Abstract:
:Wilms' tumor 1 (WT1) is constantly expressed in leukemic cells of acute leukemia and myelodysplastic syndrome (MDS). A T-cell receptor (TCR) that specifically reacts with WT1 peptide in the context of HLA-A*24:02 has been identified. We conducted a first-in-human trial of TCR-gene transduced T-cell (TCR-T-cell) transfer in patients with refractory acute myeloblastic leukemia (AML) and high-risk MDS to investigate the safety and cell kinetics of the T cells. The WT1-specific TCR-gene was transduced to T cells using a retroviral vector encoding small interfering RNAs for endogenous TCR genes. The T cells were transferred twice with a 4-week interval in a dose-escalating design. After the second transfer, sequential WT1 peptide vaccines were given. Eight patients, divided into 2 dose cohorts, received cell transfer. No adverse events of normal tissue were seen. The TCR-T cells were detected in peripheral blood for 8 weeks at levels proportional to the dose administered, and in 5 patients, they persisted throughout the study period. The persisting cells maintained ex vivo peptide-specific immune reactivity. Two patients showed transient decreases in blast counts in bone marrow, which was associated with recovery of hematopoiesis. Four of 5 patients who had persistent T cells at the end of the study survived more than 12 months. These results suggest WT1-specific TCR-T cells manipulated by ex vivo culture of polyclonal peripheral lymphocytes survived in vivo and retained the capacity to mount an immune reaction to WT1. This trial was registered at www.umin.ac.jp as #UMIN000011519.
journal_name
Bloodjournal_title
Bloodauthors
Tawara I,Kageyama S,Miyahara Y,Fujiwara H,Nishida T,Akatsuka Y,Ikeda H,Tanimoto K,Terakura S,Murata M,Inaguma Y,Masuya M,Inoue N,Kidokoro T,Okamoto S,Tomura D,Chono H,Nukaya I,Mineno J,Naoe T,Emi N,Yasukawa M,doi
10.1182/blood-2017-06-791202subject
Has Abstractpub_date
2017-11-02 00:00:00pages
1985-1994issue
18eissn
0006-4971issn
1528-0020pii
blood-2017-06-791202journal_volume
130pub_type
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