Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Based on the progress of gene-modification technologies, bispecific antibodies that possess antigen-binding sites with two different specificities have been developed. After the success of blinatumomab for treating refractory B-cell leukemia, series of clinical trials using bispecific antibodies for relapsed and refractory hematological malignancies are being conducted. Several bispecific antibodies target an antigen expressed by tumor cells and the CD3 molecule where binding of bispecific antibodies can generate artificial immunological synapses between tumor cells and human T cells. Therefore, fine tuning of binding affinity and/or structural conformation concomitant with bispecific antibodies may be required to induce antitumor effects and regulate immune-related adverse events, such as cytokine release syndrome. In the future, combination therapy of conventional chemotherapy and/or allogeneic stem-cell transplantation with bispecific antibody therapy will be necessary. Furthermore, molecular target therapy with bispecific antibody therapy is expected to pave the way for next-generation target therapy, resulting in the development of a further effective and safe treatment strategy for hematological malignancies.

DOI： 10.11406/rinketsu.63.1298

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Language：Japanese   Publisher：(一社)日本感染症学会  

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Immune checkpoint inhibitor (ICI) therapy increases the risk of immune-related adverse events (irAEs). In particular, combination checkpoint blockade (CCB) targeting inhibitory CTLA-4 and PD-1 receptors could lead to irAEs at a higher rate than ICI monotherapy. Management of irAEs is important while using ICIs. However, there are no reliable biomarkers for predicting irAEs. The aim of this study was to elucidate early B cell changes after CCB therapy in patients with renal cell carcinoma (RCC) and verify whether B cells can be a predictor of irAEs. This prospective cohort study was conducted with 23 Japanese patients with metastatic RCC. An increase in the proportion of CD21lo B cells and CD21lo memory B cells was confirmed following CCB therapy. Although there were no differences in clinical outcomes between irAE and no-irAE groups, the proportion of CD21lo B cells at baseline was lower in the irAE group, with a significant increase after the first cycle of CCB therapy. Further analysis revealed a moderate correlation between irAEs and CD21lo B cell levels at baseline (area under the curve: 0.83, cut-off: 3.13%, sensitivity: 92.3, specificity: 70.0). This finding indicates that patients with low baseline CD21lo B cell levels warrant closer monitoring for irAEs. The clinical registration number by the Certified Review Board of Ehime University is No. 1902011.

DOI： 10.3390/jpm12060888

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

<title>Abstract</title>Cancer immunotherapy using T cells redirected with chimeric antigen receptor (CAR) has shown a lot of promise. We have established a single-chain antibody (scFv) generation system in which scFv library-expressing CAR-T cells can be screened appropriately based on their antitumor functions. A variable region library containing the variable and J regions of the human immunoglobulin light or heavy chain was fused with the variable region of a heavy or light chain encoded by an existing tumor-specific antibody to generate a new scFv library. Then, scFv library-expressing CAR-T cells were generated and stimulated with target cells to concentrate the antigen-specific population. Using this system, target-specific recognition of CAR-T cells appeared to be finely tuned by selecting a new variable region. Importantly, we have demonstrated that the newly optimized scFv-expressing CAR-T cells had better proliferation capacity and durable phenotypes, enabling superior reactivity against advanced tumors in vivo in comparison with the original CAR-T cells. Therefore, the optimization of an scFv is needed to maximize the in vivo antitumor functions of CAR-T cells. This system may allow us to adjust an immunological synapse formed by an scFv expressed by CAR-T cells and a target antigen, representing an ideal form of CAR-T-cell immunotherapy.

DOI： 10.1038/s42003-021-01791-1

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Other Link： http://www.nature.com/articles/s42003-021-01791-1

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Circulation Society  

DOI： 10.1253/circj.cj-21-0366

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DOI： 10.1007/s00277-020-04151-x

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

<title>Abstract</title>
The development of chimeric antigen receptor (CAR) and bispecific T-cell engager (BiTE) has led to the successful application of cancer immunotherapy. The potential reactivity mediated by CAR- and BiTE-redirected T cells needs to be assessed to facilitate the application of these treatment options to a broader range of patients. Here, we have generated CAR and BiTE possessing the same single chain fragment variable (scFv) specific for the HLA-A2/NY-ESO-1_157-165 complex (A2/NY-ESO-1₁₅₇). Using HLA-A2⁺NY-ESO-1⁺ myeloma cells and peptides presented by HLA-A2 molecules as a model, both sets of redirected T cells recognized and killed HLA-A2⁺NY-ESO-1⁺ myeloma cells in an A2/NY-ESO-1₁₅₇-specific manner <italic>in vitro</italic>. Moreover, CAR- and BiTE-activated T cells showed similar functional avidity, as assessed by cytokine production and killing activity, both displaying antitumor reactivity against HLA-A2⁺NY-ESO-1⁺ myeloma cells <italic>in vivo</italic>. Interestingly, cross-reactivity for homologous peptides presented by HLA-A*02:01 and NY-ESO-1₁₅₇ peptide presented by HLA-A2 alleles was not identical between CAR- and BiTE-redirected T cells, probably due to structural differences of modified antibodies. These results have demonstrated that both antitumor CAR- and BiTE-activated T cells have comparable potential to recognize tumors, while paying attention to unknown off-target reactivity that would differ for each antibody-based modality even if the same scFv was employed.

DOI： 10.1038/s41598-019-49834-2

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Other Link： http://www.nature.com/articles/s41598-019-49834-2

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Cancer immunotherapy has been developed and established as a new treatment modality. Recently, adoptive transfer therapy using T cells redirected with antigen-specific antitumor receptors, such as T-cell receptor (TCR) and chimeric antigen receptor (CAR), has demonstrated clinical benefits even in patients with refractory malignancies. To advance this treatment modality, both generation of gene-modified T cells and evaluation of their reactivity with high quality in vitro are required. To achieve this, it is important to establish the ways (1) to generate optimal viral particle for T-cell transduction, (2) to transduce antitumor receptors into T cells and expand redirected T cells efficiently, and (3) to assess the functionality of antigen-specific gene-modified T cells precisely. Here, we summarize established protocols to generate and analyze antitumor receptor-transduced T cells. These procedures help to further assess characteristics of gene-modified T cells, resulting in promotion of translational research for cancer immunotherapy.

DOI： 10.1007/978-1-4939-9728-2_3

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Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

With the emergence of cancer immunotherapy, T cells have played important roles in inducing antitumor responses. Many types of antitumor receptors, which possess tumor-binding sites and T-cell activation sites, have been developed. For example, genetically engineered T-cell receptor, chimeric antigen receptor, and bispecific antibody can help us to educate and activate T cells specific for certain tumors. To generate optimal antitumor receptors, (1) selection/distribution of tumor antigens, (2) affinity/specificity and cross-reactivity of antitumor receptors, and (3) T-cell activation signals delivered from antitumor receptors should be considered. Accordingly, we explain how antitumor receptors recognize target antigens and summarize the mechanisms for on-target/off-target reactivity induced by T cells redirected with antitumor receptors. Furthermore, we discuss how antitumor receptors can be optimized for the development of next-generation cancer immunotherapy.

DOI： 10.11406/rinketsu.60.824

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1038/s41598-018-22931-4

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Other Link： http://www.nature.com/articles/s41598-018-22931-4

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Classical antigen processing leads to the presentation of antigenic peptides derived from endogenous and exogenous sources for MHC class I and class II molecules, respectively. Here we show that, unlike other class II molecules, prevalent HLA-DP molecules with beta-chains encoding Gly84 (DP84Gly) constitutively present endogenous peptides. DP84Gly does not bind invariant chain (Ii) via the class II-associated invariant chain peptide (CLIP) region, nor does it present CLIP. However, Ii does facilitate the transport of DP84Gly from the endoplasmic reticulum (ER) to the endosomal/lysosomal pathway by transiently binding DP84Gly via a non-CLIP region(s) in a pH-sensitive manner. Accordingly, like class I, DP84Gly constitutively presents endogenous peptides processed by the proteasome and transported to the ER by the transporter associated with antigen processing (TAP). Therefore, DP84Gly, found only in common chimpanzees and humans, uniquely uses both class I and II antigen-processing pathways to present peptides derived from intracellular and extracellular sources.

DOI： 10.1038/ncomms15244

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Objective. To identify risk alleles relevant to the causal and biologic mechanisms of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).
Methods. A genome-wide association study and subsequent replication study were conducted in a total cohort of 1,986 cases of AAV (patients with granulomatosis with polyangiitis [Wegener's] [GPA] or microscopic polyangiitis [MPA]) and 4,723 healthy controls. Meta-analysis of these data sets and functional annotation of identified risk loci were performed, and candidate disease variants with unknown functional effects were investigated for their impact on gene expression and/or protein function.
Results. Among the genome-wide significant associations identified, the largest effect on risk of AAV came from the single-nucleotide polymorphism variants rs141530233 and rs1042169 at the HLA-DPB1 locus (odds ratio [OR] 2.99 and OR 2.82, respectively) which, together with a third variant, rs386699872, constitute a triallelic risk haplotype associated with reduced expression of the HLA-DPB1 gene and HLA-DP protein in B cells and monocytes and with increased frequency of complementary proteinase 3 (PR3)-reactive T cells relative to that in carriers of the protective haplotype. Significant associations were also observed at the SERPINA1 and PTPN22 loci, the peak signals arising from functionally relevant missense variants, and at PRTN3, in which the top-scoring variant correlated with increased PRTN3 expression in neutrophils. Effects of individual loci on AAV risk differed between patients with GPA and those with MPA or between patients with PR3-ANCAs and those with myeloperoxidase-ANCAs, but the collective population attributable fraction for these variants was substantive, at 77%.
Conclusion. This study reveals the association of susceptibility to GPA and MPA with functional gene variants that explain much of the genetic etiology of AAV, could influence and possibly be predictors of the clinical presentation, and appear to alter immune cell proteins and responses likely to be key factors in the pathogenesis of AAV.

DOI： 10.1002/art.40034

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Publishing type：Research paper (scientific journal)   Publisher：American Society for Clinical Investigation  

DOI： 10.1172/jci.insight.89580

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Taylor and Francis Inc.  

Adult T-cell leukemia/lymphoma is caused by infection with HTLV-1, following a long latent period. Immunotherapy targeting Aurora kinase A, a tumor-associated antigen over-expressed in adult T-cell leukemia/lymphoma, holds great therapeutic potential. We review the evidence in favor of a therapeutic strategy combining vaccination and TCR-gene transfer against this target.

DOI： 10.1080/2162402X.2016.1239006

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOURNAL OF VISUALIZED EXPERIMENTS  

T cell receptors (TCRs) are used clinically to direct the specificity of T cells to target tumors as a promising modality of immunotherapy. Therefore, cloning TCRs specific for various tumor-associated antigens has been the goal of many studies. To elicit an effective T cell response, the TCR must recognize the target antigen with optimal affinity. However, cloning such TCRs has been a challenge and many available TCRs possess sub-optimal affinity for the cognate antigen. In this protocol, we describe a method of cloning de novo high affinity antigen-specific TCRs using existing TCRs by exploiting hemichain centricity. It is known that for some TCRs, each TCRa or TCRa hemichain do not contribute equally to antigen recognition, and the dominant hemichain is referred to as the centric hemichain. We have shown that by pairing the centric hemichain with counter-chains differing from the original counter-chain, we are able to maintain the antigen specificity, while modulating its interaction strength for the cognate antigen. Thus, the therapeutic potential of a given TCR can be improved by optimizing the pairing between the centric and counter hemichains.

DOI： 10.3791/54697(2016)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC CLINICAL INVESTIGATION INC  

Adoptive immunotherapy is a potentially curative therapeutic approach for patients with advanced cancer. However, the in vitro expansion of antitumor T cells prior to infusion inevitably incurs differentiation towards effector T cells and impairs persistence following adoptive transfer. Epigenetic profiles regulate gene expression of key transcription factors over the course of immune cell differentiation, proliferation, and function. Using comprehensive screening of chemical probes with defined epigenetic targets, we found that JQ1, an inhibitor of bromodomain and extra-terminal motif (BET) proteins, maintained CD8(+)T cells with functional properties of stem cell-like and central memory T cells. Mechanistically, the BET protein BRD4 directly regulated expression of the transcription factor BATF in CD8(+)T cells, which was associated with differentiation of T cells into an effector memory phenotype. JQ1-treated T cells showed enhanced persistence and antitumor effects in murine T cell receptor and chimeric antigen receptor gene therapy models. Furthermore, we found that histone acetyltransferase p300 supported the recruitment of BRD4 to the BATF promoter region, and p300 inhibition similarly augmented antitumor effects of the adoptively transferred T cells. These results demonstrate that targeting the BRD4-p300 signaling cascade supports the generation of superior antitumor T cell grafts for adoptive immunotherapy.

DOI： 10.1172/JCI86437

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Invariant natural killer T (iNKT) cells recognize self-lipids presented by CD1d through characteristic TCRs, which mainly consist of the invariant V alpha 14-J alpha 18 TCR alpha chain and V beta 8.2, 7 or 2 TCR beta chains with hypervariable CDR3 beta sequences in mice. The iNKT cell-CD1d axis is conserved between humans and mice, and human CD1d reactivity of murine iNKT cells have been described. However, the detailed differences between the recognition of human and mouse CD1d bound to various self-lipids by mouse iNKT TCRs are largely unknown. In this study, we generated a de novo murine iNKT TCR repertoire with a wider range of auto-reactivity compared with that of naturally occurring peripheral iNKT TCRs. V beta 8.2 mouse iNKT TCRs capable of recognizing the human CD1d-self-lipid tetramer were identified, although such clones were not detectable in the V beta 7 or V beta 2 iNKT TCR repertoire. In line with previously reports, clonotypic V beta 8.2 iNKT TCRs with unique CDR3 beta loops did not discriminate among lipids presented by mouse CD1d. Unexpectedly, however, these iNKT TCRs showed greater ligand selectivity toward human CD1d presenting the same lipids. Our findings demonstrated that the recognition of mouse and human CD1d-self-lipid complexes by murine iNKT TCRs is not conserved, thereby further elucidating the differences between cognate and cross-species reactivity of self-antigens by mouse iNKT TCRs.

DOI： 10.1371/journal.pone.0156114

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD  

Invariant natural killer T (INKT) cells are a subset of T lymphocytes that recognize lipid ligands presented by monomorphic CD1d. Human iNICT T cell receptor (TCR) is largely composed of invariant V alpha 24 (V alpha 24i) TCR alpha chain and semi-variant V beta 11 TCR beta chain, where complementarity-determining region (CDR)3 beta is the sole variable region. One of the characteristic features of iNKT cells is that they retain autoreactivity even after the thymic selection. However, the molecular features of human iNKT TCR CDR3 beta sequences that regulate autoreactivity remain unknown. Since the numbers of iNKT cells with detectable autoreactivity in peripheral blood is limited, we introduced the V alpha 24i gene into peripheral T cells and generated a de novo human iNKT TCR repertoire. By stimulating the transfected T cells with artificial antigen presenting cells (aAPCs) presenting self-ligands, we enriched strongly autoreactive iNKT TCRs and isolated a large panel of human iNKT TCRs with a broad range autoreactivity. From this panel of unique iNKT TCRs, we deciphered three CDR3 beta sequence motifs frequently encoded by strongly-autoreactive iNKT TCRs: a VD region with 2 or more acidic amino acids, usage of the J beta 2-5 allele, and a CDR beta region of 13 amino acids in length. iNKT TCRs encoding 2 or 3 sequence motifs also exhibit higher autoreactivity than those encoding 0 or 1 motifs. These data facilitate our understanding of the molecular basis for human iNKT cell autoreactivity involved in immune responses associated with human disease. (C) 2015 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jaut.2015.12.005

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Recent high throughput sequencing analysis has revealed that the TCR beta repertoire is largely different between CD8(+) and CD4(+) T cells. Here, we show that the transduction of SIG35 alpha, the public chain-centric HLA-A(star)02:01(A2)/MART1(27-35) TCR alpha hemichain, conferred A2/MART1(27-35) reactivity to a substantial subset of both CD8(+) and CD4(+) T cells regardless of their HLA-A2 positivity. T cells individually reconstituted with SIG35 alpha and different A2/MART1(27-35) TCR beta genes isolated from CD4(+) or CD8(+) T cells exhibited a wide range of avidity. Surprisingly, approximately half of the A2/MART1(27-35) TCRs derived from CD4(+) T cells, but none from CD8(+) T cells, were stained by A2/MART1(27-35) monomer and possessed broader cross-reactivity. Our results suggest that the differences in the primary structure of peripheral CD4(+) and CD8(+) TCR beta repertoire indeed result in the differences in their ability to form extraordinarily high avidity T cells which would otherwise have been deleted by central tolerance.

DOI： 10.1038/srep23821

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

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. To evaluate antigen-specific human CTL responses, we immunized HLA class I Tg NSG mice using polyinosinic: polycytidylic acid mixed Wilms tumor 1 (WT1) peptides, with or without WT1 peptide-loaded autologous dendritic cells. After immunization, the frequencies of HLA-restricted WT1-specific CTLs increased significantly in the spleen. Next, we transplanted the WT1-specific T-cell receptor (WT1-TCR) gene-transduced human HSCs into HLA class I Tg NSG newborn mice. WT1 tetramer-positive CD8(+) T cells differentiated from WT1-TCR-transduced HSCs in the recipients' BM, spleen, and thymus. Upon stimulation with WT1 peptide in vitro, these CTLs produced interferon-g and showed lytic activity against leukemia cells in an antigen-specific, HLA-restricted manner. HLA class I Tg NSG xenografts may serve as a preclinical model to develop effective immunotherapy against human malignancies.

DOI： 10.1182/blood-2014-10-604777

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

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-alpha/beta genes and siRNAs for endogenous TCRs (WT1-siTCR/CD4(+) T cells and WT1-siTCR/CD8(+) T cells), we examined the utility of this strategy. WT1-siTCR/CD4(+) T cells sufficiently recognized leukemia cells in an HLA class I-restricted manner and provided target-specific Th1 help for WT1-siTCR/CD8(+) T cells. By using a xenografted mouse model, we found that WT1-siTCR/CD4(+) T cells migrated to leukemia sites and subsequently attracted WT1-siTCR/CD8(+) T cells via chemotaxis. Therapy-oriented experiments revealed effective enhancement of leukemia suppression mediated by concomitant administration of WT1-siTCR/CD4(+) T cells and WT1-siTCR/CD8(+) T cells. Importantly, this augmented efficacy in the presence of WT1-siTCR/CD4(+) T cells was correlated with longer survival and enhanced formation of memory T cells by WT1-siTCR/CD8(+) T cells. Collectively, our experimental findings strongly suggest that this strategy would be clinically advantageous for the treatment of human leukemia.

DOI： 10.1038/leu.2015.155

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

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. In this study, we comprehensively studied how TCR chain centricity affects reactivity to target self-MHC/peptide complexes and alloreactivity using the TCR, clone TAK1, which is specific for human leukocyte antigen-A*24:02/Wilms tumor 1(235-243) (A24/WT1(235)) and cross-reactive with B*57:01 (B57). The TAK1 beta, but not the TAK1 alpha, hemi-chain possessed chain centricity. When paired with multiple clonotypic TCR alpha counterchains encoding TRAV12-2, 20, 36, or 38-2, the de novo TAK1 beta-containing TCRs showed enhanced, weakened, or absent reactivity to A24/WT1(235) and/or to B57. T cells reconstituted with these TCRa genes along with TAK1 beta possessed a very broad range (&gt;3 log orders) of functional and structural avidities. These results suggest that TCR chain centricity can be exploited to enhance desired antitumor TCR reactivity and eliminate unwanted TCR cross-reactivity. TCR reactivity to target MHC/peptide complexes and cross-reactivity to unrelated MHC molecules are not inextricably linked and are separable at the TCR sequence level. However, it is still mandatory to carefully monitor for possible harmful toxicities caused by adoptive transfer of T cells redirected by thymically unselected TCRs. (C) 2015 AACR.

DOI： 10.1158/2326-6066.CIR-14-0222

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

TCR alpha- and beta-chains cooperatively recognize peptide -MHC complexes. It has been shown that a "chain-centric" TCR hemichain can, by itself, dictate MHC-restricted Ag specificity without requiring major contributions from the paired TCR counterchain. Little is known, however, regarding the relative contributions and roles of chain-centric and its counter, non chain-centric, hemichains in determining T cell avidity. We comprehensively analyzed a thymically unselected T cell repertoire generated by transducing the a-chain centric HLA-A*02:01(A2)/MART1(27-35) TCR alpha, clone SIG35 alpha, into A2-matched and unmatched post-thymic T cells. Regardless of their HLA-A2 positivity, a substantial subset of peripheral T cells transduced with SIG35 alpha gained reactivity for A2/MART1(27-35). Although the generated A2/MART1(27-35) specific T cells used various TRBV genes, TRBV27 predominated with &gt;10(2) highly diverse and unique clonotypic CDR3 beta sequences. T cells individually reconstituted with various A2/MART1(27-35) TRBV27 TCR beta genes along with SIG35a possessed a wide range (&gt;2 log orders) of avidity. Approximately half possessed avidity higher than T cells expressing clone DMF5, a naturally occurring A2/MART1(27-35) TCR with one of the highest affinities. Importantly, similar findings were recapitulated with other self-Ags. Our results indicate that, although a chain-centric TCR hemichain determines Ag specificity, the paired counterchain can regulate avidity over a broad range (&gt;2 log orders) without compromising Ag specificity. TCR chain centricity can be exploited to generate a thymically unselected Ag-specific T cell repertoire, which can be used to isolate high-avidity antitumor T cells and their uniquely encoded TCRs rarely found in the periphery because of tolerance.

DOI： 10.4049/jimmunol.1401717

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Because WT1 is expressed in leukemia cells, the development of cancer immunotherapy targeting WT1 has been an attractive translational research topic. However, concern of this therapy still remains, since WT1 is abundantly expressed in renal glomerular podocytes. In the present study, we clearly showed that WT1-specific cytotoxic T lymphocytes (CTLs) certainly exerted cytotoxicity against podocytes in vitro; however, they did not damage podocytes in vivo. This might be due to the anatomical localization of podocytes, being structurally separated from circulating CTLs in glomerular capillaries by an exceptionally thick basement membrane.

DOI： 10.1186/1756-8722-7-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

Although adult T-cell leukemia (ATL) has a poor prognosis, successful allogeneic hematopoietic stem cell transplantation (allo-HSCT) in some cases suggests that a cellular immune-mediated strategy can be effective. So far, however, no effective target for anti-ATL immunotherapy has been defined. Here we demonstrated for the first time that human telomerase reverse transcriptase (hTERT) is a promising therapeutic target for ATL, and we developed a novel redirected T-cell-based immunotherapy targeting hTERT. hTERT messenger RNA was produced abundantly in ATL tumor cells but not in steady-state normal cells. Rearranged human leukocyte antigen-A*24:02 (HLA-A*24:02) -restricted and hTERT(461-469) nonameric peptide-specific T-cell receptor (TCR) alpha/beta genes were cloned from our previously established cytotoxic T lymphocyte clone (K3-1) and inserted into a novel retroviral TCR expression vector encoding small interfering RNAs for endogenous TCR genes in redirected T cells (hTERT-siTCR vector). Consequently, allogeneic or autologous gene-modified CD8(+) T cells prepared using the hTERT-siTCR vector successfully killed ATL tumor cells, but not normal cells including steady-state hematopoietic progenitors, in an HLA-A*24:02-restricted manner both in vitro and in vivo. Our experimental observations support the development of a novel hTERT-targeting redirected T-cell-based adoptive immunotherapy for ATL patients, especially those for whom suitable allo-HSCT donors are lacking.

DOI： 10.1182/blood-2012-11-465971

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Background and Purpose: Although gene-modification of T cells to express tumor-related antigen-specific T-cell receptor (TCR) or chimeric antigen receptor (CAR) has clinically proved promise, there still remains room to improve the clinical efficacy of re-directed T-cell based antitumor adoptive therapy. In order to achieve more objective clinical responses using ex vivo-expanded tumor-responsive T cells, the infused T cells need to show adequate localized infiltration into the tumor.
Methodology/Principal Findings: Human lung cancer cells variously express a tumor antigen, Wilms' Tumor gene product 1 (WT1), and an inflammatory chemokine, CCL2. However, CCR2, the relevant receptor for CCL2, is rarely expressed on activated T-lymphocytes. A HLA-A2402(+) human lung cancer cell line, LK79, which expresses high amounts of both CCL2 and WT1 mRNA, was employed as a target. Normal CD8(+) T cells were retrovirally gene-modified to express both CCR2 and HLA-A*2402-restricted and WT1235-243 nonapeptide-specific TCR as an effector. Anti-tumor functionality mediated by these effector cells against LK79 cells was assessed both in vitro and in vivo. Finally the impact of CCL2 on WT1 epitope-responsive TCR signaling mediated by the effector cells was studied. Introduced CCR2 was functionally validated using gene-modified Jurkat cells and human CD3(+) T cells both in vitro and in vivo. Double gene-modified CD3(+) T cells successfully demonstrated both CCL2-tropic tumor trafficking and cytocidal reactivity against LK79 cells in vitro and in vivo. CCL2 augmented the WT1 epitope-responsive TCR signaling shown by relevant luciferase production in double gene-modified Jurkat/MA cells to express luciferase and WT1-specific TCR, and CCL2 also dose-dependently augmented WT1 epitope-responsive IFN-gamma production and CD107a expression mediated by these double gene-modifiedCD3(+) T cells.
Conclusion/Significance: Introduction of the CCL2/CCR2 axis successfully potentiated in vivo anti-lung cancer reactivity mediated by CD8(+) T cells double gene-modified to express WT1-specific TCR and CCR2 not only via CCL2-tropic tumor trafficking, but also CCL2-enhanced WT1-responsiveness.

DOI： 10.1371/journal.pone.0056820

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Lymphoblastoid cell lines (LCLs), which are established by in vitro infection of peripheral B-lymphocytes with Epstein-Barr virus (EBV), are effective antigen-presenting cells. However, the ability of LCLs to present transduced tumor antigens has not yet been evaluated in detail. We report a single-step strategy utilizing a recombinant EBV (maxi-EBV) to convert B-lymphocytes from any individuals into indefinitely growing LCLs expressing a transgene of interest. The strategy was successfully used to establish LCLs expressing Wilms' tumor gene 1 (WT1) tumor antigen (WT1-LCLs), which is an attractive target for cancer immunotherapy. The established WT1-LCLs expressed more abundant WT1 protein than K562 leukemic cells, which are known to overexpress WT1. A WT1-specific cytotoxic T lymphocyte line efficiently lysed the WT1-LCL in a human leukocyte antigen-restricted manner, but poorly lysed control LCL not expressing WT1. These results indicate that the transduced WT1 antigen is processed and presented on the WT1-LCL. This experimental strategy can be applied to establish LCLs expressing other tumor antigens and will find a broad range of applications in the field of cancer immunotherapy.

DOI： 10.1038/cgt.2012.34

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Aurora kinase A (AURKA) is overexpressed in leukemias. Previously, we demonstrated that AURKA-specific CD8(+) T cells specifically and selectively lysed leukemia cells, indicating that AURKA is an excellent target for immunotherapy. In this study, we examined the feasibility of adoptive therapy using redirected T cells expressing an HLA-A*0201-restricted AURKA(207-215)-specific T-cell receptor (TCR). Retrovirally transduced T cells recognized relevant peptide-pulsed but not control target cells. Furthermore, TCR-redirected CD8(+) T cells lysed AURKA-overexpressing human leukemic cells in an HLA-A*0201-restricted manner, but did not kill HLA-A*0201(+) normal cells, including hematopoietic progenitors. In addition, AURKA(207-215)-specific TCR-transduced CD4(+) T cells displayed target-responsive Th1 cytokine production. Finally, AURKA(207-215)-specific TCR-transduced CD8(+) T cells displayed antileukemia efficacy in a xenograft mouse model. Collectively, these data demonstrate the feasibility of redirected T cell-based AURKA-specific immunotherapy for the treatment of human leukemia. (Blood. 2012;119(2):368-376)

DOI： 10.1182/blood-2011-06-360354

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Wilms&apos; tumor gene (WT1), which is expressed in human pancreatic cancer (PC), is a unique tumor antigen recognized by T-cell-mediated antitumor immune response. Gemcitabine (GEM), a standard therapeutic drug for PC, was examined for the regulation of WT1 expression and the sensitizing effect on PC cells with WT1-specific antitumor immune response. Expression of WT1 was examined by quantitative PCR, immunoblot analysis, and confocal microscopy. Antigenic peptide of WT1 presented on HLA class I molecules was detected by mass spectrometry. WT1-specific T-cell receptor gene-transduced human T cells were used as effecter T cells for the analysis of cytotoxic activity. GEM treatment of human MIAPaCa2 PC cells enhanced WT1 mRNA levels, and this increase is associated with nuclear factor kappa B activation. Tumor tissue from GEM-treated MIAPaCa2-bearing SCID mice also showed an increase in WT1 mRNA. Some human PC cell lines other than MIAPaCa2 showed up-regulation of WT1 mRNA levels following GEM treatment. GEM treatment shifted WT1 protein from the nucleus to the cytoplasm, which may promote proteasomal processing of WT1 protein and generation of antigenic peptide. In fact, presentation of HLA-A*2402-restricted antigenic peptide of WT1 (CMTWNQMNL) increased in GEM-treated MIAPaCa2 cells relative to untreated cells. WT1-specific cytotoxic T cells killed MIAPaCa2 cells treated with an optimal dose of GEM more efficiently than untreated MIAPaCa2 cells. GEM enhanced WT1 expression in human PC cells and sensitized PC cells with WT1-specific T-cell-mediated antitumor immune response.

DOI： 10.1007/s00262-011-1033-3

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

Adoptive T-cell therapy for malignancies using redirected T cells genetically engineered by tumor antigen-specific T-cell receptor (TCR) gene transfer is associated with mispairing between introduced and endogenous TCR chains with unknown specificity. Therefore, deterioration of antitumor reactivity and serious autoimmune reactivity are major concerns. To address this problem, we have recently established a novel retroviral vector system encoding siRNAs for endogenous TCR genes (siTCR vector). In this study, to test the clinical application of siTCR gene therapy for human leukemia, we examined in detail the efficacy and safety of WT1-siTCR-transduced T cells. Compared with conventional WT1-TCR (WT1-coTCR) gene-transduced T cells, these cells showed significant enhancement of antileukemia reactivity resulting from stronger expression of the introduced WT1-specific TCR with inhibition of endogenous TCRs. Notably, WT1-siTCR gene-transduced T cells were remarkably expandable after repetitive stimulation with WT1 peptide in vitro, without any deterioration of antigen specificity. WT1-siTCR gene-transduced T cells from leukemia patients successfully lysed autologous leukemia cells, but not normal hematopoietic progenitor cells. In a mouse xenograft model, adoptively transferred WT1-siTCR gene-transduced T cells exerted distinct antileukemia efficacy but did not inhibit human hematopoiesis. Our results suggest that gene-immunotherapy for leukemia using this WT1-siTCR system holds considerable promise. (Blood. 2011;118(6):1495-1503)

DOI： 10.1182/blood-2011-02-337089

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Authorship：Lead author   Language：English   Publisher：INFORMA HEALTHCARE  

Areas covered: This review covers selected articles detailing recent progress in this field, not only for solid tumors, but also for leukemias. In terms of achieving uniform therapeutic quality of TCR gene-modified T cells as an &apos;&apos;off-the-shelf&apos;&apos; product, the authors abstract and discuss the requisite conditions for successful outcome, including: i) the optimal target choice reflecting the specificity of the introduced TCR, ii) the quality and quantity of expressed TCRs in gene-modified T cells, and additional genetic modification reflecting enhanced antitumor functionality, and iii) &apos;&apos;on-&apos;&apos; and &apos;&apos;off-target&apos;&apos; adverse events caused by the quality of the introduced TCRs and other adverse events related to genetic modification itself. Readers will be able to readily abstract recent advances in TCR gene-transferred T-cell therapy, centering notably on efforts to obtain uniformity in the therapeutic functionality of engineered T cells
Expert opinion: Harmonizing the functionality and target specificity of TCR will allow the establishment of clinically useful adoptive immunotherapy in the near future.

DOI： 10.1517/14712598.2011.566853

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DOI： 10.1038/bcj.2011.8

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DOI： 10.2217/IMT.10.103

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Peripheral T-cell lymphoma (PTCL) is a biologically diverse lymphoid malignancy. The clinical aggressiveness associated with hemophagocytic syndrome (HS) is a characteristic of PTCL, being more distinctive in CD8(+) PTCL. However, the underlying mechanism of PTCL-associated HS has not yet been fully investigated. We newly established a novel IL-2-dependent CD8(+) PTCL lymphoma cell line (T8ML-1) from a patient with CD8(+) PTCL who suffered recurrent HS accompanying disease flare-up. Focusing on the lymphoma cell T-cell receptor (TCR), we examined the lymphoma cell functions responsible for such clinical manifestations. First, T8ML-1.1 in which endogenous TCR-alpha/beta chains were silenced by siR-NAs, and T8ML-1.2 in which endogenous TCR-alpha/beta chains were replaced with HLA-A*24:02-restricted and WT1(235-243)-specific TCR-alpha/beta, were established. T8ML-1 exerted phytohemagglutinin (PHA)-dependent cytotoxicity via granular exocytosis. Additionally, soluble factors produced by PHA-stimulated T8ML-1, which included INF-gamma and TNF-alpha, but not by simple-cultured T8ML-1, caused human monocytes to exhibit erythrophagocytosis and thrombophagocytosis in vitro. PHA binding induced phosphorylation of CD3 zeta chain. Furthermore, both cytotoxicity and hemophagocytosis were completely inhibited by T8ML-1.1, but eventually restored by T8ML-1.2. These data suggest that exogenous activation of TCR signaling in PTCL cells might play an important role in the formation of PTCL-associated HS.

DOI： 10.1007/s12185-010-0758-7

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Background: Familial hemophagocytic lymphohistiocytosis (FHL) is a rare disease of infancy or early childhood. To clarify the incidence and subtypes of FHL in Japan, we performed genetic and functional analyses of cytotoxic T lymphocytes (CTLs) in Japanese patients with FHL.
Design and Methods: Among the Japanese children with hemophagocytic lymphohistiocytosis (HLH) registered at our laboratory, those with more than one of the following findings were eligible for study entry under a diagnosis of FHL: positive for known genetic mutations, a family history of HLH, and impaired CTL-mediated cytotoxicity. Mutations of the newly identified causative gene for FHL5, STXBP2, and the cytotoxicity and degranulation activity of CTLs in FHL patients, were analyzed.
Results: Among 31 FHL patients who satisfied the above criteria, PRF1 mutation was detected in 17 (FHL2) and UNC13D mutation was in 10 (FHL3). In 2 other patients, 3 novel mutations of STXBP2 gene were confirmed (FHL5). Finally, the remaining 2 were classified as having FHL with unknown genetic mutations. In all FHL patients, CTL-mediated cytotoxicity was low or deficient, and degranulation activity was also low or absent except FHL2 patients. In 2 patients with unknown genetic mutations, the cytotoxicity and degranulation activity of CTLs appeared to be deficient in one patient and moderately impaired in the other.
Conclusions: FHL can be diagnosed and classified on the basis of CTL-mediated cytotoxicity, degranulation activity, and genetic analysis. Based on the data obtained from functional analysis of CTLs, other unknown gene(s) responsible for FHL remain to be identified.

DOI： 10.1371/journal.pone.0014173

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DOI： 10.1093/annonc/mdq544

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Whereas humanized mouse models have contributed significantly to human immunology research, human T cells developing in mouse thymic environment fail to demonstrate HLA-restricted function. To achieve HLA-restricted human immune response, we created an immune-compromised non-obese diabetic/SCID/IL2rg(null) strain (NSG) with homozygous expression of HLA class I heavy chain and light chain (NSG-HLA-A2/HHD). Transplantation of purified Lin-CD34+ CD38- human hematopoietic stem cells into NSG-HLA-A2/HHD newborns resulted in the development of human CD4+ and CD8+ TCR alpha beta+ T cells and CD4-CD8- and CD8+ TCR gamma delta+ cells in recipient bone marrow and spleen. Human cytotoxic T lymphocytes (CTLs) become functionally mature, as evidenced by the production of granzyme corresponding to phenotypic transition from nave to effector memory CTLs. In these recipients, human Th17 cells developed along with Th1 and Th2 cells. Epstein-Barr virus (EBV) infection in the humanized NSG-HLA-A2/HHD recipients resulted in the formation of lymphoproliferative lesions consisting mainly of human B cells with scattered human T cells. Human CTLs developing in the recipients recognized EBV-derived peptides in an HLA-restricted manner and exerted HLA-restricted cytotoxicity against EBV-infected human B cells. The HLA-expressing humanized mouse with functional HLA-restricted T cells and consistent representation of rare T-cell subsets overcomes a major constraint in human immunology, and serves as a useful model for investigation of human immune responses against pathogens and for the development of therapeutic strategies against human diseases.

DOI： 10.1073/pnas.1000475107

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Human herpesvirus 6 (HHV-6) has a tropism for immunocompetent cells, including T lymphocytes, monocytes/macrophages, and dendritic cells (DCs) suggesting that HHV-6 infection affects the immunosurveillance system. Tolllike receptor (TLR) system plays an important role in innate immunity against various pathogens. In the present study, we investigated the effect of HHV-6 infection on the expression and intracellular signaling of TLRs in DCs. Although expression levels of TLRs were not decreased or slightly elevated following HHV-6 infection, the amounts of cytokines produced following stimulation with ligands for TLRs appeared to be dramatically decreased in HHV-6-infected DCs as compared to mock-infected DCs. Similarly, phosphorylation levels of TAK-1, I kappa B kinase, and I kappa B-a following stimulation of HHV-6-infected DCs with lipopolysaccharide, which is the ligand for TLR4, appeared to be decreased. These data show that HHV-6 impairs intracellular signaling through TLRs indicating the novel mechanism of HHV-6-mediated immunomodulation.

DOI： 10.1186/1743-422X-7-91

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Authorship：Lead author   Language：English   Publisher：HINDAWI PUBLISHING CORPORATION  

The last decade has seen great strides in the field of cancer immunotherapy, especially the treatment of melanoma. Beginning with the identification of cancer antigens, followed by the clinical application of anti-cancer peptide vaccination, it has now been proven that adoptive T-cell therapy (ACT) using cancer antigen-specific T cells is the most effective option. Despite the apparent clinical efficacy of ACT, the timely preparation of a sufficient number of cancer antigen-specific T cells for each patient has been recognized as its biggest limitation. Currently, therefore, attention is being focused on ACT with engineered T cells produced using cancer antigen-specific T-cell receptor (TCR) gene transfer. With regard to human leukemia, ACT using engineered T cells bearing the leukemia antigen-specific TCR gene still remains in its infancy. However, several reports have provided preclinical data on TCR gene transfer using Wilms' tumor gene product 1 (WT1), and also preclinical and clinical data on TCR gene transfer involving minor histocompatibility antigen, both of which have been suggested to provide additional clinical benefit. In this review, we examine the current status of anti-leukemia ACT with engineered T cells carrying the leukemia antigen-specific TCR gene, and discuss the existing barriers to progress in this area.

DOI： 10.1155/2010/521248

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Authorship：Lead author   Language：English   Publisher：INFORMA HEALTHCARE  

Background: Although cellular immunotherapy still remains in its infancy, it is one of the important treatment options against cancer. The marked improvement of its clinical efficacy requires a &apos;better&apos; target antigen, which is well recognized by cancer-cell-specific cytotoxic T lymphocytes. We have recently demonstrated the potential of Aurora-A kinase (Aurora-A) as such a &apos;better&apos; target for cellular immunotherapy against human leukemia. Aurora-A is a member of the serine/threonine kinase family that properly regulates the cell division process, and has recently been implicated in tumorigenesis. On the other hand, small-molecule inhibitors targeting Aurora-A have recently been developed and preliminary but promising observations from Phase I clinical trials have been reported. These facts highlight the attractiveness of Aurora-A as an important target of comprehensive cancer therapies. Objective/methods: in this review, we cover Aurora-A in the areas of immunotherapy and small-molecule inhibitor therapy against cancers. Results/conclusions: Aurora-A kinase is an attractive molecule not only as a target for small-molecule inhibitors, but also as a potential target for immunotherapy against cancer.

DOI： 10.1517/14728220903307483

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC GENERAL MICROBIOLOGY  

Recently, HBZ has been reported to play an important role in the proliferation of adult T-cell leukaemia (ATL) cells and might be a target of novel therapy for ATL. To develop a novel immunotherapy for ATL, we verified the feasibility of cellular immunotherapy targeting HBZ. We established an HBZ-specific and HLA-A*0201-restricted cytotoxic T lymphocyte (CTL) clone. Detailed study using this CTL clone clearly showed that HBZ is certainly an immunogenic protein recognizable by human CTLs; however, HBZ-specific CTLs could not lyse ATL cells. Failure of HBZ-specific CTLs to recognize human T-cell leukemia virus type 1 (HTLV-1)-infected cells might be due to a low level of HBZ protein expression in ATL cells and resistance of HTLV-1 -infected cells to CTL-mediated cytotoxicity. Although HBZ plays an important role in the proliferation of HTLV-1 infected cells, it may also provide a novel mechanism that allows them to evade immune recognition.

DOI： 10.1099/vir.0.010199-0

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DOI： 10.1111/j.1365-2141.2009.07695.x

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DOI： 10.1002/ajh.21387

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

Aurora-A kinase (Aur-A) is a member of the serine/threonine kinase family that regulates the cell division process, and has recently been implicated in tumorigenesis. In this study, we identified an antigenic 9-amino-acid epitope (Aur-A(207-215): YLILEYAPL) derived from Aur-A capable of generating leukemia-reactive cytotoxic T lymphocytes (CTLs) in the context of HLA-A*0201. The synthetic peptide of this epitope appeared to be capable of binding to HLA-A*2402 as well as HLA-A*0201 molecules. Leukemia cell lines and freshly isolated leukemia cells, particularly chronic myelogenous leukemia (CML) cells, appeared to express Aur-A abundantly. Aur-A-specific CTLs were able to lyse human leukemia cell lines and freshly isolated leukemia cells, but not normal cells, in an HLA-A*0201 restricted manner. Importantly, Aur-A specific CTLs were able to lyse CD34(+) CML progenitor cells but did not show any cytotoxicity against normal CD34(+) hematopoietic stem cells. The tetramer assay revealed that the Aur-A(207-215) epitope-specific CTL precursors are present in peripheral blood of HLA-A*0201-positive and HLA-A*2402 positive patients with leukemia, but not in healthy individuals. Our results indicate that cellular immunotherapy targeting Aur-A is a promising strategy for treatment of leukemia. (Blood. 2009; 113: 66-74)

DOI： 10.1182/blood-2008-06-164889

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Patients with acquired immune deficiency syndrome (AIDS) are susceptible to secondary malignant tumors. Among those malignancies, the increased incidence of germ cell tumor (GCT) in patients with AIDS has recently been documented in Western countries, while that is still rare in Japan. Here, we report a man patient with advanced GCT (seminoma) complicated with AIDS who was continuously treated with highly active antiretroviral therapy (HAART). A partial response was obtained after resection of the primary left testis and three courses of chemotherapy. During the clinical course, he contracted unexpected gastric bleeding that made it impossible to take HAART agents and prophylactic agents for opportunistic infection. Thereafter, he suffered from a severe pulmonary infection and consequently died of severe respiratory failure. The lymphopenia related to both chemotherapy and AIDS synergistically rendered this patient immunoincompetent and thus he suffered from this fatal pulmonary infection. The recent progress in AIDS treatment has been reported to prolong the survival of tumor-bearing AIDS patients, especially GCT-bearing AIDS patients. Because of the current increase in the number of AIDS patients in Japan, it is important to report the present case which indicated that careful chemotherapy against GCT with strict management of the immunoincompetence can provide a good prognosis for GCT-bearing AIDS patients.

DOI： 10.2169/internalmedicine.48.2357

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CML66 is a newly identified differentiation antigen that is expressed broadly in human leukemia and solid tumors, but its physiological function remains unknown. In the present study, to clarify the feasibility of CML66-targeted cancer immunotherapy, we attempted to identify cytotoxic T lymphocyte (CTL) epitopes derived from CML66. An immunogenic CML66-derived epitope (amino acid residues 76 - 84; YYIDTLGRI) capable of inducing human leukocyte antigen (HLA)-A*2402-restricted CTL specific for this peptide was identified. CML66-derived peptide-specific CTL efficiently lysed human leukemia cells, but not normal cells, in a HLA-A*2402-restricted fashion. Quantitative real-time polymerase chain reaction revealed that CML66 mRNA is expressed abundantly in primary acute myeloid leukemia cells, acute lymphoid leukemia cells, and chronic myelogenous leukemia cells in advanced phase, and that the expression level of CML66 mRNA in normal cells is low compared with that in leukemia cells. CML66-specific CTL precursors were detected in the peripheral blood of patients with acute leukemia. These data indicate that the CML66-derived epitope identified in the present study is a new target antigen for cellular immunotherapy of human leukemia.

DOI： 10.1111/j.1349-7006.2008.00823.x

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72歳男。右背部の疼痛、腫脹を主訴とした。白血球・血小板の増加、幼若球の出現と好塩基球の増加、肝脾腫と背部の広範な皮下血腫を認めたため、精査加療目的で紹介受診した。骨髄生検で骨髄の線維化を認めたほか、Janus kinase 2(JAK2)V617F変異があり、白血球の著増、末梢血への赤芽球の出現、LD増加ならびに著明な脾腫があることから、骨髄線維症と診断した。また、皮下血腫に関しては血小板の著増、von Willebrand因子(vWF)活性22%、vWF抗原94%より、後天性von Willebrand症候群の合併によるものと考えられた。骨髄線維症に対してruxolitinib 40mg/日で治療を開始したところ、骨髄線維症の主症状である脾腫が改善するとともに、血小板数の低下とvWF活性の増加がみられ、皮下血腫は改善した。

DOI： 10.2169/naika.108.1448

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DOI： 10.2177/jsci.40.281a

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Adult T-cell leukemia/lymphoma is caused by infection with HTLV-1, following a long latent period. Immunotherapy targeting Aurora kinase A, a tumor-associated antigen over-expressed in adult T-cell leukemia/lymphoma, holds great therapeutic potential. We review the evidence in favor of a therapeutic strategy combining vaccination and TCR-gene transfer against this target.

DOI： 10.1080/2162402X.2016.1239006

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Language：English   Presentation type：Oral presentation (general)  

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Language：English   Presentation type：Symposium, workshop panel (public)  

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Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

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Language：English   Presentation type：Poster presentation  

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Language：English   Presentation type：Symposium, workshop panel (nominated)  

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Language：English   Presentation type：Poster presentation  

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Language：English   Presentation type：Symposium, workshop panel (nominated)  

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Language：English   Presentation type：Poster presentation  

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Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

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Language：English  

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Language：English   Presentation type：Symposium, workshop panel (public)  

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Language：English   Presentation type：Poster presentation  

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Language：English   Presentation type：Oral presentation (general)  

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Language：English   Presentation type：Symposium, workshop panel (public)  

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Language：Japanese   Presentation type：Oral presentation (general)  

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Language：Japanese   Presentation type：Oral presentation (general)  

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Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

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Presentation type：Oral presentation (invited, special)  

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Language：English   Presentation type：Oral presentation (general)  

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Language：English   Presentation type：Oral presentation (general)  

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Language：Japanese   Presentation type：Oral presentation (general)  

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Language：English   Presentation type：Poster presentation  

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Applicant：国立大学法人愛媛大学

Application no：特願2007-139441  Date applied：2007.5

Announcement no：特開2009-065835  Date announced：2009.4

Patent/Registration no：特許第5279063号  Date issued：2013.5

J-GLOBAL

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