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WT1 and TCR

Norihiro Ueda, Yasushi Uemura, Rong Zhang, Shuichi Kitayama, Shoichi Iriguchi, Yohei Kawai, Yutaka Yasui, Minako Tatsumi, Tatsuki Ueda, Tian-Yi Liu, Yasutaka Mizoro, Chihiro Okada, Akira Watanabe, Mahito Nakanishi, Satoru Senju, Yasuharu Nishimura, Kiyotaka Kuzushima, Hitoshi Kiyoi, Tomoki Naoe, Shin Kaneko
CD4+ T helper (Th) cell activation is essential for inducing cytotoxic T lymphocyte (CTL) responses against malignancy. We reprogrammed a Th clone specific for chronic myelogenous leukemia (CML)-derived b3a2 peptide to pluripotency and re-differentiated the cells into original TCR-expressing T-lineage cells (iPS-T cells) with gene expression patterns resembling those of group 1 innate lymphoid cells. CD4 gene transduction into iPS-T cells enhanced b3a2 peptide-specific responses via b3a2 peptide-specific TCR...
May 18, 2018: Stem Cell Reports
Hongtao Liu, Yuanyuan Zha, Noura Choudhury, Gregory Malnassy, Noreen Fulton, Margaret Green, Jae-Hyun Park, Yusuke Nakamura, Richard A Larson, Andres M Salazar, Olatoyosi Odenike, Thomas F Gajewski, Wendy Stock
Background: The optimal strategy for vaccination to induce CD8+ T cell responses against WT1 is not known. Methods: A pilot randomized study in HLA-A02+ patients to receive vaccination with WT1 in Montanide or in poly ICLC, a TLR3 agonist, to explore the novel immune adjuvant was conducted. Seven patients were randomized. Four patients received WT1 in Montanide, and three with WT1 in poly ICLC. Five patients were in morphologic remission and two had residual morphologic disease at the study entry...
2018: Experimental Hematology & Oncology
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 Naoe, Nobuhiko Emi, Masaki Yasukawa, Naoyuki Katayama, Hiroshi Shiku
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...
November 2, 2017: Blood
Kazushi Tanimoto, Hiroshi Fujiwara
Synthetic immunology based on rapidly-advancing gene-engineering and immunobiology has made novel anticancer adoptive immunotherapies, using gene-modified T lymphocytes to express cancer antigen-specific receptors, a reality. Various technological innovations have overcome recent difficulties and achieved clear and long-lasting clinical efficacy against tumors, while seeking more powerful effector gene-modified T cells has yielded serious treatment-related adverse events. In this article, along with introducing our clinical trial for a novel anti-leukemia adoptive immunotherapy regimen using gene-modified autologous lymphocytes to express leukemia antigen Wilms Tumor 1(WT1)-specific T cell receptor (TCR) against refractory acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), we provide an overview of the current status of this emerging treatment option and discuss its future form in the context of neoantigens encoded by mutated genes in cancer cells and immune checkpoint inhibitors...
2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Kenta Kondo, Fumihiro Fujiki, Hiroko Nakajima, Erika Yatsukawa, Soyoko Morimoto, Naoya Tatsumi, Sumiyuki Nishida, Jun Nakata, Yoshihiro Oka, Akihiro Tsuboi, Naoki Hosen, Yusuke Oji, Haruo Sugiyama
Many studies demonstrated crucial roles of avidity of T-cell receptor (TCR) in T-cell fate. However, majority of these findings resulted from analysis of non-self-antigen-specific CD8 T cells, and little is known about roles of TCR avidity in the fate of self-antigen-specific CD8 T cells. Wilms tumor gene 1 (WT1) protein is a self-antigen most suitable for addressing this issue because WT1 protein is a highly immunogenic, typical self-antigen. Here, we isolated 2 distinct and functional TCRs, TCR1 and TCR2, from murine WT1 peptide (RMFPNAPYL)-specific cytotoxic T lymphocytes (WT1-CTLs) and generated TCR1-retrogenic (Rg) and TCR2-Rg mice under T and B-cell-deficient and -reconstituted conditions...
April 2016: Journal of Immunotherapy
Adnan Jaigirdar, Steven A Rosenberg, Maria Parkhurst
Wilms tumor gene 1 (WT1) is an attractive target antigen for cancer immunotherapy because it is overexpressed in many hematologic malignancies and solid tumors but has limited, low-level expression in normal adult tissues. Multiple HLA class I and class II restricted epitopes have been identified in WT1, and multiple investigators are pursuing the treatment of cancer patients with WT1-based vaccines and adoptively transferred WT1-reactive T cells. Here we isolated an HLA-A*0201-restricted WT1-reactive T-cell receptor (TCR) by stimulating peripheral blood lymphocytes of healthy donors with the peptide WT1:126-134 in vitro...
April 2016: Journal of Immunotherapy
Yuho Najima, Mariko Tomizawa-Murasawa, Yoriko Saito, Takashi Watanabe, Rintaro Ono, Toshiki Ochi, Nahoko Suzuki, Hiroshi Fujiwara, Osamu Ohara, Leonard D Shultz, Masaki Yasukawa, Fumihiko Ishikawa
Induction of specific immune response against therapy-resistant tumor cells can potentially improve clinical outcomes in malignancies. To optimize immunotherapy in the clinic, we aimed to create an in vivo model enabling us to analyze human cytotoxic T-lymphocyte (CTL) responses against human malignancies. To this end, we developed NOD/SCID/IL2rgKO (NSG) mice expressing the HLA class I molecules HLA-A*0201 and A*2402. In the bone marrow (BM) and spleen of HLA class I transgenic (Tg) NSG mice transplanted with cord blood hematopoietic stem cells (HSCs), we found human memory CD8(+) T cells and antigen-presenting cells...
February 11, 2016: Blood
Niloufar Ataie, Jingyi Xiang, Neal Cheng, Elliott J Brea, Wenjie Lu, David A Scheinberg, Cheng Liu, Ho Leung Ng
Antibody therapies currently target only extracellular antigens. A strategy to recognize intracellular antigens is to target peptides presented by immune HLA receptors. ESK1 is a human, T-cell receptor (TCR)-mimic antibody that binds with subnanomolar affinity to the RMF peptide from the intracellular Wilms tumor oncoprotein WT1 in complex with HLA-A*02:01. ESK1 is therapeutically effective in mouse models of WT1(+) human cancers. TCR-based therapies have been presumed to be restricted to one HLA subtype. The mechanism for the specificity and high affinity of ESK1 is unknown...
January 16, 2016: Journal of Molecular Biology
Tao Dao, Dmitry Pankov, Andrew Scott, Tatyana Korontsvit, Victoriya Zakhaleva, Yiyang Xu, Jingyi Xiang, Su Yan, Manuel Direito de Morais Guerreiro, Nicholas Veomett, Leonid Dubrovsky, Michael Curcio, Ekaterina Doubrovina, Vladimir Ponomarev, Cheng Liu, Richard J O'Reilly, David A Scheinberg
Intracellular tumor antigens presented on the cell surface in the context of human leukocyte antigen (HLA) molecules have been targeted by T cell-based therapies, but there has been little progress in developing small-molecule drugs or antibodies directed to these antigens. Here we describe a bispecific T-cell engager (BiTE) antibody derived from a T-cell receptor (TCR)-mimic monoclonal antibody (mAb) ESK1, which binds a peptide derived from the intracellular oncoprotein WT1 presented on HLA-A*02:01. Despite the very low density of the complexes at the cell surface, ESK1-BiTE selectively activated and induced proliferation of cytolytic human T cells that killed cells from multiple leukemias and solid tumors in vitro and in mice...
October 2015: Nature Biotechnology
H Fujiwara, T Ochi, F Ochi, Y Miyazaki, H Asai, M Narita, S Okamoto, J Mineno, K Kuzushima, H Shiku, M Yasukawa
To develop gene-modified T-cell-based antileukemia adoptive immunotherapy, concomitant administration of CD4(+) and CD8(+) T cells that have been gene modified using identical HLA class I-restricted leukemia antigen-specific T-cell receptor (TCR) gene transfer has not yet been fully investigated. Here, using CD4(+) and CD8(+) T cells that had been gene modified with a retroviral vector expressing HLA-A*24:02-restricted and Wilms' tumor 1 (WT1)-specific TCR-α/β genes and siRNAs for endogenous TCRs (WT1-siTCR/CD4(+) T cells and WT1-siTCR/CD8(+) T cells), we examined the utility of this strategy...
December 2015: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Q Zhao, M Ahmed, D V Tassev, A Hasan, T-Y Kuo, H-F Guo, R J O'Reilly, N-K V Cheung
WT1126 (RMFPNAPYL) is a human leukocyte antigen-A2 (HLA-A2)-restricted peptide derived from Wilms tumor protein 1 (WT1), which is widely expressed in a broad spectrum of leukemias, lymphomas and solid tumors. A novel T-cell-receptor (TCR)-like single-chain variable fragment (scFv) antibody specific for the T-cell epitope consisting of the WT1/HLA-A2 complex was isolated from a human scFv phage library. This scFv was affinity-matured by mutagenesis combined with yeast display and structurally analyzed using a homology model...
November 2015: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Toshiki Ochi, Munehide Nakatsugawa, Kenji Chamoto, Shinya Tanaka, Yuki Yamashita, Tingxi Guo, Hiroshi Fujiwara, Masaki Yasukawa, Marcus O Butler, Naoto Hirano
Adoptive transfer of T cells redirected by a high-affinity antitumor T-cell receptor (TCR) is a promising treatment modality for cancer patients. Safety and efficacy depend on the selection of a TCR that induces minimal toxicity and elicits sufficient antitumor reactivity. Many, if not all, TCRs possess cross-reactivity to unrelated MHC molecules in addition to reactivity to target self-MHC/peptide complexes. Some TCRs display chain centricity, in which recognition of MHC/peptide complexes is dominated by one of the TCR hemi-chains...
September 2015: Cancer Immunology Research
Akiko Katsuhara, Fumihiro Fujiki, Nao Aoyama, Satoe Tanii, Soyoko Morimoto, Yoshihiro Oka, Akihiro Tsuboi, Hiroko Nakajima, Kenta Kondo, Naoya Tatsumi, Jun Nakata, Yoshiki Nakae, Satoshi Takashima, Sumiyuki Nishida, Naoki Hosen, Shinji Sogo, Yusuke Oji, Haruo Sugiyama
BACKGROUND/AIM: Wilms' tumor gene 1 (WT1) product is a pan-tumor-associated antigen. We previously identified WT1 protein-derived promiscuous helper peptide, WT1332. Therefore, isolation and characterization of the WT1332-specific T-cell receptors (TCRs) are useful to develop broadly applicable TCR gene-based adoptive immunotherapy. MATERIALS AND METHODS: A novel HLA-DRB1*04:05-restricted WT1332-specific TCR gene was cloned and transduced into human CD4+ T-cells by using a lentiviral vector...
March 2015: Anticancer Research
Jun An, Song-Wang Cai, Yun Li, Junhang Zhang
OBJECTIVE: To investigate the cytotoxicity of normal CD8(+) T lymphocytes retrovirally transduced with WT1 peptide-specific T-cell receptor (TCR) genes against human lung cancer cells. METHODS: HLA-A*2402-restricted and WT1 peptide-specific TCR-α/β genes were cloned from a cytotoxic T lymphocyte clone and inserted into a retroviral TCR expression vector. The cytotoxicity of normal peripheral CD8⁺ T cells transduced with the WT1-TCR genes against human lung cancer cells was evaluated using a standard ⁵¹Cr release assay...
August 2014: Nan Fang Yi Ke da Xue Xue Bao, Journal of Southern Medical University
Nicholas Veomett, Tao Dao, Hong Liu, Jingyi Xiang, Dmitry Pankov, Leonid Dubrovsky, Joseph A Whitten, Sun-Mi Park, Tatyana Korontsvit, Victoria Zakhaleva, Emily Casey, Michael Curcio, Michael G Kharas, Richard J O'Reilly, Cheng Liu, David A Scheinberg
PURPOSE: RMFPNAPYL (RMF), a Wilms' tumor gene 1 (WT1)-derived CD8 T-cell epitope presented by HLA-A*02:01, is a validated target for T-cell-based immunotherapy. We previously reported ESK1, a high avidity (Kd < 0.2 nmol/L), fully-human monoclonal antibody (mAb) specific for the WT1 RMF peptide/HLA-A*02:01 complex, which selectively bound and killed WT1(+) and HLA-A*02:01(+) leukemia and solid tumor cell lines. EXPERIMENTAL DESIGN: We engineered a second-generation mAb, ESKM, to have enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) function due to altered Fc glycosylation...
August 1, 2014: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Leonid Dubrovsky, Dmitry Pankov, Elliott Joseph Brea, Tao Dao, Andrew Scott, Su Yan, Richard J O'Reilly, Cheng Liu, David A Scheinberg
Acute and chronic leukemias, including CD34(+) CML cells, demonstrate increased expression of the Wilms tumor gene 1 product (WT1), making WT1 an attractive therapeutic target. However, WT1 is a currently undruggable, intracellular protein. ESKM is a human IgG1 T-cell receptor mimic monoclonal antibody directed to a 9-amino acid sequence of WT1 in the context of cell surface HLA-A*02. ESKM was therapeutically effective, alone and in combination with tyrosine kinase inhibitors (TKIs), against Philadelphia chromosome-positive acute leukemia in murine models, including a leukemia with the most common, pan-TKI, gatekeeper resistance mutation, T315I...
May 22, 2014: Blood
Brigitte Steger, Slavoljub Milosevic, Georg Doessinger, Susanne Reuther, Anja Liepert, Marion Braeu, Julia Schick, Valentin Vogt, Friedhelm Schuster, Tanja Kroell, Dirk H Busch, Arndt Borkhardt, Hans-Jochem Kolb, Johanna Tischer, Raymund Buhmann, Helga Schmetzer
T-cells play an important role in the remission-maintenance in AML-patients (pts) after SCT, however the role of LAA- (WT1, PR1, PRAME) or minor-histocompatibility (mHag, HA1) antigen-specific CD4(+) and CD8(+)T-cells is not defined. A LAA/HA1-peptide/protein stimulation, cloning and monitoring strategy for specific CD8(+)/CD4(+)T-cells in AML-pts after SCT is given. Our results show that (1) LAA-peptide-specific CD8+T-cells are detectable in every AML-pt after SCT. CD8(+)T-cells, recognizing two different antigens detectable in 5 of 7 cases correlate with long-lasting remissions...
April 2014: Immunobiology
Thomas M Schmitt, David H Aggen, Ingunn M Stromnes, Michelle L Dossett, Sarah A Richman, David M Kranz, Philip D Greenberg
Many of the most promising tumor antigens for T-cell-based cancer immunotherapies are unmodified self-antigens. Unfortunately, the avidity of T cells specific for these antigens is limited by central tolerance during T-cell development in the thymus, resulting in decreased anti-tumor efficacy of these T cells. One approach to overcoming this obstacle is to mutate T-cell receptor (TCR) genes from naturally occurring T cells to enhance the affinity for the target antigen. These enhanced-affinity TCRs can then be developed for use in TCR gene therapy...
July 18, 2013: Blood
Georg Dössinger, Mario Bunse, Jeannette Bet, Julia Albrecht, Paulina J Paszkiewicz, Bianca Weißbrich, Isabell Schiedewitz, Lynette Henkel, Matthias Schiemann, Michael Neuenhahn, Wolfgang Uckert, Dirk H Busch
Adoptive therapy using T cells redirected to target tumor- or infection-associated antigens is a promising strategy that has curative potential and broad applicability. In order to accelerate the screening process for suitable antigen-specific T cell receptors (TCRs), we developed a new approach circumventing conventional in vitro expansion-based strategies. Direct isolation of paired full-length TCR sequences from non-expanded antigen-specific T cells was achieved by the establishment of a highly sensitive PCR-based T cell receptor single cell analysis method (TCR-SCAN)...
2013: PloS One
Yuhung Lin, Fumihiro Fujiki, Akiko Katsuhara, Yoshihiro Oka, Akihiro Tsuboi, Nao Aoyama, Satoe Tanii, Hiroko Nakajima, Naoya Tatsumi, Soyoko Morimoto, Taichi Tamanaka, Sho Tachino, Naoki Hosen, Sumiyuki Nishida, Yusuke Oji, Atsushi Kumanogoh, Haruo Sugiyama
Wilms tumor gene 1 (WT1) is overexpressed in various malignant neoplasms, and has been demonstrated as an attractive target for cancer immunotherapy. We previously reported the identification of a WT1 protein-derived, 16-mer helper peptide WT1332 that could elicit Th1-type CD4+ T-cell response and bind to multiple HLA class II molecules. In this study, we examined the feasibility of adoptive therapy using CD4+ T cells that were transduced an HLA-DPB1*05:01-restricted, WT1332-specific T-cell receptor (TCR). HLA-DPB1*05:01-restricted, WT1332-specific TCR-transduced CD4+ T cells were successfully generated using lentiviral vector and exhibited strong proliferative response and Th1-type cytokine production in response to WT1332 peptide, WT1 protein, or WT1-expressing tumor cell lysate...
April 2013: Journal of Immunotherapy
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