Faculty Profiles - MAEDA Yoshinobu

HLA半合致末梢血幹細胞移植後に発症した進行性多巣性白質脳症の1例

池川俊太郎, 猪股知子, 池田直人, 杉浦弘幸, 黒井大雅, 浅野豪, 吉田将平, 西森久和, 松岡賢市, 前田嘉信, 谷本光音

臨床血液 58 ( 5 ) 555 - 555 2017.5

【臨床血液学-最新情報と今後の展望2017(造血幹細胞移植(がん免疫含む)-】同種造血幹細胞移植と免疫チェックポイント阻害薬

近藤英生, 前田嘉信

臨床血液 58 ( 5 ) 506 - 513 2017.5

Language：Japanese Publisher：(一社)日本血液学会-東京事務局

抗PD-1抗体や抗CTLA-4抗体など免疫チェックポイント阻害薬は,以前から大量IL-2療法などの免疫療法が行われていた悪性黒色腫において有効性が確認されたのを皮切りに,複数の固形がん,造血器腫瘍ではホジキンリンパ腫での劇的な効果も認められ,いまや「がん免疫」療法は手術,放射線,化学療法に続く第4のがん治療として確立している。昨年,同種造血幹細胞移植後の再発患者に対するipilimumab投与の第I/Ib試験結果がNEJM誌に報告され,大きな話題となった。一定の有効性および安全性が確認されたものの,免疫抑制服用やGVHD既往などによる適応症例の制限や投与量など問題もあり,日常臨床への導入は極めて高いハードルがある。今後,免疫チェックポイント阻害薬は,同種造血幹細胞移植よりリスクの低い免疫療法として,造血器腫瘍における開発が進むことを期待する。(著者抄録)

健常人ドナー末梢血幹細胞採取時のクエン酸中毒発現、電解質異常についての解析

中村真, 藤井敬子, 佐伯恭昌, 谷勝真, 黒井大雅, 高木尚江, 猪股知子, 池川俊太郎, 杉浦弘幸, 池田直人, 浅野豪, 吉田将平, 西森久和, 松岡賢市, 近藤英生, 前田嘉信, 藤井伸治, 谷本光音

臨床血液 58 ( 5 ) 553 - 553 2017.5

PD-1 modulates regulatory T-cell homeostasis during low-dose interleukin-2 therapy

Takeru Asano, Yusuke Meguri, Takanori Yoshioka, Yuriko Kishi, Miki Iwamoto, Makoto Nakamura, Yasuhisa Sando, Hideo Yagita, John Koreth, Haesook T. Kim, Edwin P. Alyea, Philippe Armand, Corey S. Cutler, Vincent T. Ho, Joseph H. Antin, Robert J. Soiffer, Yoshinobu Maeda, Mitsune Tanimoto, Jerome Ritz, Ken-ichi Matsuoka

BLOOD 129 ( 15 ) 2186 - 2197 2017.4

Language：English Publisher：AMER SOC HEMATOLOGY

CD4(+) Foxp3(+) regulatory T cells (Tregs) play a central role in the maintenance of immune tolerance after hematopoietic stem cell transplantation. We previously reported that low-dose interleukin-2 (IL-2) therapy increased circulating Tregs and improved clinical symptoms of chronic graft-versus-host-disease (cGVHD); however, the mechanisms that regulate Treg homeostasis during IL-2 therapy have not been well studied. To elucidate these regulatory mechanisms, we examined the role of inhibitory coreceptors on Tregs during IL-2 therapy in a murine model and in patients with cGVHD. Murine studies demonstrated that low-dose IL-2 selectively increased Tregs and simultaneously enhanced the expression of programmed cell death 1 (PD-1), especially on CD44(+) CD62L(+) central-memory Tregs, whereas expression of other inhibitory molecules, including CTLA-4, LAG-3, and TIM-3 remained stable. PD-1-deficient Tregs showed rapid Stat5 phosphorylation and proliferation soon after IL-2 initiation, but thereafter Tregs became proapoptotic with higher Fas and lower Bcl-2 expression. As a result, the positive impact of IL-2 on Tregs was completely abolished, and Treg levels returned to baseline despite continued IL-2 administration. We also examined circulating Tregs from patients with cGVHD who were receiving low-dose IL-2 and found that IL-2-induced Treg proliferation was promptly followed by increased PD-1 expression on central-memory Tregs. Notably, clinical improvement of GVHD was associated with increased levels of PD-1 on Tregs, suggesting that the PD-1 pathway supports Treg-mediated tolerance. These studies indicate that PD-1 is a critical homeostatic regulator for Tregs by modulating proliferation and apoptosis during IL-2 therapy. Our findings will facilitate the development of therapeutic strategies that modulate Treg homeostasis to promote immune tolerance.

DOI： 10.1182/blood-2016-09-741629

PD-1 modulates regulatory T-cell homeostasis during low-dose interleukin-2 therapy International journal

BLOOD 129 ( 15 ) 2186 - 2197 2017.4

Language：English Publisher：AMER SOC HEMATOLOGY

DOI： 10.1182/blood-2016-09-741629

Graft-versus-leukemia effect with a WT1-specific T-cell response induced by azacitidine and donor lymphocyte infusions after allogeneic hematopoietic stem cell transplantation

Tatsunori Ishikawa, Nobuharu Fujii, Masahide Imada, Michinori Aoe, Yusuke Meguri, Tomoko Inomata, Hiromi Nakashimai, Keiko Fujii, Shohei Yoshida, Hisakazu Nishimori, Ken-Ichi Matsuoka, Eisei Kondo, Yoshinobu Maeda, Mitsune Tanimoto

CYTOTHERAPY 19 ( 4 ) 514 - 520 2017.4

Language：English Publisher：ELSEVIER SCI LTD

Background. Azacitidine (Aza) and donor lymphocyte infusion (DLI) therapy has recently been reported as an effective salvage therapy for relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Despite the high response rate and relatively long period of remission, most patients relapse again. The immunologic mechanism of the response and limited efficacy remain unknown. Case Report. Aza + DLI therapy was performed for a patient with therapy-related MDS (t-MDS), who had relapsed after allogeneic peripheral blood stem cell transplantation. We observed a powerful graft versus-leukemia (GVL) effect accompanied by an evident Wilms tumor antigen 1 (WT1)-specific CD8 T-cell response. Remission continued for 15 months, but finally the patient relapsed. The kinetics of the WT1-specific CD8 T cells were inversely associated with WT1 messenger RNA (mRNA), suggesting a WT1-driven GVL effect. Discussion. A difference of T-cell phenotype between the whole T cells and the WT1-specific CD8 T cells was observed. It is of note that the memory phenotype of the WT1-specific T cell was limited and decreased early. The immunoescape mechanism was partly supported by loss of the memory phenotype due to failure of expansion and differentiation. Conclusion. Our data suggested that a WT1-specific T-cell response at least partly contributes to the GVL effect induced by Aza + DLI. A strategy for maximizing and maintaining the memory phenotype of the CTL may be required for durable remission.

DOI： 10.1016/j.jcyt.2016.12.007

Graft-versus-leukemia effect with a WT1-specific T-cell response induced by azacitidine and donor lymphocyte infusions after allogeneic hematopoietic stem cell transplantation International journal

CYTOTHERAPY 19 ( 4 ) 514 - 520 2017.4

Language：English Publisher：ELSEVIER SCI LTD

DOI： 10.1016/j.jcyt.2016.12.007

A Host-Dependent Prognostic Model for Elderly Patients with Diffuse Large B-Cell Lymphoma

Katsuhiro Miura, Jun Konishi, Takaaki Miyake, Masanori Makita, Atsuko Hojo, Yasufumi Masaki, Masatoshi Uno, Jun Ozaki, Chikamasa Yoshida, Daigo Niiya, Koichi Kitazume, Yoshinobu Maeda, Jun Takizawa, Rika Sakai, Tomofumi Yano, Kazuhiko Yamamoto, Kazutaka Sunami, Yasushi Hiramatsu, Kazutoshi Aoyama, Hideki Tsujimura, Jun Murakami, Yoshihiro Hatta, Masatoshi Kanno

ONCOLOGIST 22 ( 5 ) 554 - 560 2017

Language：English Publisher：WILEY

Background. Decision-making models for elderly patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) are in great demand.
Patients and Methods. The Society of Lymphoma Treatment in Japan (SoLT-J), in collaboration with the West-Japan Hematology and Oncology Group (West-JHOG), collected and retrospectively analyzed the clinical records of >= 65-year-old patients with DLBCL treated with R-CHOP from 19 sites across Japan to build an algorithm that can stratify adherence to R-CHOP.
Results. A total of 836 patients with a median age of 74 years ( range, 65-96 years) were analyzed. In the SoLT-J cohort (n=555), age >75 years, serum albumin level <3.7 g/dL, and Charlson Comorbidity Index score >= 3 were independent adverse risk factors and were defined as the Age, Comorbidities, and Albumin (ACA) index. Based on their ACA index score, patients were categorized into "excellent" (0 points), "good" (1 point), "moderate" (2 points), and "poor" (3 points) groups. This grouping effectively discriminated the 3-year overall survival rates, mean relative total doses (or relative dose intensity) of anthracycline and cyclophosphamide, unanticipated R-CHOP discontinuance rates, febrile neutropenia rates, and treatment-related death rates. Additionally, the ACA index showed comparable results for these clinical parameters when it was applied to the West-JHOG cohort (n5281).
Conclusion. The ACA index has the ability to stratify the prognosis, tolerability to cytotoxic drugs, and adherence to treatment of elderly patients with DLBCL treated with R-CHOP.

DOI： 10.1634/theoncologist.2016-0260

Clinicopathological analysis of primary central nervous system NK/T-cell lymphoma: rare and localised aggressive tumour among extranasal NK/T-cell tumours.

Miyata-Takata T, Takata K, Kato S, Hu LM, Noujima-Harada M, Chuang SS, Sato Y, Maeda Y, Yoshino T

0 ( 0 ) 0-0 2017

A Host-Dependent Prognostic Model for Elderly Patients with Diffuse Large B-Cell Lymphoma International journal

ONCOLOGIST 22 ( 5 ) 554 - 560 2017

Language：English Publisher：WILEY

DOI： 10.1634/theoncologist.2016-0260

慢性GVHDの予防と治療の進歩

前田嘉信

血液内科 72 ( 5 ) 2017

AMLに対する同種造血幹細胞移植前の不十分な血球回復が移植成績に与える影響

浅野豪, 池川俊太郎, 猪股知子, 池田直人, 杉浦弘幸, 黒井大雅, 吉田将平, 西森久和, 松岡賢市, 藤井伸治, 近藤英生, 前田嘉信, 谷本光音

日本造血細胞移植学会総会プログラム・抄録集 39th 2017

当院における抗MRSA薬の使用状況と治療効果

吉田将平, 佐田光, 池川俊太郎, 猪股知子, 杉浦弘幸, 池田直人, 黒井大雅, 浅野豪, 西森久和, 松岡賢市, 藤井伸治, 近藤英生, 前田嘉信, 谷本光音

日本造血細胞移植学会総会プログラム・抄録集 39th 2017

同種造血幹細胞移植におけるたんぱく質充足率が入院日数に与える影響について

庄野三友紀, 長谷川祐子, 佐田光, 高橋郁名代, 四方賢一, 西森久和, 藤井伸治, 前田嘉信

日本造血細胞移植学会総会プログラム・抄録集 40th 2017

Epstein-Barr virus-positive mucocutaneous ulcer in a patient with polycythemia vera treated with oral hydroxyurea. International journal

Toshihisa Hamada, Mariko Kawata, Yoshinobu Maeda, Tadashi Yoshino, Tomoko Miyake, Shin Morizane, Yoji Hirai, Keiji Iwatsuki

The Journal of dermatology 45 ( 4 ) 733 - 735 2017

Potential influence of interleukin-6 on the therapeutic effect of gefitinib in patients with advanced non-small cell lung cancer harbouring EGFR mutations. International journal

Tomoki Tamura, Yuka Kato, Kadoaki Ohashi, Kiichiro Ninomiya, Go Makimoto, Hiroko Gotoda, Toshio Kubo, Eiki Ichihara, Takehiro Tanaka, Koichi Ichimura, Yoshinobu Maeda, Katsuyuki Hotta, Katsuyuki Kiura

Biochemical and biophysical research communications 495 ( 1 ) 25105 - 25114 2017

Language：English

Although epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are a key therapy used for patients with EGFR-mutant non-small cell lung cancer (NSCLC), some of whom do not respond well to its therapy. Cytokine including IL-6 secreted by tumour cells is postulated as a potential mechanism for the primary resistance or low sensitivity to EGFR-TKIs. Fifty-two patients with advanced EGFR-mutant NSCLC who had received gefitinib were assessed retrospectively. The protein expression of IL-6 in the tumour cells was assessed by immunostaining and judged as positive if ≥ 50 of 100 tumour cells stained positively. Of the 52 patients, 24 (46%) and 28 (54%) were defined as IL-6-postitive (group P) and IL-6-negative (group N), respectively. Group P had worse progression-free survival (PFS) than that of group N, which was retained in the multivariate analysis (hazard ratio: 2.39; 95 %CI: 1.00-5.68; p < 0.05). By contrast, the PFS after platinum-based chemotherapy did not differ between groups P and N (p = 0.47). In cell line-based model, the impact of IL-6 on the effect of EGFR-TKIs was assessed. The combination of EGFR-TKI and anti-IL-6 antibody moderately improved the sensitivity of EGFR-TKI in lung cancer cell with EGFR mutation. Interestingly, suppression of EGFR with EGFR-TKI accelerated the activation of STAT3 induced by IL-6. Taken together, tumour IL-6 levels might indicate a subpopulation of EGFR-mutant NSCLC that benefits less from gefitinib monotherapy.

DOI： 10.1016/j.bbrc.2017.10.175