Examination of immunotherapy improvement through CD8+ T cell induction of refractory hepatocellular carcinoma and, construction of biomarkers.

• Project/Area Number: 21K07899
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Yokohama City University
• Principal Investigator: Chuma Makoto 横浜市立大学, 附属市民総合医療センター, 准教授 (30360910)
• Co-Investigator(Kenkyū-buntansha): 前田 愼 横浜市立大学, 医学研究科, 教授 (40415956) ; 魚嶋 晴紀 北里大学, 医学部, 講師 (20752869)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2023: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2021: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 肝細胞癌 / 免疫チェックポイント阻害剤 / バイオマーカー / 抗 PD-L1抗体治療 / CD8+T細胞 / β-catenin / IKK / 分子標的治療 / 肝癌 / 免疫 / CD8陽性T細胞

Outline of Research at the Start

免疫微小環境におけるCD8+T細胞の浸潤を介し、免疫調整薬での反応が乏しいと考えられている“Cold tumor”を、反応あり奏効が得られる“Hot tumor”に変化させる肝癌免疫療法の構築を試みることを第一の目的とする。また肝癌における分子、遺伝子診断に基づく免疫療法、分子標的治療は規定されておらず、現存の免疫チェックポイント阻害剤、分子標的治療薬の奏効に関するバイオマーカーを確立し、コンパニオン診断の基盤を構築することを第二の目的とする。

Outline of Final Research Achievements

The aims of this study were to identify clinically significant biomarkers of a response to combined immunotherapy therapy and to develop target strategies against hepatocellular carcinoma (HCC) and examination of immunotherapy improvement through CD8+ T cell induction of HCC. CD8+ T-cell induction in HCC did not improve combined immunotherapy. Although no ctDNA mutations in blood were found to be related to combined immunotherapy therapy efficacy, serum CXCL9 and LAG-3 levels, which are related to the cancer immune cycle, were associated with treatment efficacy and could be predictive markers of the efficacy of combined immunotherapy therapy in HCC patients.

Academic Significance and Societal Importance of the Research Achievements

本研究より、複合免疫療法の治療効果に関して、がんの免疫サイクルにおけるケモカインが有用なマーカーである事が示され、HCCにおける複数の化学療法において、バイオマーカーに基づく個別化医療への橋渡しが期待される。

Research Products

• [Journal Article] Identification of CT Values That Could Be Predictive of Necrosis (N-CTav) in Hepatocellular Carcinoma after Lenvatinib Treatment (2022)
  • Author(s): Makoto Chuma, Hideki Yokoo, Atsushi Hiraoka, Kazuhiko Ueda, et al.
  • Journal Title: Current Oncology Volume: - Issue: 5 Pages: 3259-3271
  • DOI: 10.3390/curroncol29050266
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impact of psoas muscle index assessed by a simple measurement method on tolerability and duration of continued treatment with sorafenib in hepatocellular carcinoma patients (2022)
  • Author(s): Ogushi Katsuaki、Chuma Makoto、Numata Kazushi、Nozaki Akito、Moriya Satoshi、Uojima Haruki、Kondo Masaki、Morimoto Manabu、Maeda Shin
  • Journal Title: European Journal of Gastroenterology & Hepatology Volume: Publish Ahead of Print Issue: 7 Pages: 1-1
  • DOI: 10.1097/meg.0000000000002346
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The change rate in serum nitric oxide may affect lenvatinib therapy in hepatocellular carcinoma. (2022)
  • Author(s): Kawamura A, Uojima H, Chuma M, Shao X, Hidaka H, Nakazawa T, Take A, Sakaguchi Y, Numata K, Kako M, Nozaki A, Azuma S, Horio K, Kusano C, Atsuda K
  • Journal Title: BMC Cancer Volume: 22 Issue: 1 Pages: 912-921
  • DOI: 10.1186/s12885-022-10002-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] EGFR inhibition reverses resistance to lenvatinib in hepatocellular carcinoma cells (2022)
  • Author(s): He Xiaoping、Hikiba Yohko、Suzuki Yoshimasa、Nakamori Yoshinori、Kanemaru Yushi、Sugimori Makoto、Sato Takeshi、Nozaki Akito、Chuma Makoto、Maeda Shin
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 8007-8007
  • DOI: 10.1038/s41598-022-12076-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A prospective observational cohort study of lenvatinib as initial treatment in patients with BCLC-defined stage B hepatocellular carcinoma (2022)
  • Author(s): Kobayashi S, Fukushima T, Ueno M, Moriya S, Chuma M, Numata K, Tsuruya K, Hirose S, Kagawa T, Hattori N, Watanabe T, Matsunaga K, Suzuki M, Uojima H, Hidaka H, Kusano C, Suzuki M, Morimoto M.
  • Journal Title: BMC Cancer Volume: 22 Issue: 1 Pages: 517-517
  • DOI: 10.1186/s12885-022-09625-x
  • Peer Reviewed / Open Access
• [Journal Article] Safety and efficacy of atezolizumab plus bevacizumab in patients with unresectable hepatocellular carcinoma in early clinical practice: A multicenter analysis (2021)
  • Author(s): Chuma Makoto、Hattori Nobuhiro、Watanabe Tsunamasa、Maeda Shin
  • Journal Title: Hepatology Research Volume: 52 Issue: 3 Pages: 269-280
  • DOI: 10.1111/hepr.13732
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Analysis of efficacy of lenvatinib treatment in highly advanced hepatocellular carcinoma with tumor thrombus in the main trunk of the portal vein or tumor with more than 50% liver occupation: A multicenter analysis. (2021)
  • Author(s): 1.Chuma M, Uojima H, Hiraoka A, et al.
  • Journal Title: Hepatology Research Volume: 51 Issue: 2 Pages: 201-215
  • DOI: 10.1111/hepr.13592
  • Peer Reviewed
• [Journal Article] NAFLD exacerbates cholangitis and promotes cholangiocellular carcinoma in mice. (2021)
  • Author(s): Maeda S, Hikiba Y, Fujiwara H, Ikenoue T, Sue S, Sugimori M, Matsubayashi M, Kaneko H, Irie K, Sasaki T, Chuma M
  • Journal Title: Cancer Sci, Volume: 12 Issue: 4 Pages: 1471-1480
  • DOI: 10.1111/cas.14828
  • Peer Reviewed / Open Access
• [Presentation] Safety and efficacy of atezolizumab plus bevacizumab in patients with unresectable hepatocellular carcinoma in early clinical practice: A multicenter analysis. (2022)
  • Author(s): Chuma M, Uojima H, Hattori N, Arase Y, Fukushima T, Hirose S, Hidaka H, Morimoto M, Numata K, Kagawa T, Maeda S
  • Organizer: 30th. United European Gastroenterology
  • Int'l Joint Research
• [Presentation] Identification of CT Values That Could Be Predictive of Necrosis (N-CTav) in Hepatocellular Carcinoma after Lenvatinib Treatment (2022)
  • Author(s): Chuma M, Yokoo H, Hiraoka A, Ueda K, Tsuji K, Shimada N, Uojima H, Kobayashi S, Hattori N, Okubo T, Atsukawa M, Ishikawa T, Toyoda H, Tada T, Saito Y, Hidaka H, Morimoto M, Numata K, Kagawa T, Sakamoto M, Kumada T
  • Organizer: 30th. United European Gastroenterology
  • Int'l Joint Research
• [Presentation] Circulating microRNA-1246 as a Possible Biomarker for Early Tumor Recurrence of Hepatocellular Carcinoma. (2022)
  • Author(s): Chuma M, Toyoda H, Yokoo H, Nozaki A, Ogushi K, Tada T, Ogawa K, Numata K, Kumada T, Taketomi A, Naoya S, Maeda S
  • Organizer: Asian Pacific Association for the Study of the Liver (APASL) Oncology
  • Int'l Joint Research
• [Presentation] 肝細胞癌の免疫療法+分子標的治療の実臨床における成績と効果関連バイオマーカーの選定 (2022)
  • Author(s): 中馬誠, 加川建弘, 豊田秀徳
  • Organizer: 第30回日本消化器関連学会週間 (JDDW2022)
• [Presentation] 切除不能肝細胞癌におけるAtezolizumab+Bevacizumabの安全性、有効性に関する多施設共同研究 (2022)
  • Author(s): 中馬誠, 魚嶋晴紀, 福島泰斗
  • Organizer: 第58回日本肝臓学会総会
• [Presentation] 進行肝癌におけるアテゾリズマブ/ベバシズマブの治療効果、安全性に関する多施設共同研究 (2021)
  • Author(s): 中馬誠, 森本学, 加川建弘
  • Organizer: 第29回日本消化器関連学会週間 (JDDW2021)
• [Presentation] 進行肝癌に対するAtezolizumab+Bevacizumabの初期治療成績 (2021)
  • Author(s): 中馬誠, 魚嶋晴紀, 服部伸洋
  • Organizer: 第57回日本肝臓学会総会