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

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

Blood

journal_title

Blood

authors

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-2017-06-791202

subject

Has Abstract

pub_date

2017-11-02 00:00:00

pages

1985-1994

issue

18

eissn

0006-4971

issn

1528-0020

pii

blood-2017-06-791202

journal_volume

130

pub_type

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