Safety and persistence of WT1-specific T-cell receptor gene2transduced lymphocytes in patients with AML and MDS

Isao Tawara, Shinichi Kageyama, Yoshihiro Miyahara, Hiroshi Fujiwara, Tetsuya Nishida, Yoshiki Akatsuka, Hiroaki Ikeda, Kazushi Tanimoto, Seitaro Terakura, Makoto Murata, Yoko Inaguma, Masahiro Masuya, Naoki Inoue, Tomohide Kidokoro, Sachiko Okamoto, Daisuke Tomura, Hideto Chono, Ikuei Nukaya, Junichi Mineno, Tomoki NaoeNobuhiko Emi, Masaki Yasukawa, Naoyuki Katayama, Hiroshi Shiku

Research output: Contribution to journalArticle

26 Citations (Scopus)

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-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.

Original languageEnglish
Pages (from-to)1985-1994
Number of pages10
JournalBlood
Volume130
Issue number18
DOIs
Publication statusPublished - 02-11-2017

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T-cells
Wilms Tumor
Lymphocytes
Myelodysplastic Syndromes
T-Cell Antigen Receptor
Acute Myeloid Leukemia
Tumors
T-Lymphocytes
Safety
T-Cell Receptor Genes
Genes
Antigen-antibody reactions
Patient Transfer
Peptides
Subunit Vaccines
Hematopoiesis
Cell culture
Refractory materials
Small Interfering RNA
Bone

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Tawara, I., Kageyama, S., Miyahara, Y., Fujiwara, H., Nishida, T., Akatsuka, Y., ... Shiku, H. (2017). Safety and persistence of WT1-specific T-cell receptor gene2transduced lymphocytes in patients with AML and MDS. Blood, 130(18), 1985-1994. https://doi.org/10.1182/blood-2017-06-791202
Tawara, Isao ; Kageyama, Shinichi ; Miyahara, Yoshihiro ; Fujiwara, Hiroshi ; Nishida, Tetsuya ; Akatsuka, Yoshiki ; Ikeda, Hiroaki ; Tanimoto, Kazushi ; Terakura, Seitaro ; Murata, Makoto ; Inaguma, Yoko ; Masuya, Masahiro ; Inoue, Naoki ; Kidokoro, Tomohide ; Okamoto, Sachiko ; Tomura, Daisuke ; Chono, Hideto ; Nukaya, Ikuei ; Mineno, Junichi ; Naoe, Tomoki ; Emi, Nobuhiko ; Yasukawa, Masaki ; Katayama, Naoyuki ; Shiku, Hiroshi. / Safety and persistence of WT1-specific T-cell receptor gene2transduced lymphocytes in patients with AML and MDS. In: Blood. 2017 ; Vol. 130, No. 18. pp. 1985-1994.
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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-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.",
author = "Isao Tawara and Shinichi Kageyama and Yoshihiro Miyahara and Hiroshi Fujiwara and Tetsuya Nishida and Yoshiki Akatsuka and Hiroaki Ikeda and Kazushi Tanimoto and Seitaro Terakura and Makoto Murata and Yoko Inaguma and Masahiro Masuya and Naoki Inoue and Tomohide Kidokoro and Sachiko Okamoto and Daisuke Tomura and Hideto Chono and Ikuei Nukaya and Junichi Mineno and Tomoki Naoe and Nobuhiko Emi and Masaki Yasukawa and Naoyuki Katayama and Hiroshi Shiku",
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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, Katayama, N & Shiku, H 2017, 'Safety and persistence of WT1-specific T-cell receptor gene2transduced lymphocytes in patients with AML and MDS', Blood, vol. 130, no. 18, pp. 1985-1994. https://doi.org/10.1182/blood-2017-06-791202

Safety and persistence of WT1-specific T-cell receptor gene2transduced lymphocytes in patients with AML and MDS. / Tawara, Isao; Kageyama, Shinichi; Miyahara, Yoshihiro; Fujiwara, Hiroshi; Nishida, Tetsuya; Akatsuka, Yoshiki; Ikeda, Hiroaki; Tanimoto, Kazushi; Terakura, Seitaro; Murata, Makoto; Inaguma, Yoko; Masuya, Masahiro; Inoue, Naoki; Kidokoro, Tomohide; Okamoto, Sachiko; Tomura, Daisuke; Chono, Hideto; Nukaya, Ikuei; Mineno, Junichi; Naoe, Tomoki; Emi, Nobuhiko; Yasukawa, Masaki; Katayama, Naoyuki; Shiku, Hiroshi.

In: Blood, Vol. 130, No. 18, 02.11.2017, p. 1985-1994.

Research output: Contribution to journalArticle

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

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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Tawara I, Kageyama S, Miyahara Y, Fujiwara H, Nishida T, Akatsuka Y et al. Safety and persistence of WT1-specific T-cell receptor gene2transduced lymphocytes in patients with AML and MDS. Blood. 2017 Nov 2;130(18):1985-1994. https://doi.org/10.1182/blood-2017-06-791202