict of interest.

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Supplementary Information accompanies this paper on the Leukemia website

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