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Hochnadel I, Hoenicke L, Petriv N, Suo H, Groebe L, Olijnik C, Bondarenko N, Alfonso JC, Jarek M, Shi R, Jeron A, Timrott K, Hirsch T, Jedicke N, Bruder D, Klawonn F, Lichtinghagen R, Geffers R, Lenzen H, Manns MP, Yevsa T. In vivo RNAi screen and validation reveals Ngp, Hba-a1, and S100a8 as novel inhibitory targets on T lymphocytes in liver cancer. Front Immunol 2025; 16:1549229. [PMID: 40352930 PMCID: PMC12061932 DOI: 10.3389/fimmu.2025.1549229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 03/21/2025] [Indexed: 05/14/2025] Open
Abstract
Background Hepatocellular carcinoma (HCC) represents the third deadliest cancer worldwide with limited treatment options. Immune checkpoint inhibitors (ICIs) have revolutionized HCC therapy, but immune suppression within the tumor microenvironment remains a major challenge. Therefore, in this study, we aimed to define novel ICI molecules arising on T cells during aggressive HCC development. Methods Using autochthonous HCC models, we performed microarray analyses followed by in vivo RNA interference screen and identified several new ICI molecules on CD4 and CD8 T lymphocytes in HCC-bearing mice. Short hairpin RNA (shRNA)-mediated knockdown of the ICI molecules was performed to validate their functional role in T cell activity and survival of HCC-bearing mice. Finally, we searched for the presence of the defined ICI molecules in HCC patients. Results We identified neutrophilic granule protein (Ngp), hemoglobin subunit alpha-1 (Hba-a1), and S100 calcium-binding protein a8 (S100a8) as novel inhibitory molecules of T cells in HCC. The specific shRNA-based knockdown of these inhibitory targets was safe, led to a downregulation of classical ICI molecules (PD-1, PD-L1, 4-1BBL, CD160), and kept liver parameters under control in murine HCC. Besides, we detected upregulation of S100A8 and S100A9 in blood and liver tissues in HCC patients, supporting their clinical relevance. Conclusion The obtained results pave the way for the use of the newly defined ICI molecules Ngp, Hba-a1, and S100a8 as novel immunotherapeutic targets in further preclinical and clinical studies in HCC patients.
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Affiliation(s)
- Inga Hochnadel
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School (MHH), Hannover, Germany
| | - Lisa Hoenicke
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School (MHH), Hannover, Germany
| | - Nataliia Petriv
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School (MHH), Hannover, Germany
| | - Huizhen Suo
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School (MHH), Hannover, Germany
| | - Lothar Groebe
- Experimental Immunology, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany
| | - Chantal Olijnik
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School (MHH), Hannover, Germany
| | - Nina Bondarenko
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School (MHH), Hannover, Germany
- Department of Pathological Anatomy, Forensic Medicine and Pathological Physiology, Dnipro State Medical University, Dnipro, Ukraine
| | - Juan C. Alfonso
- Department of Systems Immunology, Technical University Braunschweig and HZI, Braunschweig, Germany
| | | | - Ruibing Shi
- Biostatistics Research Group, HZI, Braunschweig, Germany
| | - Andreas Jeron
- Immune Regulation Group, HZI, Braunschweig, Germany
- Infection Immunology Group, Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Kai Timrott
- Department of General, Visceral and Transplant Surgery, MHH, Hannover, Germany
| | | | - Nils Jedicke
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School (MHH), Hannover, Germany
| | - Dunja Bruder
- Immune Regulation Group, HZI, Braunschweig, Germany
- Infection Immunology Group, Institute of Medical Microbiology and Hospital Hygiene, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Frank Klawonn
- Biostatistics Research Group, HZI, Braunschweig, Germany
- Munich Biomarker Research Center, Institute of Laboratory Medicine, German Heart Center, Technical University of Munich, Munich, Germany
- Department of Computer Science, Ostfalia University, Wolfenbüttel, Germany
| | | | | | - Henrike Lenzen
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School (MHH), Hannover, Germany
- Department of Gastroenterology, Hepatology, Interventional Endoscopy and Diabetology, Academic Teaching Hospital Braunschweig, Braunschweig, Germany
| | - Michael P. Manns
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School (MHH), Hannover, Germany
| | - Tetyana Yevsa
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School (MHH), Hannover, Germany
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Chen QF, Jiang XY, Chen MS, Lyu N, Zhao M. A Metrology Informatics Investigation of Conversion Therapy in Hepatocellular Carcinoma: 2014-2023. ANNALS OF SURGERY OPEN 2025; 6:e562. [PMID: 40134489 PMCID: PMC11932632 DOI: 10.1097/as9.0000000000000562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 02/07/2025] [Indexed: 03/27/2025] Open
Abstract
Background With advancements in drug therapy, local treatments, and evolving concepts, conversion therapy has shown benefits for patients initially diagnosed with unresectable hepatocellular carcinoma (HCC). Over the past 10 years, the conversion therapy field has accumulated a vast amount of underutilized data, necessitating in-depth bibliometric evaluation. Methods This cross-sectional retrospective study collected a substantial amount of research on conversion therapy published between 2014 and 2023, adhering to strict search criteria. The primary outcomes were publication volume, citation count, and interstudy relationships. Comprehensive analysis was conducted using unsupervised hierarchical clustering, spatiotemporal analysis, regression model, and the Walktrap algorithm. Results Over the past decade, conversion therapy has demonstrated significant progress, with an annual growth rate of 23.0%. Post-2020, these metrics saw a marked increase, reaching 116 publications and 1943 citations by 2023. Cluster analysis grouped 244 authors into 17 clusters, highlighting early and sustained contributions from Western authors compared with later-emerging Eastern authors. Research characteristics in HCC conversion therapy were classified into 5 clusters, with Cluster 2 (Target Therapy and Immunotherapy) emerging as a new focus. Thematic analysis categorized research characteristics into 4 quadrants, identifying "immune checkpoint inhibitor" and "combination therapy" as highly relevant and rapidly developing themes, while "hepatic arterial infusion chemotherapy" and "radioembolization" show high potential for future research. Conclusions This study highlights key contributors and emerging trends and provides important predictions for future research directions. To achieve effective conversion therapy for HCC, researchers may prioritize immunotherapy and locoregional treatments such as hepatic arterial infusion chemotherapy or radioembolization.
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Affiliation(s)
- Qi-Feng Chen
- From the Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiong-Ying Jiang
- From the Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Min-Shan Chen
- Department of Liver Surgery, Liver Cancer Study and Service Group, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ning Lyu
- From the Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ming Zhao
- From the Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
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Zhang YZ, Ma Y, Ma E, Chen X, Zhang Y, Yin B, Zhao J. Sophisticated roles of tumor microenvironment in resistance to immune checkpoint blockade therapy in hepatocellular carcinoma. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2025; 8:10. [PMID: 40051497 PMCID: PMC11883234 DOI: 10.20517/cdr.2024.165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 01/13/2025] [Accepted: 02/21/2025] [Indexed: 03/09/2025]
Abstract
Hepatocellular carcinoma (HCC) remains a serious threat to global health, with rising incidence and mortality rates. Therapeutic options for advanced HCC are quite limited, and the overall prognosis remains poor. Recent advancements in immunotherapy, particularly immune-checkpoint blockade (ICB) targeting anti-PD1/PD-L1 and anti-CTLA4, have facilitated a paradigm shift in cancer treatment, demonstrating substantial survival benefits across various cancer types, including HCC. However, only a subset of HCC patients exhibit a favorable response to ICB therapy, and its efficacy is often hindered by the development of resistance. There are many studies to explore the underlying mechanisms of ICB response. In this review, we compiled the latest progression in immunotherapies for HCC and systematically summarized the sophisticated mechanisms by which components of the tumor microenvironment (TME) regulate resistance to ICB therapy. Additionally, we also outlined some scientific rationale strategies to boost antitumor immunity and enhance the efficacy of ICB in HCC. These insights may serve as a roadmap for future research and help improve outcomes for HCC patients.
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Affiliation(s)
- Yi-Zhe Zhang
- Hepatobiliary Surgery Center, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
- Authors contributed equally
| | - Yunshu Ma
- Hepatobiliary Surgery Center, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
- Authors contributed equally
| | - Ensi Ma
- Liver Transplantation Center, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
- Institute of Organ Transplantation, Fudan University, Shanghai 200040, China
| | - Xizhi Chen
- Hepatobiliary Surgery Center, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Yue Zhang
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang, China
| | - Baobing Yin
- Hepatobiliary Surgery Center, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
- Department of Hepatobiliary surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, Fujian, China
| | - Jing Zhao
- Hepatobiliary Surgery Center, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
- Department of Hepatobiliary surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, Fujian, China
- Cancer Metastasis Institute, Fudan University, Shanghai 201206, China
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Esmail A, Xu J, Burns EA, Abboud K, Sheikh A, Umoru G, Gee K, Wiechmann C, Zhang Y, Abdelrahim M. The Impact of Infections in Patients Treated with Atezolizumab Plus Bevacizumab for Unresectable Hepatocellular Carcinoma. J Clin Med 2024; 13:4994. [PMID: 39274206 PMCID: PMC11396642 DOI: 10.3390/jcm13174994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 08/02/2024] [Accepted: 08/19/2024] [Indexed: 09/16/2024] Open
Abstract
Background: The therapeutic landscape of unresectable hepatocellular carcinoma (uHCC) continues to evolve. Atezolizumab, an anti-programmed cell death ligand 1 (PD-1) immune checkpoint inhibitor (ICI), in combination with bevacizumab, has substantially improved outcomes. This study aims to evaluate the incidence, risk factors, and outcomes in patients who develop infections while receiving atezolizumab and bevacizumab for uHCC. Methods: Patients who received atezolizumab and bevacizumab for uHCC at a single hospital network were included. Types and rates of infections were reported. Covariates compared among infected and non-infected cohorts included age, sex, race, comorbidities, Eastern Cooperative Oncology Group (ECOG) performance status, immunosuppressive use, chronic infections, number of cycles of ICIs given, antibiotic or antiviral therapies at ICI initiation, and line of therapy (first-line, second-line, greater than second-line). Results: Out of 810 evaluable patients, 34 uHCC patients were treated with atezolizumab plus bevacizumab. The mean ± SD age was 66.29 ± 9.39; 28 (82.35%) were males. There were 17 (50%) patients with reported infection, with bacterial infection occurring in 12 (70.59%) patients and COVID-19 in 4 (23.5%). Of the infected patients, eight (47.06%) had one infection, five (29.41%) had two infections, and two (11.76%) had three or more infections. Infected and non-infected patients received a median of 12 (IQR: 5-17) and 4 (IQR: 3-12) ICI cycles (p = 0.18), respectively. Infections did not negatively impact OS or PFS but resulted in treatment delays and discontinuation in 11 (64.71%) and 7 (41.18%) patients, respectively. At the last follow-up, 19 (55.88%) patients died, 9 (52.94%) in the non-infected group vs. 10 (58.82%) in the infected group (p = 1.0). Conclusions: While a broad array of infections occurred in 50% of the patients in this cohort, it did not negatively impact survival outcomes. However, it did impact morbidity, with more all-cause admissions and treatment delays.
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Affiliation(s)
- Abdullah Esmail
- Houston Methodist Neal Cancer Center, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Jiaqiong Xu
- Houston Methodist Neal Cancer Center, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Ethan A Burns
- Houston Methodist Neal Cancer Center, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Karen Abboud
- Houston Methodist Neal Cancer Center, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Ali Sheikh
- Department of Medicine, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Godsfavour Umoru
- Houston Methodist Neal Cancer Center, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Kelly Gee
- Department of Medicine, Houston Methodist Hospital, Houston, TX 77030, USA
| | | | - Yuqi Zhang
- Houston Methodist Neal Cancer Center, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Maen Abdelrahim
- Houston Methodist Neal Cancer Center, Houston Methodist Hospital, Houston, TX 77030, USA
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Chen QF, Chen S, Chen M, Lyu N, Zhao M. Improving the Conversion Success Rate of Hepatocellular Carcinoma: Focus on the Use of Combination Therapy with a High Objective Response Rate. J Clin Transl Hepatol 2024; 12:298-304. [PMID: 38426191 PMCID: PMC10899866 DOI: 10.14218/jcth.2023.00403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 12/03/2023] [Accepted: 12/25/2023] [Indexed: 03/02/2024] Open
Abstract
The high mortality rate in hepatocellular carcinoma (HCC) is partially due to the fact that a significant number of patients are diagnosed at an intermediate or advanced stage, with surgical treatment options unavailable. Conversion therapy, which involves both locoregional and systemic treatments, has the potential to downstage tumors in selected patients with initially unresectable HCC, thereby making surgical treatment a possibility and potentially increasing long-term survival. To optimize the conversion rate, it is necessary to maximize successful conversions and clearly define the target population for conversion treatment through a collaborative effort. In this review article, we summarize the clinical experience and evidence for conversion therapy in patients with 'potentially resectable' HCC from four perspectives: 1) defining the target population for conversion therapy, 2) selecting the appropriate conversion strategy, placing emphasis on the utilization of combination therapy that exhibits a significant objective response rate, 3) determining the timing and urgency of surgical resection, 4) promoting the adoption of a multidisciplinary team model. The authors are optimistic that with the continuous progress in treatment and a deeper understanding of HCC, the success rate of HCC conversion therapy will increase, and the overall survival of HCC patients will be prolonged.
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Affiliation(s)
- Qi-Feng Chen
- Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, China
| | - Song Chen
- Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, China
| | - Minshan Chen
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Ning Lyu
- Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, China
| | - Ming Zhao
- Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, China
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Cui JW, Li Y, Yang Y, Yang HK, Dong JM, Xiao ZH, He X, Guo JH, Wang RQ, Dai B, Zhou ZL. Tumor immunotherapy resistance: Revealing the mechanism of PD-1 / PD-L1-mediated tumor immune escape. Biomed Pharmacother 2024; 171:116203. [PMID: 38280330 DOI: 10.1016/j.biopha.2024.116203] [Citation(s) in RCA: 43] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 01/15/2024] [Accepted: 01/22/2024] [Indexed: 01/29/2024] Open
Abstract
Tumor immunotherapy, an innovative anti-cancer therapy, has showcased encouraging outcomes across diverse tumor types. Among these, the PD-1/PD-L1 signaling pathway is a well-known immunological checkpoint, which is significant in the regulation of immune evasion by tumors. Nevertheless, a considerable number of patients develop resistance to anti-PD-1/PD-L1 immunotherapy, rendering it ineffective in the long run. This research focuses on exploring the factors of PD-1/PD-L1-mediated resistance in tumor immunotherapy. Initially, the PD-1/PD-L1 pathway is characterized by its role in facilitating tumor immune evasion, emphasizing its role in autoimmune homeostasis. Next, the primary mechanisms of resistance to PD-1/PD-L1-based immunotherapy are analyzed, including tumor antigen deletion, T cell dysfunction, increased immunosuppressive cells, and alterations in the expression of PD-L1 within tumor cells. The possible ramifications of altered metabolism, microbiota, and DNA methylation on resistance is also described. Finally, possible resolution strategies for dealing with anti-PD-1/PD-L1 immunotherapy resistance are discussed, placing particular emphasis on personalized therapeutic approaches and the exploration of more potent immunotherapy regimens.
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Affiliation(s)
- Jia-Wen Cui
- Department of Pharmacy, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China; College of Pharmacy, Jinan University, Guangzhou, China
| | - Yao Li
- College of Pharmacy, Macau University of Science and Technology (MUST), China
| | - Yang Yang
- Department of Pharmacy, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China; College of Pharmacy, Faculty of Medicine, Macau University of Science and Technology, Macau SAR, China
| | - Hai-Kui Yang
- Department of Pharmacy, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
| | - Jia-Mei Dong
- Department of Pharmacy, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
| | - Zhi-Hua Xiao
- Department of Pharmacy, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China; College of Pharmacy, Jinan University, Guangzhou, China
| | - Xin He
- Department of Pharmacy, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
| | - Jia-Hao Guo
- Department of Pharmacy, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China; College of Pharmacy, Jinan University, Guangzhou, China
| | - Rui-Qi Wang
- Department of Pharmacy, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China.
| | - Bo Dai
- Department of Cardiology, The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan City 528200, Guangdong Province, China.
| | - Zhi-Ling Zhou
- Department of Pharmacy, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China.
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Li J, Zhou K, Wu M, Zhang R, Jin X, Qiao H, Li J, Cao X, Zhang S, Dong G. The Characteristics of Transcription Factors Regulating T Cell Exhaustion Were Analyzed to Predict the Prognosis and Therapeutic Effect in Patients with HCC. Int J Gen Med 2023; 16:5597-5619. [PMID: 38045905 PMCID: PMC10693252 DOI: 10.2147/ijgm.s435620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Accepted: 11/08/2023] [Indexed: 12/05/2023] Open
Abstract
Purpose Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer-related deaths, posing a significant threat to people in diverse regions. T-cell exhaustion (Tex) can hinder the efficacy of immunotherapy in patients with HCC, and the transcription factors that regulate Tex in HCC have not yet been fully elucidated. Patients and Methods We used the single sample gene set enrichment analysis (ssGSEA) method to define the transcription factor pathway that regulates Tex and employed LASSO regression analysis to establish Tex related genes (TEXRS). To predict differences in immunotherapy efficacy between the two groups, we used the immunophenotype score and submap algorithm. RT-qPCR was used to detect the expression levels of the model genes in 21 pairs of HCC tissues. Finally, we assessed the cell communication strength and identified ligand receptors using the "CellChat" R package. Results Nine Tex transcription factors were identified as regulators of the HCC immune microenvironment, with Tex scores affecting patient survival. Patients with a high Tex Risk Score (TEXRS) had significantly worse overall survival compared to patients with low TEXRS. After adjusting for confounding factors, TEXRS remained an independent prognostic factor. Importantly, TEXRS performed well in multiple independent external validation cohorts. Various algorithms have shown that patients in the low-TEXRS group might benefit more from immunotherapy. Finally, RT-qPCR analysis of 21 HCC samples showed that C7, CD5L, and SDS were significantly downregulated in HCC tissues, consistent with the bioinformatics analysis results. Conclusion TEXRS proved to be a valuable predictor of immunotherapy and transcatheter arterial chemoembolization efficacy in patients with HCC. This holds promise for enhancing the prognosis and treatment outcomes of patients with HCC.
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Affiliation(s)
- Jingbo Li
- Department of Anesthesiology Research Institute, The Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Kun Zhou
- Department of Clinical Laboratory, Beidahuang Industry Group General Hospital, Harbin, People’s Republic of China
- Scientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Meng Wu
- Scientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Rongzheng Zhang
- Scientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Xi Jin
- Scientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Han Qiao
- Scientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Jiaqi Li
- Scientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Xinyang Cao
- Scientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Shuyun Zhang
- Scientific Research Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Guanglu Dong
- Department of Tumor Radiotherapy, The Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
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Chiu Y, Ni C, Huang Y. Deconvolution of bulk gene expression profiles reveals the association between immune cell polarization and the prognosis of hepatocellular carcinoma patients. Cancer Med 2023; 12:15736-15760. [PMID: 37366298 PMCID: PMC10417088 DOI: 10.1002/cam4.6197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/02/2023] [Accepted: 05/23/2023] [Indexed: 06/28/2023] Open
Abstract
BACKGROUND Many studies have utilized computational methods, including cell composition deconvolution (CCD), to correlate immune cell polarizations with the survival of cancer patients, including those with hepatocellular carcinoma (HCC). However, currently available cell deconvolution estimated (CDE) tools do not cover the wide range of immune cell changes that are known to influence tumor progression. RESULTS A new CCD tool, HCCImm, was designed to estimate the abundance of tumor cells and 16 immune cell types in the bulk gene expression profiles of HCC samples. HCCImm was validated using real datasets derived from human peripheral blood mononuclear cells (PBMCs) and HCC tissue samples, demonstrating that HCCImm outperforms other CCD tools. We used HCCImm to analyze the bulk RNA-seq datasets of The Cancer Genome Atlas (TCGA)-liver hepatocellular carcinoma (LIHC) samples. We found that the proportions of memory CD8+ T cells and Tregs were negatively associated with patient overall survival (OS). Furthermore, the proportion of naïve CD8+ T cells was positively associated with patient OS. In addition, the TCGA-LIHC samples with a high tumor mutational burden had a significantly high abundance of nonmacrophage leukocytes. CONCLUSIONS HCCImm was equipped with a new set of reference gene expression profiles that allowed for a more robust analysis of HCC patient expression data. The source code is provided at https://github.com/holiday01/HCCImm.
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Affiliation(s)
- Yen‐Jung Chiu
- Institute of Biomedical InformaticsNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
- Department of Biomedical EngineeringMing Chuan UniversityTaoyuanTaiwan
| | - Chung‐En Ni
- Institute of Biomedical InformaticsNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
| | - Yen‐Hua Huang
- Institute of Biomedical InformaticsNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
- Center for Systems and Synthetic BiologyNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
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Li J, Huang L, Ge C, Zhu X, Qiu M, Chen C, Wei S, Yan Y. Simultaneous and Sequential Use of Molecular Targeted Agents Plus Immune Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma: A Real-World Practice in China. J Hepatocell Carcinoma 2023; 10:949-958. [PMID: 37361905 PMCID: PMC10290454 DOI: 10.2147/jhc.s415941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 06/07/2023] [Indexed: 06/28/2023] Open
Abstract
Purpose Molecular targeted agents (MTAs) plus immune checkpoint inhibitors (ICIs) treatment for advanced hepatocellular carcinoma (HCC) has shown an exciting prospect. This study aimed to report the efficacy of the Simultaneous and Sequential use of them in a real-world practice. Patients and Methods From April 2019 to December 2020, patients with advanced HCC in three Chinese medical centers receiving MTAs and ICIs as their initial systemic therapy were enrolled. Participants were classified into the Simultaneous group (treated with them simultaneously) and the Sequential group (treated with MTAs initially and added ICIs after tumor progression). Toxicity, tumor response, survival outcomes and prognostic factors were investigated. Results One hundred and ten consecutive patients participated in the study (64 in the Simultaneous group and 46 in the Sequential group). A total of 93 (84.5%) patients experienced treatment-related adverse events (AEs), of which 55 (85.9%) in the Simultaneous group and 38 (82.6%) in the Sequential group (P=0.19). Grade 3/4 AEs were observed in 9 (8.2%) patients. Patients in the Simultaneous group achieved a higher objective response rate than those in the Sequential group (25.0% vs 4.3%, p=0.04). The median overall survival (OS) of the entire cohort was 14.8 [95% confidence interval (CI): 4.6-25.5] months and the OS rates at 6 and 12 months were 80.6% and 60.9%, respectively. Patients in the Simultaneous group achieved better survival outcomes than those in the Sequential group, but without statistically significant differences. Child-Pugh 6 scores (HR: 2.97, 95% CI: 1.33-6.61, P=0.008), tumor number ≤3 (HR: 0.18, 95% CI: 0.04-0.78, P=0.022), extrahepatic metastasis (HR: 3.05, 95% CI: 1.35-6.87, P=0.007) were independent prognostic factors for survival. Conclusion The combined treatment of MTAs and ICIs shows good tumor response and survival outcomes with acceptable toxicity for advanced HCC in the real-world practice, in particular when they are applied simultaneously.
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Affiliation(s)
- Jing Li
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, People’s Republic of China
- Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China
| | - Liang Huang
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, People’s Republic of China
| | - Chao Ge
- Department of General Surgery, Ningbo Development Zone Hospital, Ningbo, People’s Republic of China
| | - Xingwu Zhu
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, People’s Republic of China
| | - Maixuan Qiu
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, People’s Republic of China
| | - Chaopan Chen
- Department of General Surgery, Ningbo Development Zone Hospital, Ningbo, People’s Republic of China
| | - Shaohua Wei
- Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China
| | - Yiqun Yan
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, People’s Republic of China
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Jost-Brinkmann F, Demir M, Wree A, Luedde T, Loosen SH, Müller T, Tacke F, Roderburg C, Mohr R. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma: Results from a German real-world cohort. Aliment Pharmacol Ther 2023; 57:1313-1325. [PMID: 36883351 DOI: 10.1111/apt.17441] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 12/18/2022] [Accepted: 02/18/2023] [Indexed: 03/09/2023]
Abstract
BACKGROUND AND AIMS Phase III trials have established atezolizumab plus bevacizumab as the novel standard of care for patients with unresectable hepatocellular carcinoma (HCC). However, these trials raised concerns regarding treatment efficacy in non-viral HCC, and it remains unclear whether combination immunotherapy is safe and effective in patients with advanced cirrhosis. METHODS One hundred patients with unresectable HCC initiated therapy with atezolizumab plus bevacizumab at our centre between January 2020 and March 2022. The control cohort consisted of 80 patients with advanced HCC who received either sorafenib (n = 43) or lenvatinib (n = 37) as systemic treatment. RESULTS Overall survival (OS) and progression-free survival (PFS) were significantly longer within the atezolizumab/bevacizumab group and comparable to phase III data. The benefits in terms of increased objective response rate (ORR), OS and PFS were consistent across subgroups, including non-viral HCC (58%). The ROC-optimised neutrophil-to-lymphocyte ratio (NLR) cut-off of 3.20 was the strongest independent predictor of ORR and PFS. In patients with advanced cirrhosis Child-Pugh B, liver function was significantly better preserved with immunotherapy. Patients with Child-Pugh B cirrhosis showed similar ORR but shorter OS and PFS compared to patients with preserved liver function. CONCLUSIONS Atezolizumab plus bevacizumab showed good efficacy and safety in patients with unresectable HCC and partially advanced liver cirrhosis in a real-world setting. Moreover, the NLR was able to predict response to atezolizumab/bevacizumab treatment and may guide patient selection.
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Affiliation(s)
- Fabian Jost-Brinkmann
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
| | - Münevver Demir
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
| | - Alexander Wree
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Sven H Loosen
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Tobias Müller
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
| | - Christoph Roderburg
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Raphael Mohr
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
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11
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Zhang C, Zhang C, Wang H. Immune-checkpoint inhibitor resistance in cancer treatment: Current progress and future directions. Cancer Lett 2023; 562:216182. [PMID: 37076040 DOI: 10.1016/j.canlet.2023.216182] [Citation(s) in RCA: 48] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 04/07/2023] [Accepted: 04/11/2023] [Indexed: 04/21/2023]
Abstract
Cancer treatment has been advanced with the advent of immune checkpoint inhibitors (ICIs) exemplified by anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), anti-programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) drugs. Patients have reaped substantial benefit from ICIs in many cancer types. However, few patients benefit from ICIs whereas the vast majority undergoing these treatments do not obtain survival benefit. Even for patients with initial responses, they may encounter drug resistance in their subsequent treatments, which limits the efficacy of ICIs. Therefore, a deepening understanding of drug resistance is critically important for the explorations of approaches to reverse drug resistance and to boost ICI efficacy. In the present review, different mechanisms of ICI resistance have been summarized according to the tumor intrinsic, tumor microenvironment (TME) and host classifications. We further elaborated corresponding strategies to battle against such resistance accordingly, which include targeting defects in antigen presentation, dysregulated interferon-γ (IFN-γ) signaling, neoantigen depletion, upregulation of other T cell checkpoints as well as immunosuppression and exclusion mediated by TME. Moreover, regarding the host, several additional approaches that interfere with diet and gut microbiome have also been described in reversing ICI resistance. Additionally, we provide an overall glimpse into the ongoing clinical trials that utilize these mechanisms to overcome ICI resistance. Finally, we summarize the challenges and opportunities that needs to be addressed in the investigation of ICI resistance mechanisms, with the aim to benefit more patients with cancer.
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Affiliation(s)
- Chenyue Zhang
- Department of Integrated Therapy, Fudan University Shanghai Cancer Center, Shanghai Medical College, Shanghai, China
| | - Chenxing Zhang
- Department of Nephrology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haiyong Wang
- Department of Internal Medicine-Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
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12
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Serum CXCL5 Detects Early Hepatocellular Carcinoma and Indicates Tumor Progression. Int J Mol Sci 2023; 24:ijms24065295. [PMID: 36982370 PMCID: PMC10049661 DOI: 10.3390/ijms24065295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 03/05/2023] [Accepted: 03/08/2023] [Indexed: 03/12/2023] Open
Abstract
Chemokines or chemotactic cytokines play a pivotal role in the immune pathogenesis of liver cirrhosis and hepatocellular carcinoma (HCC). Nevertheless, comprehensive cytokine profiling data across different etiologies of liver diseases are lacking. Chemokines might serve as diagnostic and prognostic biomarkers. In our study, we analyzed serum concentrations of 12 inflammation-related chemokines in a cohort of patients (n = 222) with cirrhosis of different etiologies and/or HCC. We compared 97 patients with cirrhosis and treatment-naïve HCC to the chemokine profile of 125 patients with cirrhosis but confirmed absence of HCC. Nine out of twelve chemokines were significantly elevated in sera of cirrhotic patients with HCC compared to HCC-free cirrhosis controls (CCL2, CCL11, CCL17, CCL20, CXCL1, CXCL5, CXCL9, CXCL10, CXCL11). Among those, CXCL5, CXCL9, CXCL10, and CXCL11 were significantly elevated in patients with early HCC according to the Barcelona Clinic Liver Cancer (BCLC) stages 0/A compared to cirrhotic controls without HCC. In patients with HCC, CXCL5 serum levels were associated with tumor progression, and levels of CCL20 and CXCL8 with macrovascular invasion. Importantly, our study identified CXCL5, CXCL9, and CXCL10 as universal HCC markers, independent from underlying etiology of cirrhosis. In conclusion, regardless of the underlying liver disease, patients with cirrhosis share an HCC-specific chemokine profile. CXCL5 may serve as a diagnostic biomarker in cirrhotic patients for early HCC detection as well as for tumor progression.
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13
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Jiang C, Sun XD, Qiu W, Chen YG, Sun DW, Lv GY. Conversion therapy in liver transplantation for hepatocellular carcinoma: What's new in the era of molecular and immune therapy? Hepatobiliary Pancreat Dis Int 2023; 22:7-13. [PMID: 36825482 DOI: 10.1016/j.hbpd.2022.10.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Accepted: 10/18/2022] [Indexed: 11/04/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the sixth most common cancer globally, with limited therapies and unsatisfactory prognosis once in the advanced stages. With promising advances in locoregional and systematic treatments, fast development of targeted drugs, the success of immunotherapy, as well as the emergence of the therapeutic alliance, conversion therapy has recently become more well developed and an effective therapeutic strategy. This article aimed to review recent developments in conversion therapy in liver transplantation (LT) for HCC. DATA SOURCES We searched for relevant publications on PubMed before September 2022, using the terms "HCC", "liver transplantation", "downstaging", "bridging treatment" and "conversion therapy." RESULTS Conversion therapy was frequently represented as a combination of multiple treatment modalities to downstage HCC and make patients eligible for LT. Although combining various local and systematic treatments in conversion therapy is still controversial, growing evidence has suggested that multimodal combined treatment strategies downstage HCC in a shorter time, which ultimately increases the opportunities for LT. Moreover, the recent breakthrough of immunotherapy and targeted therapy for HCC also benefit patients with advanced-stage tumors. CONCLUSIONS In the era of targeted therapy and immunotherapy, applying the thinking of transplant oncology to benefit HCC patients receiving LT is a new topic that has shed light on advanced-stage patients. With the expansion of conversion therapy concepts, further investigation and research is required to realize the full potential of conversion treatment strategies, including accurately selecting candidates, determining the timing of surgery, improving the conversion rate, and guaranteeing the safety and long-term efficacy of treatment.
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Affiliation(s)
- Chao Jiang
- General Surgery Center, Department of Hepatobiliary and Pancreatic Surgery, the First Hospital of Jilin University, Changchun 130021, China
| | - Xiao-Dong Sun
- General Surgery Center, Department of Hepatobiliary and Pancreatic Surgery, the First Hospital of Jilin University, Changchun 130021, China
| | - Wei Qiu
- General Surgery Center, Department of Hepatobiliary and Pancreatic Surgery, the First Hospital of Jilin University, Changchun 130021, China
| | - Yu-Guo Chen
- General Surgery Center, Department of Hepatobiliary and Pancreatic Surgery, the First Hospital of Jilin University, Changchun 130021, China
| | - Da-Wei Sun
- General Surgery Center, Department of Hepatobiliary and Pancreatic Surgery, the First Hospital of Jilin University, Changchun 130021, China
| | - Guo-Yue Lv
- General Surgery Center, Department of Hepatobiliary and Pancreatic Surgery, the First Hospital of Jilin University, Changchun 130021, China.
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Lutz MS, Zekri L, Weßling L, Berchtold S, Heitmann JS, Lauer UM, Jung G, Salih HR. IgG-based B7-H3xCD3 bispecific antibody for treatment of pancreatic, hepatic and gastric cancer. Front Immunol 2023; 14:1163136. [PMID: 37122707 PMCID: PMC10140336 DOI: 10.3389/fimmu.2023.1163136] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 03/30/2023] [Indexed: 05/02/2023] Open
Abstract
T cell-based immunotherapy has significantly improved treatment options for many malignancies. However, despite these and other therapeutic improvements over the last decades, gastrointestinal cancers, in particular pancreatic, hepatic and gastric cancer, are still characterized by high relapse rates and dismal prognosis, with an accordingly high unmet medical need for novel treatment strategies. We here report on the preclinical characterization of a novel bispecific antibody in an IgG-based format termed CC-3 with B7-H3xCD3 specificity. In many cancer entities including pancreatic, hepatic and gastric cancers, B7-H3 (CD276) is overexpressed on tumor cells and also on the tumor vasculature, the latter allowing for improved access of immune effector cells into the tumor site upon therapeutic targeting. We demonstrate that CC-3 induces profound T cell reactivity against various pancreatic, hepatic and gastric cancer cell lines as revealed by analysis of activation, degranulation and secretion of IL2, IFNγ as well as perforin, resulting in potent target cell lysis. Moreover, CC-3 induced efficient T cell proliferation and formation of T cell memory subsets. Together, our results emphasize the potential of CC-3, which is presently being GMP-produced to enable clinical evaluation for treatment of pancreatic, hepatic and gastric cancer.
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Affiliation(s)
- Martina S. Lutz
- Department of Internal Medicine, Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), University Hospital Tuebingen, Tuebingen, Germany
- Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tuebingen, Tuebingen, Germany
| | - Latifa Zekri
- Department of Internal Medicine, Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), University Hospital Tuebingen, Tuebingen, Germany
- Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tuebingen, Tuebingen, Germany
- Department of Immunology, Eberhard Karls Universität Tübingen, Tuebingen, Germany
| | - Laura Weßling
- Department of Internal Medicine, Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), University Hospital Tuebingen, Tuebingen, Germany
- Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tuebingen, Tuebingen, Germany
| | - Susanne Berchtold
- Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tuebingen, Tuebingen, Germany
- Department of Internal Medicine VIII, Medical Oncology & Pneumology, University Hospital Tübingen, Tuebingen, Germany
- German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Tübingen, Germany
| | - Jonas S. Heitmann
- Department of Internal Medicine, Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), University Hospital Tuebingen, Tuebingen, Germany
- Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tuebingen, Tuebingen, Germany
| | - Ulrich M. Lauer
- Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tuebingen, Tuebingen, Germany
- Department of Internal Medicine VIII, Medical Oncology & Pneumology, University Hospital Tübingen, Tuebingen, Germany
- German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Tübingen, Germany
| | - Gundram Jung
- Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tuebingen, Tuebingen, Germany
- Department of Immunology, Eberhard Karls Universität Tübingen, Tuebingen, Germany
| | - Helmut R. Salih
- Department of Internal Medicine, Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), University Hospital Tuebingen, Tuebingen, Germany
- Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tuebingen, Tuebingen, Germany
- *Correspondence: Helmut R. Salih,
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Transarterial chemoembolisation plus I125 seeds implantation for people with unresectable hepatocellular carcinoma. Cochrane Database Syst Rev 2022; 2022:CD015389. [PMCID: PMC9744102 DOI: 10.1002/14651858.cd015389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the benefits and harms of transarterial chemoembolisation (TACE) plus I125 seeds implantation compared with TACE alone, regardless of chemotherapeutic drugs and vascular occlusive agents, for people with unresectable hepatocellular carcinoma.
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Ouranos K, Chatziioannou A, Goulis I, Sinakos E. Role of immunotherapy in downsizing hepatocellular carcinoma prior to liver transplantation. World J Transplant 2022; 12:331-346. [PMID: 36437845 PMCID: PMC9693898 DOI: 10.5500/wjt.v12.i11.331] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 08/10/2022] [Accepted: 10/19/2022] [Indexed: 11/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive primary liver neoplasm that, according to tumor stage, can be treated with resection, transplantation, locoregional treatment options, or systemic therapy. Although interventions only in early-stage disease can offer complete tumor regression, systemic therapy in advanced disease can significantly prolong overall survival, according to published clinical trials. The emergence of immunotherapy in the field of cancer therapy has had a positive impact on patients with HCC, resulting in atezolizumab–bevacizumab currently being the first-line option for treatment of advanced HCC. In light of this, application of immunotherapy in the preoperative process could increase the number of patients fulfilling the criteria for liver transplantation (LT). Implementation of this approach is faced with challenges regarding the safety of immunotherapy and the possibly increased risk of rejection in the perioperative period. Case reports and clinical trials assessing the safety profile and effectiveness of neoadjuvant immunotherapy, highlight important aspects regarding this newly evolving approach to HCC management. More studies need to be conducted in order to reach a consensus regarding the optimal way to administer immunotherapy prior to LT. In this review, we summarize the role, safety profile and future considerations regarding the use of neoadjuvant immunotherapy prior to LT in patients with HCC.
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Affiliation(s)
- Konstantinos Ouranos
- 4th Medical Department, Hippokratio Hospital, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Anthi Chatziioannou
- 4th Medical Department, Hippokratio Hospital, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Ioannis Goulis
- 4th Medical Department, Hippokratio Hospital, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Emmanouil Sinakos
- 4th Medical Department, Hippokratio Hospital, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
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Ramai D, Shapiro A, Facciorusso A, Bareggi C, Gambini D, Rijavec E, Tomasello G, Galassi B, Ghidini M. Immune checkpoint inhibitor therapy for hepatocellular carcinoma. Ann Gastroenterol 2022; 35:568-576. [PMID: 36406972 PMCID: PMC9648525 DOI: 10.20524/aog.2022.0746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 02/16/2022] [Indexed: 11/24/2022] Open
Abstract
Liver cancer is the third most common cause of cancer-associated death. Advances in the last decade have provided more options for treating hepatocellular carcinoma. The use of immune checkpoint inhibitors represents a leap forward and broadens the armamentarium for clinicians. In this article, we provide a state-of-the-art review of molecular therapy. We also detail the mechanisms of checkpoint inhibitor therapy, which blocks the interaction of programmed cell death receptor protein with programmed cell death ligand, reducing the immune checkpoint activity on regulatory T cells, thereby inhibiting tumor cell growth.
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Affiliation(s)
- Daryl Ramai
- Division of Gastroenterology and Hepatology, University of Utah School of Medicine, Salt Lake City, UT, USA (Daryl Ramai)
| | - Alexandra Shapiro
- St George’s University School of Medicine, True Blue, Grenada, West Indies (Alexandra Shapiro)
| | - Antonio Facciorusso
- Section of Gastroenterology, Department of Medical Sciences, University of Foggia, Foggia, Italy (Antonio Facciorusso)
| | - Claudia Bareggi
- Operative Unit of Oncology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy (Claudia Bareggi, Donatella Gambini, Erika Rijavec, Gianluca Tomasello, Barbara Galassi, Michele Ghidini)
| | - Donatella Gambini
- Operative Unit of Oncology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy (Claudia Bareggi, Donatella Gambini, Erika Rijavec, Gianluca Tomasello, Barbara Galassi, Michele Ghidini)
| | - Erika Rijavec
- Operative Unit of Oncology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy (Claudia Bareggi, Donatella Gambini, Erika Rijavec, Gianluca Tomasello, Barbara Galassi, Michele Ghidini)
| | - Gianluca Tomasello
- Operative Unit of Oncology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy (Claudia Bareggi, Donatella Gambini, Erika Rijavec, Gianluca Tomasello, Barbara Galassi, Michele Ghidini)
| | - Barbara Galassi
- Operative Unit of Oncology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy (Claudia Bareggi, Donatella Gambini, Erika Rijavec, Gianluca Tomasello, Barbara Galassi, Michele Ghidini)
| | - Michele Ghidini
- Operative Unit of Oncology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy (Claudia Bareggi, Donatella Gambini, Erika Rijavec, Gianluca Tomasello, Barbara Galassi, Michele Ghidini)
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18
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Griffiths CD, Zhang B, Tywonek K, Meyers BM, Serrano PE. Toxicity Profiles of Systemic Therapies for Advanced Hepatocellular Carcinoma: A Systematic Review and Meta-analysis. JAMA Netw Open 2022; 5:e2222721. [PMID: 35849393 PMCID: PMC9295000 DOI: 10.1001/jamanetworkopen.2022.22721] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 06/02/2022] [Indexed: 11/14/2022] Open
Abstract
Importance The recent development of targeted therapy and immunotherapy has made neoadjuvant therapy an attractive option for patients with hepatocellular carcinoma (HCC). However, surgeons are concerned that adverse effects of neoadjuvant therapy with these agents could lead to delayed or even cancelled surgeries. Objective To summarize the current evidence regarding toxicity profiles for tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) among patients with HCC. Data Sources Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched from January 1990 and December 2021. Study Selection Single-group, placebo-controlled, and dual-agent clinical trials comparing TKIs and ICIs in patients with HCC were eligible for inclusion. Data Extraction and Synthesis Following the Preferred Reporting Items in Systematic Reviews and Meta-analysis guideline, 2 reviewers independently extracted data. A random-effects model was used. Main Outcomes and Measures The primary outcome was the proportion of patients with clinically significant liver-related adverse events. Secondary outcomes included the proportion of patients who experienced clinically relevant (grade 3 or higher) adverse events and significant adverse events (ie, those that were life threatening, required hospitalization, or prolonged disability) as well as the risk ratio (RR) of these complications. Results Overall, 30 studies with 12 921 patients were included. Patients had a mean (range) age of 62 (18-89) years; a mean (SD) 84% (3) were male; a mean (SD) 82% (16) had Barcelona Clinic Liver Cancer stage C HCC; and a mean (SD) 97% (6) had Childs A cirrhosis. Overall, 21% (95% CI, 16%-26%) of patients receiving TKIs had liver toxic effects compared with 28% (95% CI, 21%-35%) of patients receiving ICIs. Severe adverse events occurred in 46% (95% CI, 40%-51%) of patients receiving TKIs compared with 24% (95% CI, 13%-35%) of patients receiving ICIs. Compared with patients receiving sorafenib, other TKIs were associated with similar rates of liver toxic effects (RR, 1.06; 95% CI, 0.92-1.24) but higher rates of severe adverse events (RR, 1.24; 95% CI, 1.07-1.44). Comparing ICIs with sorafenib, there were similar rates of liver toxic effects (RR, 1.10; 95% CI, 0.86-1.40) and severe adverse events (RR, 1.19; 95% CI, 0.95-1.50). Conclusions and Relevance In this systematic review and meta-analysis, serious adverse events were lower with ICIs than with TKIs, while liver toxic effects were similar. Combination therapy with novel ICIs is an appealing option in trials of neoadjuvant therapy for patients with HCC, requiring evaluation in preoperative trials.
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Affiliation(s)
| | - Betty Zhang
- Department of Anesthesia, University of Ottawa, Ottawa, Ontario, Canada
| | - Kasia Tywonek
- Department of Surgery, McMaster University, Hamilton, Ontario, Canada
| | - Brandon M. Meyers
- Department of Oncology, McMaster University, Hamilton, Ontario, Canada
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Pablo E. Serrano
- Department of Surgery, McMaster University, Hamilton, Ontario, Canada
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
- Division of General Surgery, Juravinski Hospital, Hamilton, Ontario, Canada
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Awosika J, Sohal D. A narrative review of systemic treatment options for hepatocellular carcinoma: state of the art review. J Gastrointest Oncol 2022; 13:426-437. [PMID: 35284102 PMCID: PMC8899752 DOI: 10.21037/jgo-21-274] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 12/14/2021] [Indexed: 06/23/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive cancer that typically develops in the setting of underlying cirrhosis of the liver. HCC commonly presents in advanced stages and if eligible orthotopic liver transplantation (OLT) and surgical resection/ablation remain as the only curative options. Prior to 2007, no systemic therapy was available that demonstrated an improvement in survival. Underlying cirrhosis and poor synthetic hepatic function provides a major challenge into effective systemic options contributing to the poor success of cytotoxic chemotherapy in HCC. The first drug to achieve clinical success was sorafenib despite the underwhelming overall survival of 3 months. Since then, other targeted therapies have shown modest benefit as well. Most recently, immunotherapy advances have come to the forefront in the management of HCC and combination therapy with immunotherapy and monoclonal antibodies have now surpassed sorafenib as first line treatment. This article will review the various approved and emerging therapies that have had a significant clinical impact and highlight the future directions and ongoing research that will hopefully translate into better outcomes in the treatment approach of advanced HCC.
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Rai V, Mukherjee S. Targets of immunotherapy for hepatocellular carcinoma: An update. World J Hepatol 2022; 14:140-157. [PMID: 35126844 PMCID: PMC8790386 DOI: 10.4254/wjh.v14.i1.140] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 07/20/2021] [Accepted: 12/25/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma, the most common primary liver cancer, in an immunogenic tumor with a poor prognosis because these tumors are diagnosed at late stages. Although, surgical resection, ablation, liver transplant, and locoregional therapies are available for early stages; however, there are yet no effective treatment for advanced and recurrent tumors. Immune checkpoint inhibitor therapy and adoptive cell transfer therapy has gained the popularity with some positive results because these therapies overcome anergy and systemic immune suppression. However, still there is a lack of an effective treatment and thus there is an unmet need of a novel treatment. At present, the focus of the research is on oncolytic viral therapy and combination therapy where therapies including radiotherapy, immune checkpoint therapy, adoptive cell transfer therapy, and vaccines are combined to get an additive or synergistic effect enhancing the immune response of the liver with a cytotoxic effect on tumor cells. This review discusses the recent key development, the basis of drug resistance, immune evasion, immune tolerance, the available therapies based on stage of the tumor, and the ongoing clinical trials on immune checkpoint inhibitor therapy, adoptive cell transfer therapy, oncolytic viral vaccine therapy, and combination therapy.
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Affiliation(s)
- Vikrant Rai
- Department of Translational Research, Western University of Health Sciences, Pomona, CA 91766, United States
| | - Sandeep Mukherjee
- Department of Medicine, Creighton University School of Medicine, Omaha, NE 68124, United States.
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21
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Advances in locoregional therapy for hepatocellular carcinoma combined with immunotherapy and targeted therapy. J Interv Med 2021; 4:105-113. [PMID: 34805958 PMCID: PMC8562181 DOI: 10.1016/j.jimed.2021.05.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 05/11/2021] [Accepted: 05/13/2021] [Indexed: 12/11/2022] Open
Abstract
Locoregional therapies (LRTs) of hepatocellular carcinoma (HCC) represented by ablation and TACE has become the main means for the clinical treatment of unresectable HCC. Among these, TACE is used throughout the stage Ib to IIIb of HCC treatment. In recent years, immunotherapy led by immune checkpoint inhibitors has become a hot direction in clinical research. At the same time, targeted drugs such as Sorafenib and Apatinib have played an important role in the treatment and complementary therapy of advanced HCC, and their clinical application has been quite mature. HCC is the sixth most common malignant tumor in the world. When it comes to its treatment, different therapies have different indications, and their individual efficacies are not satisfactory, which makes the exploration of the use of combination therapy in HCC treatment become a new trend. In this paper, the status of the three therapies and the progress of their combined application are briefly reviewed.
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22
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Mohr R, Tacke F. Therapie des hepatozellulären Karzinoms – eine neue Dekade? Drug Res (Stuttg) 2021; 71:S22-S23. [PMID: 34788884 DOI: 10.1055/a-1606-5955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Han JE, Cho HJ, Kim SS, Cheong JY. Infiltrative hepatocellular carcinoma with multiple lung metastasis completely cured using nivolumab: a case report. JOURNAL OF LIVER CANCER 2021; 21:169-176. [PMID: 37383079 PMCID: PMC10035689 DOI: 10.17998/jlc.2021.08.26] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 08/05/2021] [Accepted: 08/26/2021] [Indexed: 06/30/2023]
Abstract
The current Food and Drug Administration-approved systemic treatments for advanced hepatocellular carcinoma (HCC) include multikinase inhibitors (tyrosine kinase inhibitor [TKI]) and immune checkpoint inhibitors (ICIs). Among ICIs, nivolumab is used as second-line therapy for advanced HCC after sorafenib failure or patient intolerance. In this case, a patient with infiltrative HCC and portal vein tumor thrombosis was treated with hepatic arterial infusion chemotherapy (HAIC) and radiation therapy. New lung metastasis developed after HAICs; thus, lenvatinib treatment was initiated. However, the disease progressed. Thereafter, sorafenib treatment was initiated but he developed intolerance, with grade 3 sorafenib-related diarrhea. Subsequently, nivolumab was administered as rescue therapy. He demonstrated a partial response to nivolumab after the third treatment and viable HCCs in the lungs and liver completely disappeared after the 24th treatment. These findings suggest that nivolumab could be used as an effective rescue therapy for advanced HCC progression after TKI treatment.
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Affiliation(s)
- Ji Eun Han
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Hyo Jung Cho
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Soon Sun Kim
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Jae Youn Cheong
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
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24
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Rizzo A, Ricci AD. PD-L1, TMB, and other potential predictors of response to immunotherapy for hepatocellular carcinoma: how can they assist drug clinical trials? Expert Opin Investig Drugs 2021; 31:415-423. [PMID: 34429006 DOI: 10.1080/13543784.2021.1972969] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) represents the sixth most commonly diagnosed malignancy worldwide, accounting for millions of deaths annually. Despite immune checkpoint inhibitors (ICIs) reported important results, only a minority of HCC patients benefit from these treatments, and the identification of predictive biomarkers of response still remains a highly unmet need. AREAS COVERED Herein, we provide a timely overview of available evidence on biochemical predictors of response to immunotherapy in advanced HCC patients; we speculate on how PD-L1, TMB, and other emerging biomarkers could assist drug clinical trials in the near future. A literature search was conducted in June 2021 using Pubmed/Medline, Cochrane library, and Scopus databases. EXPERT OPINION Reliable predictors of response to ICIs are of pivotal importance to allow a proper stratification and selection of HCC patients that could derive more benefit from immunotherapy. Well-designed, multicenter clinical trials specifically focused on predictive biomarkers are warranted in this setting, where most of evidence currently derives from retrospective, single-center studies with small sample size.
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Affiliation(s)
- Alessandro Rizzo
- Medical Oncology, Irccs Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italia
| | - Angela Dalia Ricci
- Medical Oncology, Irccs Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italia
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