Faculty Profiles - IMAI Norihiro

MAGE-A4 pMHC-targeted CAR-T cells exploiting TCR machinery exhibit significantly improved in vivo function while retaining antigen specificity Open Access

特集消化管静脈瘤診療Update [胃静脈瘤] 【Note】胃静脈瘤に対するcyanoacrylate注入のコツ

横山晋也, 石津洋二, 本多隆, 今井則博, 伊藤隆徳, 山本健太, 川嶋啓揮

消化器内視鏡 Vol. 36 ( 12 ) page： 1682 - 1685 2024.12

Liu, M; Akahori, Y; Imai, N; Wang, LN; Negishi, K; Kato, T; Fujiwara, H; Miwa, H; Shiku, H; Miyahara, Y

JOURNAL FOR IMMUNOTHERAPY OF CANCER Vol. 12 ( 11 ) 2024.11

Language：English Publishing type：Research paper (scientific journal) Publisher：Journal for ImmunoTherapy of Cancer

Background The development of chimeric antigen receptor (CAR)-T cell therapies for solid tumors has attracted considerable attention, yet their clinical efficacy remains limited. Therefore, various efforts have been made to improve the efficacy of CAR-T cell therapy. As one promising strategy, incorporating the T-cell receptor (TCR) machinery into CAR structures has been reported to improve the efficacy of CAR-T cells in studies using conventional CARs targeting such as EGFR. However, in the case of peptide/major histocompatibility complex (pMHC)-targeted CARs, the advantages of exploiting TCR machinery have not been fully elucidated. We recently developed MAGE-A4-derived pMHC (MAGE-A4 pMHC)-targeted CAR-T cells (MA-CAR-T cells) using a highly specific human scFv antibody against MAGE-A4 p230-239 /HLA-A∗02:01. We aimed to determine whether MAGE-A4 pMHC-targeted CAR-T cells using the TCR machinery (Hybrid MA-TCR-T cells) exhibit superior functionality without compromising antigen specificity. Methods We constructed a retroviral vector expressing Hybrid MA-TCR where MAGE-A4 pMHC-specific scFv are fused to human TCR constant chains. Results Hybrid MA-TCR-T cells demonstrated superior in vitro functions compared with MA-CAR-T cells, while maintaining strict antigen specificity. In addition, functional superiority of Hybrid MA-TCR-T cells to MA-CAR-T cells became more pronounced on repetitive antigen stimulation. In particular, Hybrid MA-TCR-T cells significantly inhibited tumor growth in an immunodeficient mouse model more effectively than MA-CAR-T cells. Ex vivo analyses indicated that their enhanced therapeutic efficacy might result from higher infiltration of functionally active, less differentiated Hybrid MA-TCR-T cells in tumor tissues. Conclusions These findings suggest that leveraging the TCR machinery is a promising strategy for enhancing pMHC-targeted CAR-T cell therapy for solid tumors, potentially leading to more effective treatments.

DOI： 10.1136/jitc-2024-010248

A Proposal for a Simple Subclassification of Advanced Hepatocellular Carcinoma in Systemic Treatment

Imai, N; Yamamoto, T; Mizuno, K; Yokoyama, S; Yamamoto, K; Ito, T; Ishizu, Y; Kuzuya, T; Honda, T; Ishikawa, T; Kawashima, H

CANCERS Vol. 16 ( 22 ) 2024.11

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

Objectives: This study focused on the presence or absence of vascular invasion and extrahepatic metastasis in hepatocellular carcinoma (HCC) and examined their impact on systemic treatment outcomes. Methods: We retrospectively analyzed 362 patients with unresectable HCC who received first-line systemic therapy. The prognostic evaluation was based on the presence of vascular invasion and extrahepatic metastasis at the time of treatment initiation. Results: Patients with vascular invasion or extrahepatic metastasis (advanced group) had significantly worse outcomes than those without these features (intermediate group), with median survival times of 434 and 658 days, respectively. Further subdivision of the advanced group into three categories—patients with only extrahepatic metastasis (m group, n = 77), patients with only vascular invasion (v group, n = 78), and patients with both vascular invasion and extrahepatic metastasis (vm group, n = 52)—revealed that the m group had significantly better outcomes than those in the other two groups, with median survival times of 649, 323, and 187 days, respectively. A comparison of the clinical backgrounds among the three groups demonstrated that the m group had significantly better liver function at the time of treatment initiation than that in the other two groups. Multivariable analysis, including performance status, Child–Pugh score, and the use of immune checkpoint inhibitors as first-line therapy, identified the m group as an independent and significant prognostic factor (hazard ratio, 0.50). Conclusions: Unresectable HCC with extrahepatic metastasis and no vascular invasion represents a novel staging category for systemic treatment.

DOI： 10.3390/cancers16223797

Type 2 Diabetes and Hypertension as Risk Factors for Advanced Fibrosis in Biopsy Proven Metabolic Dysfunction-Associated Steatotic Liver Disease

Inukai, Y; Ito, T; Yokoyama, S; Yamamoto, K; Imai, N; Ishizu, Y; Honda, T; Shimizu, T; Hattori, M; Takeyama, T; Ando, Y; Nishikawa, T; Morita, K; Toyoda, H; Ishigami, M; Kawashima, H

JOURNAL OF DIGESTIVE DISEASES Vol. 25 ( 11-12 ) page： 685 - 693 2024.11

Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Digestive Diseases

Objectives: To identify the diagnostic criteria for metabolic dysfunction–associated steatotic liver disease (MASLD) related to liver fibrosis and to characterize patients with cryptogenic steatotic liver disease (SLD) (non-MASLD) among those previously diagnosed with nonalcoholic fatty liver disease (NAFLD). Methods: This multicenter retrospective study included 511 patients diagnosed with NAFLD via liver biopsy, and the prevalence of MASLD was assessed based on the diagnostic criteria. Patients were divided into those who met the MASLD criteria and those who did not, and the characteristics of advanced fibrosis and associated cardiometabolic factors were evaluated. Results: Of the 475 patients with NAFLD, 458 (96.4%) met the criteria for MASLD, showing a high overlap between classical NAFLD and MASLD populations. Severe fibrosis was observed, regardless of the number of cardiometabolic factors. Hypertension and diabetes mellitus significantly contributed to advanced fibrosis (≥ F3), with odds ratio of 1.92 and 2.00 (95% confidence interval of 1.17–3.16 and 1.22–3.28, respectively; both p < 0.01) on multivariate analysis. The other seventeen (3.6%) patients did not meet the diagnostic criteria for MASLD. Among them, seven had significant fibrosis and a high fibrosis-4 index. Conclusions: Diabetes mellitus and hypertension are key metabolic factors associated with advanced fibrosis. Some cases, classified as cryptogenic SLD, also exhibit significant fibrosis. Consequently, identifying high-risk patients, including those undergoing noninvasive tests for fibrosis, is crucial.

DOI： 10.1111/1751-2980.13325

EFFECT OF AGE AND DEVELOPMENT OF LIVER AND OTHER ORGAN CANCERS ON HBS ANTIGEN LOSS IN HEPATITIS B PATIENTS

Activity and phosphatidylcholine transfer protein interactions of skeletal muscle thioesterase Them2 enable hepatic steatosis and insulin resistance.

Xie Y, Liu X, Liu W, Carr LR, Lee LP, Imai N, Ortlund EA, Cohen DE

The Journal of biological chemistry page： 107855 2024.10

Honda, T; Mizuno, K; Yokoyama, S; Yamamoto, K; Ito, T; Imai, N; Ishizu, Y; Murakami, Y; Ishikawa, T; Kawashima, H

HEPATOLOGY Vol. 80 page： S253 - S254 2024.10

RISK FACTORS ASSOCIATED WITH DECREASED BONE MINERAL DENSITY IN PATIENTS WITH METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE: A CROSS-SECTIONAL STUDY AT A HEALTH EXAMINATION CENTER

Yokoyama, S; Honda, T; Yamamoto, K; Ito, T; Imai, N; Ishizu, Y; Mizuno, K; Kojima, T; Kariya, N; Kawashima, H

HEPATOLOGY Vol. 80 page： S552 - S553 2024.10

PATHOLOGICAL SIGNIFICANCE OF INTRANUCLEAR LIPID DROPLETS AND GLYCOGENATED NUCLEI IN LIVER BIOPSY

Imai, N; Ohsaki, Y; Cheng, J; Yokoyama, S; Yamamoto, K; Ito, T; Ishizu, Y; Honda, T; Wake, H; Kawashima, H; Zhang, J

HEPATOLOGY Vol. 80 page： S615 - S615 2024.10

INTESTINE- SPECIFIC FAF2 DEPLETION AMELIORATES METABOLIC DYSFUNCTIONASSOCIATED STEATOTIC LIVER DISEASE BY IMPAIRING LIPID ABSORPTION

Zhang, JJ; Imai, N; Yokoyama, S; Yamamoto, K; Ito, T; Ishizu, Y; Honda, T; Sugiyama, A; Cohen, D; Kawashima, H

HEPATOLOGY Vol. 80 page： S45 - S46 2024.10

FEVER AFTER THE ADMINISTRATION OF ATEZOLIZUMAB AND BEVACIZUMAB PREDICTS LIVER INJURY IN PATIENTS WITH UNRESECTABLE HEPATOCELLULAR CARCINOMA: A PROSPECTIVE OBSERVATIONAL ANALYSIS USING A MULTIPLEX BEAD-BASED IMMUNOASSAY

Ito, T; Yamamoto, T; Nishida, K; Kobayashi, Y; Mizuno, K; Yokoyama, S; Imai, N; Ishizu, Y; Honda, T; Ishigami, M; Koya, T; Nakashima, S; Naito, T; Yasuda, S; Kuzuya, T; Toyoda, H; Ando, Y; Yoshio, S; Kawashima, H

HEPATOLOGY Vol. 80 2024.10

Impact of BMI and Body Composition on First-line Systemic Treatment for Unresectable Hepatocellular Carcinoma

Yamamoto, T; Ito, T; Mizuno, K; Yokoyama, S; Yamamoto, K; Imai, N; Ishizu, Y; Honda, T; Kawashima, H

ANTICANCER RESEARCH Vol. 44 ( 9 ) page： 4101 - 4111 2024.9

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

Background/Aim: The effects of body mass index (BMI) and body composition on the outcomes of systemic treatment for unresectable hepatocellular carcinoma (uHCC) remain unclear. Patients and Methods: In this retrospective study, patients with uHCC treated with lenvatinib (LEN) or atezolizumab+bevacizumab, were classified into high- (≥25 kg/m2) and low- (<25 kg/m2) BMI groups and evaluated for prognosis. Prognostic impact of body composition was also evaluated. Results: Patients with a high BMI had lower skeletal mass index (SMI), subcutaneous adipose tissue index (SATI), and visceral adipose tissue index (VATI) compared to those in the low-BMI cohort. The baseline Child-Pugh scores and Barcelona Clinic Liver Cancer stages were comparable between the two cohorts. The overall survival (OS) was better in the high BMI group compared to the low BMI group (median, 913 vs. 484 days; p=0.008). SMI had a strong influence on OS. Additionally, low BMI, VATI, SATI, and visceral-to-subcutaneous fat ratio (VSR) in the LEN treatment group were associated with shorter progression-free survival (PFS). Conclusion: Following systemic treatment for uHCC, patients with low BMI have a poor prognosis. Among anthropometric factors, low SMI is associated with poor OS. In the LEN treatment group, low VATI may impact PFS negatively.

DOI： 10.21873/anticanres.17239

Reply - Letter to the editor

Yokoyama, S; Honda, T; Ishizu, Y; Imai, N; Ito, T; Yamamoto, K; Mizuno, K; Kojima, T; Kariya, N; Nakamura, M; Kawashima, H

CLINICAL NUTRITION Vol. 43 ( 8 ) page： 1855 - 1856 2024.8

Predicting early rebleeding and mortality after endoscopic hemostasis of esophagogastric varices: Diagnostic performance of aspartate aminotransferase-to-platelet ratio index and model for end-stage liver disease-Na score

Yokoyama, S; Honda, T; Ishizu, Y; Imai, N; Ito, T; Yamamoto, K; Mizuno, K; Nakamura, M; Kawashima, H

JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2024.7

Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Hepato-Biliary-Pancreatic Sciences

Background: Endoscopic variceal ligation and sclerotherapy are recommended for esophagogastric variceal bleeding (EGVB) in cirrhosis but can be complicated by early rebleeding and death. This study aimed to identify noninvasive markers accurately predicting early rebleeding and mortality after endoscopic hemostasis for EGVB. Methods: Among 116 patients with endoscopically confirmed EGVB and endoscopic hemostasis, various noninvasive markers were calculated, and their predictive accuracy was compared by receiver-operating characteristic curve analysis. Endpoints included 5-day rebleeding, 5-day mortality, 6-week rebleeding, and 6-week mortality. Results: The median age was 63 years. Child-Pugh class B and C patients accounted for 40.5% and 34.5%, respectively. Only the aspartate aminotransferase-to-platelet ratio index (APRI) significantly predicted 5-day rebleeding, with an area under the curve (AUC) of 0.777 (95% confidence interval [CI]: 0.537–1). The model for end-stage liver disease-Na (MELD-Na) score showed good predictive accuracy for 5-day mortality (AUC: 0.839, 95% CI: 0.681–0.997), 6-week rebleeding (AUC: 0.797, 95% CI: 0.663–0.932), and 6-week mortality (AUC: 0.888, 95% CI: 0.797–0.979). Conclusions: Patients with cirrhosis with a high APRI and MELD-Na score were at high risk of early rebleeding and death after EGVB. Allocating appropriate monitoring and care for those patients is necessary.

DOI： 10.1002/jhbp.12057

A 70-year-old Woman with Asymptomatic Ferroportin Disease

Ishikawa Tetsuya, Tatsumi Yasuaki, Kato Koichi, Hayashi Yumi, Imai Norihiro, Ito Takanori, Ishizu Youji, Ishigami Masatoshi, Nihei Wataru, Kato Ayako, Hayashi Hisao

Internal Medicine Vol. advpub ( 0 ) 2024.2

Language：English Publishing type：Research paper (scientific journal) Publisher：The Japanese Society of Internal Medicine

A 59-year-old Japanese woman presented with hyperferritinemia. We decided against iron removal treatment because there were no symptoms or signs of iron-induced organ damage. A follow-up study revealed a gradual increase in transferrin saturation. The patient underwent a second examination at 66 years old. A liver biopsy showed substantial iron deposits in hepatocytes and Kupffer cells but no inflammation or fibrosis. Serum hepcidin-25 levels were highly parallel with hyperferritinemia. A genetic analysis revealed a G80S mutation in SLC40A1. These features are compatible with those of ferroportin disease. The patient remained asymptomatic at 70 years old, suggesting that the iron-loading condition may have been benign.

DOI： 10.2169/internalmedicine.2392-23

Impact of elobixibat on liver tumors, microbiome, and bile acid levels in a mouse model of nonalcoholic steatohepatitis

CiNii Research

Sugiyama, Y; Yamamoto, K; Honda, T; Kato, A; Muto, H; Yokoyama, S; Ito, T; Imai, N; Ishizu, Y; Nakamura, M; Asano, T; Enomoto, A; Zaitsu, K; Ishigami, M; Fujishiro, M; Kawashima, H

HEPATOLOGY INTERNATIONAL Vol. 17 ( 6 ) page： 1378 - 1392 2023.12

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

Background: Elevated bile acid levels have been associated with liver tumors in fatty liver. Ileal bile acid transporter inhibitors may inhibit bile acid absorption in the distal ileum and increase bile acid levels in the colon, potentially decreasing the serum and hepatic bile acid levels. This study aimed to investigate the impact of these factors on liver tumor. Methods: C57BL/6J mice received a one-time intraperitoneal injection of 25-mg/kg diethylnitrosamine. They were fed a choline-deficient high-fat diet for 20 weeks starting from 8 weeks of age, with or without elobixibat (EA Pharma, Tokyo, Japan). Results: Both groups showed liver fat accumulation and fibrosis, with no significant differences between the two groups. However, mice with elobixibat showed fewer liver tumors. The total serum bile acid levels, including free, tauro-conjugated, glyco-conjugated, and tauro-α/β-muricholic acids in the liver, were noticeably reduced following elobixibat treatment. The proportion of gram-positive bacteria in feces was significantly lower in the group treated with elobixibat (5.4%) than in the group without elobixibat (33.7%). Conclusion: Elobixibat suppressed tumor growth by inhibiting bile acid reabsorption, and decreasing total bile acid and primary bile acid levels in the serum and liver. Additionally, the presence of bile acids in the colon may have led to a significant reduction in the proportion of gram-positive bacteria, potentially resulting in decreased secondary bile acid synthesis.

DOI： 10.1007/s12072-023-10581-2

A new criterion including the aspartate aminotransferase-to-platelet ratio index and liver and spleen stiffness to rule out varices needing treatment in children with biliary atresia: Modification of the Baveno VII criteria

Yokoyama, S; Ishizu, Y; Honda, T; Imai, N; Ito, T; Yamamoto, K; Muto, H; Shirota, C; Tainaka, T; Sumida, W; Makita, S; Takada, S; Nakagawa, Y; Maeda, T; Nakamura, M; Ishigami, M; Uchida, H; Kawashima, H

HEPATOLOGY RESEARCH 2023.10

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

Aims: Biliary atresia (BA) is a congestive biliary disease that develops in the neonatal period or early infancy. It may present with portal hypertension and varices needing treatment (VNT) even after successful Kasai portoenterostomy. This study aimed to stratify the risk of VNT in children and adolescents with BA. Methods: In this prospective cross-sectional study, we measured liver stiffness (LS) and spleen stiffness (SS) by two-dimensional shear wave elastography and checked for VNT endoscopically in 53 patients with BA who attended for follow-up between July 2018 and September 2022. Varices needing treatment were defined as large esophageal varices, esophageal varices of any size with red color signs, and/or gastric varices along the cardia. Results: Twenty-five patients (aged 0–18 years) had VNT. Eighteen patients met the Baveno VI criteria (LS <20 kPa; platelet count >150 000/L) and were deemed to be at low risk of VNT (spared endoscopies) while three had missed VNT (16.7%). Applying the Baveno VII criteria, which combines the SS cut-off value of 40 kPa with the Baveno VI criteria, resulted in five missed VNTs among 22 spared endoscopies (22.7%). A modification of the Baveno VII criteria using the aspartate aminotransferase-to-platelet ratio index (APRI) instead of the platelet count with cut-off values of 25 kPa, 30 kPa, and 1.04 for LS, SS, and APRI, respectively, missed only one VNT (5.0%) among 20 spared endoscopies. Conclusions: A novel diagnostic criterion that combines LS, SS, and APRI reduced the risk of missing VNT to 5% in children and adolescents with BA.

DOI： 10.1111/hepr.13976