Effect of tyrosine kinase inhibitor for immunological microenviroment of hepatocellular carcinoma
Project/Area Number |
18K07922
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 53010:Gastroenterology-related
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Research Institution | Kindai University |
Principal Investigator |
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Co-Investigator(Kenkyū-buntansha) |
西田 直生志 近畿大学, 医学部, 准教授 (60281755)
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Project Period (FY) |
2018-04-01 – 2021-03-31
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Project Status |
Completed (Fiscal Year 2020)
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Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000)
Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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Keywords | 肝細胞癌 / 微小免疫環境 / 免疫チェックポイント阻害剤 / チロシンキナーゼ阻害剤 / PI3K-Akt経路 / β-catenin経路 / b-カテニン経路 / 腫瘍免疫 / 遺伝子変異 / PI3K / βカテニン / 免疫チェックポイント / PD-L1 / 免疫微小環境 / 免疫 |
Outline of Final Research Achievements |
To know how the effectively the response to immune checkpoint inhibitors (ICIs) can be enhanced, we explored the immunological and molecular characteristics of HCCs. Programmed cell death ligand 1 (PD-L1)-positive HCCs frequently showed inflamed phenotype; a subset of HCCs carried mutation in PI3K-Akt pathway. In HCCs with infiltration of TILs, CD8+ cells expressed multiple co-inhibitory receptors, suggesting T-cell exhaustion. On the other hands, PD-L1-negative HCCs showed activating mutations in β-catenin, such tumor exhibited non-inflamed phenotype. Through the analysis of the HCC patients treated with anti-PD-1 therapy, the combined of Wnt/β-catenin activation, PD-L1 expression, and degree of CD8+ TILs in HCC are revealed to be the predicting factor for the response to ICI. Tyrosine kinase inhibitor involving PI3K/Akt pathway, in combination with ICI, might effective in HCC with mutation in PI3K-Akt. Role of β-catenin inhibitor on immune cold HCC should also be explored.
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Academic Significance and Societal Importance of the Research Achievements |
PD-L1陽性肝癌は免疫細胞浸潤(TIL)が多く、しかしTILには複数の抑制型受容体が発現しており、PI3K-Akt変異例が比較的多い。従って、PI3K-Akt活性に介在するチロシンキナーゼ阻害剤が併用に有利である可能性がある。PD-L1陰性肝癌はTILに乏しく β-カテニン経路活性型変異を持つ。β-カテニン阻害剤の腫瘍免疫への影響を検討する余地がある。PD-L1発現肝癌は、CK-19やSALL4陽性例が多いが、従来治療に難治であり、ICIとPI3K-Ak阻害剤併用に期待が持たれる。TILに複数の抑制型受容体が発現していることより、2種の抑制型受容体に対する複合免疫療法にも期待される。
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Report
(4 results)
Research Products
(45 results)
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[Journal Article] Exploratory Analysis of Lenvatinib Therapy in Patients with Unresectable Hepatocellular Carcinoma Who Have Failed Prior PD-1/PD-L1 Checkpoint Blockade.2021
Author(s)
Aoki T, Kudo M, Ueshima K, Morita M, Chishina H, Takita M, Hagiwara S, Ida H, Minami Y, Tsurusaki M, Nishida N.
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Journal Title
Cancers (Basel).
Volume: 12
Issue: 10
Pages: 3048-3048
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] The Efficacy of Sonazoid-enhanced Ultrasonography in Decision-making for Liver Abscess Treatment2020
Author(s)
Morita M, Ogawa C, Omura A, Noda T, Kubo A, Matsunaka T, Tamaki H, Shibatoge M, Seno H, Minami Y, Ueshima K, Sakurai T, Nishida N, Kudo M.
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Journal Title
Internal Medicine
Volume: 59
Issue: 4
Pages: 471-477
DOI
NAID
ISSN
0918-2918, 1349-7235
Year and Date
2020-02-15
Related Report
Peer Reviewed / Open Access
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[Journal Article] Lenvatinib as an Initial Treatment in Patients with Intermediate-Stage Hepatocellular Carcinoma Beyond Up-To-Seven Criteria and Child-Pugh A Liver Function: A Proof-Of-Concept Study.2019
Author(s)
Kudo M, Ueshima K, Chan S, Minami T, Chishina H, Aoki T, Takita M, Hagiwara S, Minami Y, Ida H, Takenaka M, Sakurai T, Watanabe T, Morita M, Ogawa C, Wada Y, Ikeda M, Ishii H, Izumi N, Nishida N.
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Journal Title
Cancers (Basel)
Volume: 11
Issue: 8
Pages: 1084-1084
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Impact of Baseline ALBI Grade on the Outcomes of Hepatocellular Carcinoma Patients Treated with Lenvatinib: A Multicenter Study.2019
Author(s)
Ueshima K, Nishida N, Hagiwara S, Aoki T, Minami T, Chishina H, Takita M, Minami Y, Ida H, Takenaka M, Sakurai T, Watanabe T, Morita M, Ogawa C, Hiraoka A, Johnson P, Kudo M.
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Journal Title
Cancers (Basel)
Volume: 11
Issue: 7
Pages: 952-952
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Efficacy and Safety of Chemotherapy Following Anti-PD-1 Antibody Therapy for Gastric Cancer: A Case of Sclerosing Cholangitis.2019
Author(s)
Kono M, Sakurai T, Okamoto K, Masaki S, Nagai T, Komeda Y, Kamata K, Minaga K, Yamao K, Takenaka M, Watanabe T, Nishida N, Kudo M.
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Journal Title
Intern Med.
Volume: 58
Pages: 1263-1266
NAID
Related Report
Peer Reviewed
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[Journal Article] Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial.2019
Author(s)
Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, Assenat E, Brandi G, Pracht M, Lim HY, Rau KM, Motomura K, Ohno I, Merle P, Daniele B, Shin DB, Gerken G, Borg C, Hiriart JB, Okusaka T, Morimoto M, Hsu Y, Abada PB, Kudo M; REACH-2 study investigators
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Journal Title
Lancet Oncol.
Volume: 20
Issue: 2
Pages: 282-296
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Development of pre and post-operative models to predict early recurrence of hepatocellular carcinoma after surgical resection.2018
Author(s)
Chan AWH, Zhong J, Berhane S, Toyoda H, Cucchetti A, Shi K, Tada T, Chong CCN, Xiang BD, Li LQ, Lai PBS, Mazzaferro V, Kudo M, Kumada T, Roayaie S, Johnson PJ.
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Journal Title
J Hepatol.
Volume: 69
Issue: 6
Pages: 1284-1293
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Regional Differences in Efficacy, Safety, and Biomarkers for Second-Line Axitinib in Patients with Advanced Hepatocellular Carcinoma: From a Randomized Phase II Study.2018
Author(s)
Kudo M, Kang YK, Park JW, Qin S, Inaba Y, Assenat E, Umeyama Y, Lechuga MJ, Valota O, Fujii Y, Martini JF, Williams JA, Obi S.
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Journal Title
Liver Cancer.
Volume: 7
Issue: 2
Pages: 148-164
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial.2018
Author(s)
Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, Verslype C, Zagonel V, Fartoux L, Vogel A, Sarker D, Verset G, Chan SL, Knox J, Daniele B, Webber AL, Ebbinghaus SW, Ma J, Siegel AB, Cheng AL, Kudo M; KEYNOTE-224 investigators.
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Journal Title
Lancet Oncol. 2018 Jul;19(7):940-952
Volume: 19
Issue: 7
Pages: 940-952
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.2018
Author(s)
Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, Blanc JF, Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M, Cheng AL.
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Journal Title
Lancet. 2018 Mar 24;391(10126):1163-1173
Volume: 24
Issue: 10126
Pages: 1163-1173
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Presentation] IMPACT OF BASELINE ALBI GRADE ON THE OUTCOMES OF HEPATOCELLULAR CARCINOMA PATIENTS TREATED WITH LENVATINIB: A MULTICENTER STUDY2019
Author(s)
Masatoshi Kudo, Kazuomi Ueshima, Naoshi Nishida, Satoru Hagiwara, Tomoko Aoki, Tomohiro Minami, Hirokazu Chishina, Masahiro Takita, Yasunori Minami, Hiroshi Ida, Mamoru Takenaka, Toshiharu Sakurai, Tomohiro Watanabe, Masahiro Morita, Chikara Ogawa, Atsushi Hiraoka
Organizer
American Society for the Study of Liver Disease (AASLD)
Related Report
Int'l Joint Research
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[Presentation] LENVATINIB AS AN INITIAL TREATMENT IN PATIENTS WITH INTERMEDIATE-STAGE HEPATOCELLULAR CARCINOMA BEYOND UP-TO-SEVEN CRITERIA AND CHILD-PUGH A LIVER FUNCTION: A MULTICENTER PROPENSITY-SCORE MATCHED STUDY2019
Author(s)
Kazuomi Ueshima, Stephen L. Chan, Tomohiro Minami, Hirokazu Chishina, Tomoko Aoki, Masahiro Takita, Satoru Hagiwara, Yasunori Minami, Hiroshi Ida, Mamoru Takenaka, Toshiharu Sakurai, Tomohiro Watanabe, Masahiro Morita, Chikara Ogawa, Yoshiyuki Wada, Masafumi Ikeda, Hiroshi Ishii, Namiki Izumi, Naoshi Nishida
Organizer
American Society for the Study of Liver Disease (AASLD)
Related Report
Int'l Joint Research
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