Safety and persistence of WT1-specific T-cell receptor gene−transduced lymphocytes in patients with AML and MDS
| Autor: | Nobuhiko Emi, Naoki Inoue, Sachiko Okamoto, Naoyuki Katayama, Isao Tawara, Tomohide Kidokoro, Ikuei Nukaya, Junichi Mineno, Kazushi Tanimoto, Hiroshi Fujiwara, Yoshiki Akatsuka, Yoshihiro Miyahara, Tetsuya Nishida, Hideto Chono, Tomoki Naoe, Masaki Yasukawa, Seitaro Terakura, Makoto Murata, Yoko Inaguma, Daisuke Tomura, Hiroshi Shiku, Hiroaki Ikeda, Masahiro Masuya, Shinichi Kageyama |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Adoptive cell transfer Myeloid Acute myeloblastic leukemia T-Lymphocytes Immunology Biochemistry 03 medical and health sciences 0302 clinical medicine Bone Marrow Transduction Genetic medicine Humans WT1 Proteins Aged Acute leukemia business.industry Cell Biology Hematology Middle Aged medicine.disease Adoptive Transfer Genes T-Cell Receptor Kinetics Leukemia Myeloid Acute Leukemia Haematopoiesis 030104 developmental biology medicine.anatomical_structure Myelodysplastic Syndromes 030220 oncology & carcinogenesis Female Bone marrow Peptides business Ex vivo |
| Zdroj: | Blood. 130:1985-1994 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2017-06-791202 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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