TY - JOUR
T1 - Safety and persistence of WT1-specific T-cell receptor gene2transduced lymphocytes in patients with AML and MDS
AU - Tawara, Isao
AU - Kageyama, Shinichi
AU - Miyahara, Yoshihiro
AU - Fujiwara, Hiroshi
AU - Nishida, Tetsuya
AU - Akatsuka, Yoshiki
AU - Ikeda, Hiroaki
AU - Tanimoto, Kazushi
AU - Terakura, Seitaro
AU - Murata, Makoto
AU - Inaguma, Yoko
AU - Masuya, Masahiro
AU - Inoue, Naoki
AU - Kidokoro, Tomohide
AU - Okamoto, Sachiko
AU - Tomura, Daisuke
AU - Chono, Hideto
AU - Nukaya, Ikuei
AU - Mineno, Junichi
AU - Naoe, Tomoki
AU - Emi, Nobuhiko
AU - Yasukawa, Masaki
AU - Katayama, Naoyuki
AU - Shiku, Hiroshi
N1 - Publisher Copyright:
© 2017 by The American Society of Hematology.
PY - 2017/11/2
Y1 - 2017/11/2
N2 - 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-inhuman 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.
AB - 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-inhuman 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.
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U2 - 10.1182/blood-2017-06-791202
DO - 10.1182/blood-2017-06-791202
M3 - Article
C2 - 28860210
AN - SCOPUS:85032792769
SN - 0006-4971
VL - 130
SP - 1985
EP - 1994
JO - Blood
JF - Blood
IS - 18
ER -