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Miri H, Rahimzadeh P, Hashemi M, Nabavi N, Aref AR, Daneshi S, Razzaghi A, Abedi M, Tahmasebi S, Farahani N, Taheriazam A. Harnessing immunotherapy for hepatocellular carcinoma: Principles and emerging promises. Pathol Res Pract 2025; 269:155928. [PMID: 40184729 DOI: 10.1016/j.prp.2025.155928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 03/12/2025] [Accepted: 03/26/2025] [Indexed: 04/07/2025]
Abstract
HCC is considered as one of the leadin causes of death worldwide, with the ability of resistance towards therapeutics. Immunotherapy, particularly ICIs, have provided siginficant insights towards harnessing the immune system. The present review introduces the concepts and possibilities of immunotherapy for HCC treatment, emphasizing its underlying mechanisms and capacity to enhance patient results, focusing on both pre-clinical and clinical insights. The functions of TME and immune evasion mechanisms typical of HCC would be evaluated along with how contemporary immunotherapeutic approaches are designed to address these challenges. Furthermore, the clinical application of immunotherapy in HCC is discussed, emphasizing recent trial findings demonstrating the effectiveness and safety of drugs. In addition, the problems caused by immune evasion and resistance would be discussed to increase potential of immunotherapy along with combination therapy.
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Affiliation(s)
- Hossein Miri
- Faculty of Medicine, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Payman Rahimzadeh
- Surgical Research Society (SRS), Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Noushin Nabavi
- Independent Researcher, Victoria, British Columbia V8V 1P7, Canada
| | - Amir Reza Aref
- Department of Vitro Vision, DeepkinetiX, Inc, Boston, MA, USA
| | - Salman Daneshi
- Department of Public Health, School of Health, Jiroft University Of Medical Sciences, Jiroft, Iran
| | - Alireza Razzaghi
- Social Determinants of Health Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Maryam Abedi
- Department of Pathology, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Safa Tahmasebi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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Guo X, Zhao Z, Zhu L, Liu S, Zhou L, Wu F, Fang S, Chen M, Zheng L, Ji J. The evolving landscape of biomarkers for systemic therapy in advanced hepatocellular carcinoma. Biomark Res 2025; 13:60. [PMID: 40221793 PMCID: PMC11993949 DOI: 10.1186/s40364-025-00774-2] [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: 01/26/2025] [Accepted: 03/29/2025] [Indexed: 04/14/2025] Open
Abstract
Hepatocellular carcinoma (HCC) remains one of the most prevalent and deadliest cancers. With the approval of multiple first- and second-line agents, especially the combination therapies based on immune checkpoint inhibitor (ICI) regimens, the landscape of systemic therapy for advanced HCC (aHCC) is more diverse than ever before. The efficacy of current systemic therapies shows great heterogeneity in patients with aHCC, thereby identifying biomarkers for response prediction and patient stratification has become an urgent need. The main biomarkers for systemic therapy in hepatocellular carcinoma are derived from peripheral blood, tissues, and imaging. Currently, the understanding of the clinical response to systemic therapy indicates unequivocally that a single biomarker cannot be used to identify patients who are likely to benefit from these treatments. In this review, we provide an integrated landscape of the recent development in molecular targeted therapies and ICIs-based therapies, especially focusing on the role of clinically applicable predictive biomarkers. Additionally, we further highlight the latest advancements in biomarker-driven therapies, including targeted treatments, adoptive cell therapies, and bispecific antibodies.
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Affiliation(s)
- Xinyu Guo
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Zhongwei Zhao
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Lingyi Zhu
- The 2nd Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310000, China
| | - Shuang Liu
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Lingling Zhou
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Fazong Wu
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Shiji Fang
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Minjiang Chen
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Liyun Zheng
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China.
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China.
- Zhejiang Key Laboratory of Imaging and Interventional Medicine, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, 323000, China.
| | - Jiansong Ji
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China.
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China.
- Zhejiang Key Laboratory of Imaging and Interventional Medicine, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, 323000, China.
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Muhammed TM, Jasim SA, Zwamel AH, Rab SO, Ballal S, Singh A, Nanda A, Ray S, Hjazi A, Yasin HA. T lymphocyte-based immune response and therapy in hepatocellular carcinoma: focus on TILs and CAR-T cells. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04035-9. [PMID: 40100377 DOI: 10.1007/s00210-025-04035-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 03/06/2025] [Indexed: 03/20/2025]
Abstract
Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related death worldwide. The primary therapies for HCC are liver transplantation, hepatic tumor excision, radiofrequency ablation, and molecular-targeted medicines. An unfavorable prognosis marks HCC and has limited pharmacological response in therapeutic studies. The tumor immune microenvironment (TME) imposes significant selection pressure on HCC, resulting in its evolution and recurrence after various treatments. As the principal cellular constituents of tumor-infiltrating lymphocytes (TILs), T cells have shown both anti-tumor and protumor actions in HCC. T cell-mediated immune responses are pivotal in cancer monitoring and elimination. TILs are recognized for their critical involvement in the progression, prognosis, and immunotherapeutic management of HCC. Foxp3 + , CD8 + , CD3 + , and CD4 + T cells are the extensively researched subtypes of TILs. This article examines the functions and processes of several subtypes of TILs in HCC. Emerging T cell-based therapies, including TILs and chimeric antigen receptor (CAR)-T cell therapy, have shown tumor regression in several clinical and preclinical studies. Herein, it also delves into the existing T cell-based immunotherapies in HCC, with emphasis on TILs and CAR-T cells.
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Affiliation(s)
- Thikra Majid Muhammed
- Biology Department, College of Education for Pure Sciences, University of Anbar, Anbar, Iraq
| | - Saade Abdalkareem Jasim
- Medical Laboratory Techniques Department, College of Health and Medical Technology, University of Al-Maarif, Anbar, Iraq.
| | - Ahmed Hussein Zwamel
- Department of Medical Analysis, Medical Laboratory Technique College, The Islamic University, Najaf, Iraq
- Department of Medical Analysis, Medical Laboratory Technique College, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- Department of Medical Analysis, Medical Laboratory Technique College, The Islamic University of Babylon, Babylon, Iraq
| | - Safia Obaidur Rab
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Abhayveer Singh
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, 140401, Punjab, India
| | - Anima Nanda
- Department of Biomedical, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
| | - Subhashree Ray
- Department of Biochemistry, IMS and SUM Hospital, Siksha 'O' Anusandhan (Deemed to Be University), Bhubaneswar, Odisha, 751003, India
| | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia.
| | - Hatif Abdulrazaq Yasin
- Department of Medical Laboratories Technology, Al-Nisour University College, Nisour Seq. Karkh, Baghdad, Iraq
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Ren Z, Wang Y, Jiang D, Liu Y, Yang X, Wang T, Zhu J, Wang W, Chen Q, Zhang Y. PD1 + Treg cell remodeling promotes immune homeostasis within peripheral blood and tumor microenvironment after microparticles-transarterial chemoembolization in hepatocellular carcinoma. Cancer Immunol Immunother 2025; 74:109. [PMID: 39937280 PMCID: PMC11822157 DOI: 10.1007/s00262-025-03962-z] [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: 12/23/2024] [Accepted: 01/28/2025] [Indexed: 02/13/2025]
Abstract
The effects of transarterial chemoembolization (TACE) on the systemic immune in hepatocellular carcinoma (HCC) are not well understood. We aimed to reveal the temporal and spatial changes in the immune profile of peripheral blood and tumor tissues in HCC patients following TACE. Eighty-four HCC patients were included, 20 of whom received TACE with a median follow-up of 28 months. Immune cell proportion within peripheral blood was profiled with flow cytometry, and therapeutic efficacy was evaluated by imaging examinations. Additionally, cell distribution within tumor microenvironment (TME) were compared between the necrotic tumor infiltration zone (N-IZ) and the residual tumor infiltration zone (R-IZ) by multiplex immunofluorescence. Among 20 patients, 25% (5/20) achieved complete response, and 75% (15/20) showed partial response. Fourteen patients received combinational targeted therapy and immunotherapy and the median progression-free survival was 15.5 months. Compared to healthy individuals, HCC exhibited significantly higher proportions of regulatory T cells (Tregs) and programmed death-1 receptor (PD1)+ Tregs within peripheral blood. PD1+ Treg cells, PD1+ CD4+ T cells and PD1+ CD8+ T cells decreased significantly within peripheral blood after TACE. In TME, N-IZ showed significantly lower CD4+ T, CD8+ T and FOXP3+ Tregs, higher PD1+ CD8+/CD8+ and PD1+ CD8+/ PD1+ FOXP3+. Moreover, the spatial distance between CD8+ T cells and the nearest FOXP3+ Tregs in N-IZ was significantly greater than in R-IZ. Our findings demonstrated that TACE could both remodel the immune components in peripheral blood and TME, strengthening the rationale for developing immunotherapy alongside TACE.
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Affiliation(s)
- Zhizhong Ren
- Department of Hepatobiliary Intervention, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, China
| | - Yaqin Wang
- Department of Hepatobiliary Intervention, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, China
| | | | - Ying Liu
- Department of Hepatobiliary Intervention, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, China
| | - Xiaowei Yang
- Department of Hepatobiliary Intervention, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, China
| | - Tianxiao Wang
- Department of Hepatobiliary Intervention, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, China
| | - Junqi Zhu
- Thorgene Co., Ltd., Beijing, 100176, China
| | - Wenya Wang
- Medical Research Center, Beijing Tsinghua Changgung Hospital Affiliated to Tsinghua University, Beijing, 102218, China.
| | - Qian Chen
- Thorgene Co., Ltd., Beijing, 100176, China.
| | - Yuewei Zhang
- Department of Hepatobiliary Intervention, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, China.
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Piao M, Zhang N, Li J, Li C, Xun Z, Zhang L, Wang S, Sun B, Li S, Yang X, Yang X, Wang H, Zhao H. Peripheral blood PD-1 + T lymphocytes as biomarkers in liquid biopsies for solid tumors: Clinical significance and prognostic applications. Int Immunopharmacol 2025; 147:114052. [PMID: 39799737 DOI: 10.1016/j.intimp.2025.114052] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/06/2025] [Accepted: 01/06/2025] [Indexed: 01/15/2025]
Abstract
A shift toward a T cell exhaustion phenotype is associated with the upregulation of expression of programmed cell death protein 1 (PD-1) on T lymphocytes in patients with malignant solid tumors. The interaction between PD-1 and programmed death-ligand 1 (PD-L1) inhibits PD-1+ T lymphocyte function, impacting their anti-tumor immune activity. Immune checkpoint inhibitors targeting PD-1/PD-L1 have revolutionized the treatment of various solid malignancies, improving therapeutic efficacy and survival outcomes. Peripheral blood analysis of liquid biopsies is being increasingly used to identify populations most likely to benefit from various treatment modalities. PD-1+ T lymphocytes represent the primary cell population responsive to immunotherapeutic interventions for patients with solid malignancies, as evidenced by the altered PD-1 expression levels and proportion of cells comprising the overall population of immunocytes. PD-1+ T cells in peripheral blood exert an associative and reciprocal predictive effect on homologous intratumoral cells. Distinct subpopulations of PD-1+ T cells exhibit differential ability to proliferate in the periphery and can be characterized by tumor antigen-specific and exhaustion phenotypes. These characteristics have prognostic implications, aiding in the prediction of the efficacy of antitumor therapy and predicting survival outcomes. We highlight distinct subpopulations of PD-1+ T cells, their exhaustion and antigen-specific phenotypes, and their dynamic changes over treatment, providing insights into their utility for tailoring personalized therapies. For the first time, this review discusses the role of peripheral PD-1+ T lymphocytes as prognostic biomarkers in liquid biopsies, focusing on their clinical significance, predictive value during therapy, and future research directions.
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Affiliation(s)
- Mingjian Piao
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing, China
| | - Nan Zhang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing, China
| | - Jiongyuan Li
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing, China
| | - Chengjie Li
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing, China
| | - Ziyu Xun
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing, China
| | - Longhao Zhang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing, China
| | - Shanshan Wang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing, China
| | - Boyu Sun
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing, China
| | - Shuofeng Li
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing, China
| | - Xu Yang
- Department of Breast Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing, China
| | - Xiaobo Yang
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing, China.
| | - Hanping Wang
- Division of Pulmonary and Critical Care Medicine, State Key Laboratory of Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing, China.
| | - Haitao Zhao
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing, China.
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Hapaer G, Che F, Xu Q, Li Q, Liang A, Wang Z, Ziluo J, Zhang X, Wei Y, Yuan Y, Song B. Radiomics-based biomarker for PD-1 status and prognosis analysis in patients with HCC. Front Immunol 2025; 16:1435668. [PMID: 39944703 PMCID: PMC11813882 DOI: 10.3389/fimmu.2025.1435668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 01/13/2025] [Indexed: 03/17/2025] Open
Abstract
Purpose To investigate the impact of preoperative contrast-enhanced CT-based radiomics model on PD-1 prediction in hepatocellular carcinoma (HCC) patients. Methods The study included 105 HCC patients (training cohort: 72; validation cohort: 33) who underwent preoperative contrast-enhanced CT and received systemic sorafenib treatment after surgery. Radiomics score was built for each patient and was integrated with independent clinic radiologic predictors into the radiomics model using multivariable logistic regression analysis. Results Seventeen radiomics features were finally selected to construct the radiomics score. In multivariate analysis, serum creatine and peritumoral enhancement were significant independent factors for PD-1 prediction. The radiomics model integrated radiomics signature with serum creatine and peritumoral enhancement showed good discriminative performance (AUC of 0.897 and 0.794 in the training and validation cohort). Overall survival (OS) was significantly different between the radiomics-predicted PD-1-positive and PD-1-negative groups (OS: 29.66 months, CI:16.03-44.40 vs. 31.04 months, CI: 17.10-44.07, P<0.001). Radiomics-predicted PD-1 was an independent predictor of OS of patients treated with sorafenib after surgery. (Hazard ratio [HR]: 1.61 [1.23-2.1], P<0.001). Conclusion The proposed model based on radiomic signature helps to evaluate PD-1 status of HCC patients and may be used for evaluating patients most likely to benefit from sorafenib as a potentially combination therapy regimen with immune checkpoint therapies.
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Affiliation(s)
- Gulizaina Hapaer
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Feng Che
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Qing Xu
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Qian Li
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ailin Liang
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zhou Wang
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jituome Ziluo
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xin Zhang
- Pharmaceutical Diagnostics, General Electric (GE) Healthcare, Shanghai, China
| | - Yi Wei
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yuan Yuan
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Bin Song
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Radiology, Sanya People’s Hospital, Sanya, China
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Zheng XQ, Sun LB, Jin WJ, Liu H, Song WY, Xu H, Wu JS, Wang XJ, Gou CY, Ding HG. Five-year complete remission of super-giant hepatocellular carcinoma with hepatectomy followed by sorafenib plus camrelizumab: A case report. World J Gastrointest Surg 2025; 17:99752. [PMID: 39872790 PMCID: PMC11757199 DOI: 10.4240/wjgs.v17.i1.99752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 09/23/2024] [Accepted: 10/28/2024] [Indexed: 12/27/2024] Open
Abstract
BACKGROUND Cirrhotic patients with super-giant hepatocellular carcinoma (HCC) and portal vein invasion generally have a poor prognosis. This paper presents a patient with super-giant HCC and portal vein invasion, who underwent hepatectomy followed by a combination of sorafenib and camrelizumab, resulting in complete remission (CR) for 5 years. CASE SUMMARY A 40-year-old male with compensated hepatitis B-related cirrhosis was diagnosed with HCC, Barcelona Clinic Liver Cancer stage C. Enhanced computed tomography imaging revealed a 152 mm × 171 mm tumor in the right liver, invading the portal vein and hepatic vein. Liver function was normal. The patient successfully underwent hepatectomy on July 18, 2019. However, by December 2019, HCC recurrence with lung metastases and portal vein invasion were detected. He started treatment with sorafenib (200 mg twice daily) and camrelizumab (200 mg every 3 weeks). By May 12, 2020, the patient was confirmed to have CR. Camrelizumab was adjusted to 200 mg every 12 weeks from June 16, 2021, with the last infusion on March 29, 2024. Although no further tumor recurrence was observed, he experienced two episodes of gastrointestinal bleeding due to esophagogastric varices, which were managed with endoscopic therapy. To date, the patient has remained in CR for 5 years. CONCLUSION The combination of hepatectomy with sorafenib and camrelizumab can achieve durable CR in patients with super-giant HCC and portal vein invasion. Further research is necessary to address these challenges and improve patient outcomes.
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Affiliation(s)
- Xiao-Qin Zheng
- Integrated Traditional Chinese and Western Medicine Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Li-Bo Sun
- Department of Surgery, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Wen-Jie Jin
- Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona 6500, Ticino, Switzerland
| | - Hui Liu
- Department of Pathology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Wen-Yan Song
- Department of Radiology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Hui Xu
- Integrated Traditional Chinese and Western Medicine Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Ju-Shan Wu
- Department of Surgery, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Xiao-Jun Wang
- Integrated Traditional Chinese and Western Medicine Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Chun-Yan Gou
- Integrated Traditional Chinese and Western Medicine Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Hui-Guo Ding
- Department of Gastroenterology and Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
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Lee HW, Park S, Park HJ, Cho KJ, Kim DY, Hwang B, Park JY. T-Cell Dynamics Predicts Prognosis of Patients with Hepatocellular Carcinoma Receiving Atezolizumab Plus Bevacizumab. Int J Mol Sci 2024; 25:10958. [PMID: 39456740 PMCID: PMC11507274 DOI: 10.3390/ijms252010958] [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: 09/20/2024] [Revised: 10/05/2024] [Accepted: 10/09/2024] [Indexed: 10/28/2024] Open
Abstract
Atezolizumab and bevacizumab show promise for treating hepatocellular carcinoma (HCC), but identifying responsive patients remains challenging, due to tumor heterogeneity. This study explores immune dynamics following this combination therapy. Between 2020 and 2023, 29 patients with advanced HCC who received atezolizumab plus bevacizumab at Severance Hospital, Seoul, were enrolled in this study. Peripheral blood mononuclear cells were analyzed using flow cytometry and statistical methods to assess immune alterations and identify biomarkers. Baseline characteristics showed a diverse HCC cohort with a mean age of 64 years and 82.8% male predominance. Absence of extrahepatic metastasis was associated with better overall survival. Immune responses revealed distinct CD4+ T-cell phenotypes between the 'partial response (PR) + stable disease (SD)' and 'progressive disease (PD)' groups, with an overall increase in CD8+ T-cell phenotypes. Patients with higher frequencies of CD8+PD-1+Ki-67+ T cells experienced significantly improved overall survival, while those with lower frequencies of CD4+Foxp3+PD-1+LAG3+ T cells also had notable survival benefits. These findings enhance the overall understanding of immune responses to this combination therapy, facilitating improved patient stratification and personalized therapeutic approaches for HCC.
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Affiliation(s)
- Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; (H.W.L.); (H.J.P.); (K.J.C.); (J.Y.P.)
- Insitute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul 03722, Republic of Korea
| | - Suebin Park
- Department of Clinical Drug Discovery & Development, Yonsei University College of Medicine, Seoul 03722, Republic of Korea;
| | - Hye Jung Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; (H.W.L.); (H.J.P.); (K.J.C.); (J.Y.P.)
- Yonsei Liver Center, Severance Hospital, Seoul 03722, Republic of Korea
| | - Kyung Joo Cho
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; (H.W.L.); (H.J.P.); (K.J.C.); (J.Y.P.)
- Yonsei Liver Center, Severance Hospital, Seoul 03722, Republic of Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; (H.W.L.); (H.J.P.); (K.J.C.); (J.Y.P.)
- Insitute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul 03722, Republic of Korea
| | - Byungjin Hwang
- Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; (H.W.L.); (H.J.P.); (K.J.C.); (J.Y.P.)
- Insitute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul 03722, Republic of Korea
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9
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El-Khoueiry AB, Trojan J, Meyer T, Yau T, Melero I, Kudo M, Hsu C, Kim TY, Choo SP, Kang YK, Yeo W, Chopra A, Soleymani S, Yao J, Neely J, Tschaika M, Welling TH, Sangro B. Nivolumab in sorafenib-naive and sorafenib-experienced patients with advanced hepatocellular carcinoma: 5-year follow-up from CheckMate 040. Ann Oncol 2024; 35:381-391. [PMID: 38151184 DOI: 10.1016/j.annonc.2023.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 12/07/2023] [Accepted: 12/11/2023] [Indexed: 12/29/2023] Open
Abstract
BACKGROUND Patients with advanced hepatocellular carcinoma (aHCC) have a poor prognosis and high mortality. Nivolumab monotherapy demonstrated clinical benefit with an acceptable safety profile in patients with aHCC in the CheckMate 040 study. Five-year follow-up of the sorafenib-naive and sorafenib-experienced groups of CheckMate 040 is presented here. PATIENTS AND METHODS Patients received nivolumab monotherapy at dose levels of 0.1-10.0 mg/kg (dose-escalation phase) or 3 mg/kg (dose-expansion phase) every 2 weeks until disease progression or unacceptable toxicity. Primary endpoints were safety and tolerability (dose escalation), and objective response rate (ORR) by blinded independent central review (BICR) and by investigator as per RECIST version 1.1 (dose expansion). RESULTS Eighty sorafenib-naive and 154 sorafenib-experienced patients were treated. Minimum follow-up in both groups was 60 months. ORR as per BICR was 20% [95% confidence interval (CI) 12% to 30%] and 14% (95% CI 9% to 21%) in the sorafenib-naive and sorafenib-experienced groups, respectively. Responses occurred regardless of HCC etiology or baseline tumor cell programmed death-ligand 1 (PD-L1) expression levels. Median overall survival (OS) was 26.6 months (95% CI 16.6-30.6 months) and 15.1 months (95% CI 13.0-18.2 months) in sorafenib-naive and sorafenib-experienced patients, respectively. The 3-year OS rates were 28% in the sorafenib-naive and 20% in the sorafenib-experienced groups; 5-year OS rates were 14% and 12%, respectively. No new safety signals were identified; grade 3/4 treatment-related adverse events were observed in 33% and 21% of patients in the sorafenib-naive and sorafenib-experienced groups, respectively. Biomarker analyses showed that baseline PD-L1 expression ≥1% was associated with higher ORR and longer OS compared with PD-L1 <1%. In the sorafenib-naive group, patients with OS ≥3 years exhibited higher baseline CD8 T-cell density compared with those with OS <1 year. CONCLUSION With 5 years of follow-up, nivolumab monotherapy continued to provide durable clinical benefit with manageable safety in sorafenib-naive and sorafenib-experienced patients with aHCC.
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Affiliation(s)
- A B El-Khoueiry
- Division of Medical Oncology, USC Norris Comprehensive Cancer Center, Los Angeles, USA.
| | - J Trojan
- Department of Medicine, Goethe University Hospital and Cancer Center, Frankfurt, Germany
| | - T Meyer
- Department of Oncology, Royal Free Hospital, London, UK
| | - T Yau
- Department of Medicine, University of Hong Kong, Hong Kong, China
| | - I Melero
- Department of Immunology, Clinica Universidad de Navarra and CIBERONC, Pamplona, Spain
| | - M Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - C Hsu
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan; Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - T-Y Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - S-P Choo
- Division of Medical Oncology, National Cancer Center and Curie Oncology, Singapore, Republic of Singapore
| | - Y-K Kang
- Department of Oncology, Asan Medical Center, University of Ulsan, Seoul, Korea
| | - W Yeo
- Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong, China
| | - A Chopra
- Department of Medical Oncology, Johns Hopkins Singapore International Medical Centre, Singapore, Republic of Singapore
| | - S Soleymani
- Global Biometrics & Data Sciences, Bristol Myers Squibb, Princeton, USA
| | - J Yao
- Informatics and Predictive Sciences, Bristol Myers Squibb, Princeton, USA
| | - J Neely
- Translational Medicine, Bristol Myers Squibb, Princeton, USA
| | - M Tschaika
- Oncology Clinical Development, Bristol Myers Squibb, Princeton, USA
| | - T H Welling
- Perlmutter Cancer Center and Department of Surgery, NYU Langone Health, New York, USA
| | - B Sangro
- Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra and CIBEREHD, Pamplona, Spain
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10
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Alfar R, Napoleon JV, Shahriar I, Finnell R, Walchle C, Johnson A, Low PS. Selective reprogramming of regulatory T cells in solid tumors can strongly enhance or inhibit tumor growth. Front Immunol 2023; 14:1274199. [PMID: 37928524 PMCID: PMC10623129 DOI: 10.3389/fimmu.2023.1274199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 09/26/2023] [Indexed: 11/07/2023] Open
Abstract
Folate receptor delta (FRδ) has been used as a biomarker for regulatory T cells (Tregs), because its expression is limited to Tregs and ovum. Although FRδ is unable to bind folate, we have used molecular docking software to identify a folate congener that binds FRδ with high affinity and have exploited this FRδ-specific ligand to target attached drugs (imaging agents, immune activators, and immune suppressors) specifically to Tregs in murine tumor xenografts. Analysis of treated tumors demonstrates that targeting of a Toll-like receptor 7 agonist inhibits Treg expression of FOXP3, PD-1, CTLA4, and HELIOS, resulting in 40-80% reduction in tumor growth and repolarization of other tumor-infiltrating immune cells to more inflammatory phenotypes. Targeting of the immunosuppressive drug dexamethasone, in contrast, promotes enhanced tumor growth and shifts the tumor-infiltrating immune cells to more anti-inflammatory phenotypes. Since Tregs comprise <1% of cells in the tumor masses examined, and since the targeted drugs are not internalized by cancer cells, these data demonstrate that Tregs exert a disproportionately large effect on tumor growth. Because the targeted drug did not bind to Tregs or other immune cells in healthy tissues, the data demonstrate that the immunosuppressive properties of Tregs in tumors can be manipulated without causing systemic toxicities associated with global reprogramming of the immune system.
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Affiliation(s)
- Rami Alfar
- Department of Chemistry, Purdue Institute for Drug Discovery, Purdue University, West Lafayette, IN, United States
| | - John V. Napoleon
- Department of Chemistry, Purdue Institute for Drug Discovery, Purdue University, West Lafayette, IN, United States
| | - Imrul Shahriar
- Department of Chemistry, Purdue Institute for Drug Discovery, Purdue University, West Lafayette, IN, United States
| | - Richard Finnell
- Departments of Molecular and Cellular Biology, Molecular and Human Genetics and Medicine, Baylor College of Medicine, Houston, TX, United States
| | - Cole Walchle
- Department of Chemistry, Purdue Institute for Drug Discovery, Purdue University, West Lafayette, IN, United States
| | - Austin Johnson
- Department of Chemistry, Purdue Institute for Drug Discovery, Purdue University, West Lafayette, IN, United States
| | - Philip S. Low
- Department of Chemistry, Purdue Institute for Drug Discovery, Purdue University, West Lafayette, IN, United States
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11
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Wei Y, Yang M, Xu L, Liu M, Zhang F, Xie T, Cheng X, Wang X, Che F, Li Q, Xu Q, Huang Z, Liu M. Novel Computed-Tomography-Based Transformer Models for the Noninvasive Prediction of PD-1 in Pre-Operative Settings. Cancers (Basel) 2023; 15:cancers15030658. [PMID: 36765615 PMCID: PMC9913645 DOI: 10.3390/cancers15030658] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/05/2023] [Accepted: 01/12/2023] [Indexed: 01/24/2023] Open
Abstract
The expression status of programmed cell death protein 1 (PD-1) in patients with hepatocellular carcinoma (HCC) is associated with the checkpoint blockade treatment responses of PD-1/PD-L1. Thus, accurately and preoperatively identifying the status of PD-1 has great clinical implications for constructing personalized treatment strategies. To investigate the preoperative predictive value of the transformer-based model for identifying the status of PD-1 expression, 93 HCC patients with 75 training cohorts (2859 images) and 18 testing cohorts (670 images) were included. We propose a transformer-based network architecture, ResTransNet, that efficiently employs convolutional neural networks (CNNs) and self-attention mechanisms to automatically acquire a persuasive feature to obtain a prediction score using a nonlinear classifier. The area under the curve, receiver operating characteristic curve, and decision curves were applied to evaluate the prediction model's performance. Then, Kaplan-Meier survival analyses were applied to evaluate the overall survival (OS) and recurrence-free survival (RFS) in PD-1-positive and PD-1-negative patients. The proposed transformer-based model obtained an accuracy of 88.2% with a sensitivity of 88.5%, a specificity of 88.9%, and an area under the curve of 91.1% in the testing cohort.
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Affiliation(s)
- Yi Wei
- Department of Radiology, West China Hospital, Sichuan University, Chengdu 610000, China
| | - Meiyi Yang
- School of Computer Science and Engineering, University of Electronic Science and Technology of China, Chengdu 610000, China
| | - Lifeng Xu
- Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Quzhou 324000, China
| | - Minghui Liu
- School of Computer Science and Engineering, University of Electronic Science and Technology of China, Chengdu 610000, China
| | - Feng Zhang
- Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Quzhou 324000, China
| | - Tianshu Xie
- School of Computer Science and Engineering, University of Electronic Science and Technology of China, Chengdu 610000, China
- Yangtze Delta Region Institute (Quzhou), University of Electronic Science and Technology of China, Quzhou 324000, China
| | - Xuan Cheng
- School of Computer Science and Engineering, University of Electronic Science and Technology of China, Chengdu 610000, China
| | - Xiaomin Wang
- School of Computer Science and Engineering, University of Electronic Science and Technology of China, Chengdu 610000, China
| | - Feng Che
- Department of Radiology, West China Hospital, Sichuan University, Chengdu 610000, China
| | - Qian Li
- Department of Radiology, West China Hospital, Sichuan University, Chengdu 610000, China
| | - Qing Xu
- Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu 610000, China
| | - Zixing Huang
- Department of Radiology, West China Hospital, Sichuan University, Chengdu 610000, China
- Correspondence: (Z.H.); (M.L.)
| | - Ming Liu
- Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Quzhou 324000, China
- Correspondence: (Z.H.); (M.L.)
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12
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Liang L, Wang X, Huang S, Chen Y, Zhang P, Li L, Cui Y. Tyrosine kinase inhibitors as potential sensitizers of adoptive T cell therapy for hepatocellular carcinoma. Front Immunol 2023; 14:1046771. [PMID: 36936932 PMCID: PMC10014465 DOI: 10.3389/fimmu.2023.1046771] [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: 09/17/2022] [Accepted: 02/13/2023] [Indexed: 03/04/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. However, either targeted therapy or immunotherapy alone is inefficient and has limited survival benefits on part of HCC patients. Investigations have proved that tyrosine kinase inhibitors (TKIs) have regulatory effects on the tumor microenvironment and immune response, which are potential sensitizers for immunotherapy. Herein, a combination therapy using TKIs and immunotherapy has been explored and demonstrated to improve the effectiveness of treatment. As an effective immunotherapy, adoptive T cell therapy in solid tumors is required to improve tumor infiltration and killing activity which can be possibly achieved by combination with TKIs.
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Affiliation(s)
- Linjun Liang
- Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Department of Oncology, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, Guangdong, China
| | - Xiaoyan Wang
- Department of Oncology, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, Guangdong, China
| | - Shuying Huang
- Department of Oncology, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, Guangdong, China
| | - Yanwei Chen
- Department of Pulmonary Critical Care Medicine of Tangdu Hospital, Fourth Military Medical University, Xi’an, China
| | - Peng Zhang
- Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- *Correspondence: Peng Zhang, ; Liang Li, ; Yong Cui,
| | - Liang Li
- School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China
- *Correspondence: Peng Zhang, ; Liang Li, ; Yong Cui,
| | - Yong Cui
- Department of Oncology, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, Guangdong, China
- *Correspondence: Peng Zhang, ; Liang Li, ; Yong Cui,
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13
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Barnestein R, Galland L, Kalfeist L, Ghiringhelli F, Ladoire S, Limagne E. Immunosuppressive tumor microenvironment modulation by chemotherapies and targeted therapies to enhance immunotherapy effectiveness. Oncoimmunology 2022; 11:2120676. [PMID: 36117524 PMCID: PMC9481153 DOI: 10.1080/2162402x.2022.2120676] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
With the rapid clinical development of immune checkpoint inhibitors (ICIs), the standard of care in cancer management has evolved rapidly. However, immunotherapy is not currently beneficial for all patients. In addition to intrinsic tumor factors, other etiologies of resistance to ICIs arise from the complex interplay between cancer and its microenvironment. Recognition of the essential role of the tumor microenvironment (TME) in cancer progression has led to a shift from a tumor-cell-centered view of cancer development, to the concept of a complex tumor ecosystem that supports tumor growth and metastatic dissemination. The expansion of immunosuppressive cells represents a cardinal strategy deployed by tumor cells to escape detection and elimination by the immune system. Regulatory T lymphocytes (Treg), myeloid-derived suppressor cells (MDSCs), and type-2 tumor-associated macrophages (TAM2) are major components of these inhibitory cellular networks, with the ability to suppress innate and adaptive anticancer immunity. They therefore represent major impediments to anticancer therapies, particularly immune-based interventions. Recent work has provided evidence that, beyond their direct cytotoxic effects on cancer cells, several conventional chemotherapeutic (CT) drugs and agents used in targeted therapies (TT) can promote the elimination or inactivation of suppressive immune cells, resulting in enhanced antitumor immunity. In this review, we will analyze findings pertaining to this concept, discuss the possible molecular bases underlying the selective targeting of these immunosuppressive cells by antineoplastic agents (CT and/or TT), and consider current challenges and future prospects related to the integration of these molecules into more efficient anticancer strategies, in the era of immunotherapy.
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Affiliation(s)
- Robby Barnestein
- University of Burgundy, Dijon, France
- Platform of Transfer in Cancer Biology, Georges François Leclerc Cancer Center, Dijon, France
| | - Loïck Galland
- University of Burgundy, Dijon, France
- Platform of Transfer in Cancer Biology, Georges François Leclerc Cancer Center, Dijon, France
- Department of Medical Oncology, Georges François Leclerc Center, Dijon, France
| | - Laura Kalfeist
- University of Burgundy, Dijon, France
- Platform of Transfer in Cancer Biology, Georges François Leclerc Cancer Center, Dijon, France
- Centre de Recherche INSERM LNC-UMR1231, Dijon, France
- Genomic and Immunotherapy Medical Institute, Dijon University Hospital, Dijon, France
| | - François Ghiringhelli
- University of Burgundy, Dijon, France
- Platform of Transfer in Cancer Biology, Georges François Leclerc Cancer Center, Dijon, France
- Department of Medical Oncology, Georges François Leclerc Center, Dijon, France
- Centre de Recherche INSERM LNC-UMR1231, Dijon, France
- Genomic and Immunotherapy Medical Institute, Dijon University Hospital, Dijon, France
| | - Sylvain Ladoire
- University of Burgundy, Dijon, France
- Platform of Transfer in Cancer Biology, Georges François Leclerc Cancer Center, Dijon, France
- Department of Medical Oncology, Georges François Leclerc Center, Dijon, France
- Centre de Recherche INSERM LNC-UMR1231, Dijon, France
- Genomic and Immunotherapy Medical Institute, Dijon University Hospital, Dijon, France
| | - Emeric Limagne
- University of Burgundy, Dijon, France
- Platform of Transfer in Cancer Biology, Georges François Leclerc Cancer Center, Dijon, France
- Department of Medical Oncology, Georges François Leclerc Center, Dijon, France
- Centre de Recherche INSERM LNC-UMR1231, Dijon, France
- Genomic and Immunotherapy Medical Institute, Dijon University Hospital, Dijon, France
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14
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Zheng J, Qiu D, Jiang X, Zhao Y, Zhao H, Wu X, Chen J, Lai J, Zhang W, Li X, Li Y, Wu X, Jin Z. Increased PD-1 +Foxp3 + γδ T cells associate with poor overall survival for patients with acute myeloid leukemia. Front Oncol 2022; 12:1007565. [PMID: 36591503 PMCID: PMC9799959 DOI: 10.3389/fonc.2022.1007565] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 11/21/2022] [Indexed: 12/23/2022] Open
Abstract
Problems γδ T cells are essential for anti-leukemia function in immunotherapy, however, γδ T cells have different functional subsets, including regulatory cell subsets expressing the Foxp3. Whether they are correlated with immune-checkpoint mediated T cell immune dysfunction remains unknown in patients with acute myeloid leukemia (AML). Methods In this study, we used RNA-seq data from 167 patients in TCGA dataset to analyze the correlation between PD-1 and FOXP3 genes and these two genes' association with the prognosis of AML patients. The expression proportion of Foxp3+/PD-1+ cells in γδ T cells and two subgroups Vδ1 and Vδ2 T cells were performed by flow cytometry. The expression level of FOXP3 and PD-1 genes in γδ T cells were sorted from peripheral blood by MACS magnetic cell sorting technique were analyzed by quantitative real-time PCR. Results We found that PD-1 gene was positively correlated with FOXP3 gene and highly co-expressed PD-1 and FOXP3 genes were associated with poor overall survival (OS) from TCGA database. Then, we detected a skewed distribution of γδ T cells with increased Vδ1 and decreased Vδ2 T cell subsets in AML. Moreover, significantly higher percentages of PD-1+ γδ, Foxp3+ γδ, and PD-1+Foxp3+ γδ T cells were detected in de novo AML patients compared with healthy individuals. More importantly, AML patients containing higher PD-1+Foxp3+ γδ T cells had lower OS, which might be a potential therapeutic target for leukemia immunotherapy. Conclusion A significant increase in the PD-1+Foxp3+ γδ T cell subset in AML was associated with poor clinical outcome, which provides predictive value for the study of AML patients.
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Affiliation(s)
- Jiamian Zheng
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, China
| | - Dan Qiu
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, China,Department of Traditional Chinese Medicine, Heyuan People’s Hospital, Heyuan, China
| | - Xuan Jiang
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, China
| | - Yun Zhao
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, China
| | - Haotian Zhao
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, China
| | - Xiaofang Wu
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, China
| | - Jie Chen
- Department of Hematology, First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Jing Lai
- Department of Hematology, First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Wenbin Zhang
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, China
| | - Xutong Li
- Department of Oncology, First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Yangqiu Li
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, China,*Correspondence: Yangqiu Li, ; Xiuli Wu, ; Zhenyi Jin,
| | - Xiuli Wu
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, China,*Correspondence: Yangqiu Li, ; Xiuli Wu, ; Zhenyi Jin,
| | - Zhenyi Jin
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, China,Department of Pathology, School of Medicine, Jinan University, Guangzhou, China,*Correspondence: Yangqiu Li, ; Xiuli Wu, ; Zhenyi Jin,
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15
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Laba S, Mallett G, Amarnath S. The depths of PD-1 function within the tumor microenvironment beyond CD8 + T cells. Semin Cancer Biol 2022; 86:1045-1055. [PMID: 34048897 DOI: 10.1016/j.semcancer.2021.05.022] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/30/2021] [Accepted: 05/18/2021] [Indexed: 02/07/2023]
Abstract
Programmed cell death-1 (PD-1; CD279) is a cell surface receptor that is expressed in both innate and adaptive immune cells. The role of PD-1 in adaptive immune cells, specifically in CD8+ T cells, has been thoroughly investigated but its significance in other immune cells is yet to be well established. This review will address the role of PD-1 based therapies in enhancing non-CD8+ T cell immune responses within cancer. Specifically, the expression and function of PD-1 in non-CD8+ immune cell compartments such as CD4+ T helper cell subsets, myeloid cells and innate lymphoid cells (ILCs) will be discussed. By understanding the immune cell specific function of PD-1 within tissue resident innate and adaptive immune cells, it will be possible to stratify patients for PD-1 based therapies for both immunogeneic and non-immunogeneic neoplastic disorders. With this knowledge from fundamental and translational studies, PD-1 based therapies can be utilized to enhance T cell independent immune responses in cancers.
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Affiliation(s)
- Stephanie Laba
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, NE2 4HH, United Kingdom.
| | - Grace Mallett
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, NE2 4HH, United Kingdom
| | - Shoba Amarnath
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, NE2 4HH, United Kingdom.
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16
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Sové RJ, Verma BK, Wang H, Ho WJ, Yarchoan M, Popel AS. Virtual clinical trials of anti-PD-1 and anti-CTLA-4 immunotherapy in advanced hepatocellular carcinoma using a quantitative systems pharmacology model. J Immunother Cancer 2022; 10:e005414. [PMID: 36323435 PMCID: PMC9639136 DOI: 10.1136/jitc-2022-005414] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/05/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and is the third-leading cause of cancer-related death worldwide. Most patients with HCC are diagnosed at an advanced stage, and the median survival for patients with advanced HCC treated with modern systemic therapy is less than 2 years. This leaves the advanced stage patients with limited treatment options. Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) or its ligand, are widely used in the treatment of HCC and are associated with durable responses in a subset of patients. ICIs targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) also have clinical activity in HCC. Combination therapy of nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) is the first treatment option for HCC to be approved by Food and Drug Administration that targets more than one immune checkpoints. METHODS In this study, we used the framework of quantitative systems pharmacology (QSP) to perform a virtual clinical trial for nivolumab and ipilimumab in HCC patients. Our model incorporates detailed biological mechanisms of interactions of immune cells and cancer cells leading to antitumor response. To conduct virtual clinical trial, we generate virtual patient from a cohort of 5,000 proposed patients by extending recent algorithms from literature. The model was calibrated using the data of the clinical trial CheckMate 040 (ClinicalTrials.gov number, NCT01658878). RESULTS Retrospective analyses were performed for different immune checkpoint therapies as performed in CheckMate 040. Using machine learning approach, we predict the importance of potential biomarkers for immune blockade therapies. CONCLUSIONS This is the first QSP model for HCC with ICIs and the predictions are consistent with clinically observed outcomes. This study demonstrates that using a mechanistic understanding of the underlying pathophysiology, QSP models can facilitate patient selection and design clinical trials with improved success.
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Affiliation(s)
- Richard J Sové
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Babita K Verma
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Hanwen Wang
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Won Jin Ho
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Mark Yarchoan
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Aleksander S Popel
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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17
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Kazemi MH, Sadri M, Najafi A, Rahimi A, Baghernejadan Z, Khorramdelazad H, Falak R. Tumor-infiltrating lymphocytes for treatment of solid tumors: It takes two to tango? Front Immunol 2022; 13:1018962. [PMID: 36389779 PMCID: PMC9651159 DOI: 10.3389/fimmu.2022.1018962] [Citation(s) in RCA: 86] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Accepted: 10/14/2022] [Indexed: 07/30/2023] Open
Abstract
Tumor-infiltrating lymphocytes (TILs), frontline soldiers of the adaptive immune system, are recruited into the tumor site to fight against tumors. However, their small number and reduced activity limit their ability to overcome the tumor. Enhancement of TILs number and activity against tumors has been of interest for a long time. A lack of knowledge about the tumor microenvironment (TME) has limited success in primary TIL therapies. Although the advent of engineered T cells has revolutionized the immunotherapy methods of hematologic cancers, the heterogeneity of solid tumors warrants the application of TILs with a wide range of specificity. Recent advances in understanding TME, immune exhaustion, and immune checkpoints have paved the way for TIL therapy regimens. Nowadays, TIL therapy has regained attention as a safe personalized immunotherapy, and currently, several clinical trials are evaluating the efficacy of TIL therapy in patients who have failed conventional immunotherapies. Gaining favorable outcomes following TIL therapy of patients with metastatic melanoma, cervical cancer, ovarian cancer, and breast cancer has raised hope in patients with refractory solid tumors, too. Nevertheless, TIL therapy procedures face several challenges, such as high cost, timely expansion, and technical challenges in selecting and activating the cells. Herein, we reviewed the recent advances in the TIL therapy of solid tumors and discussed the challenges and perspectives.
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Affiliation(s)
- Mohammad Hossein Kazemi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Sadri
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Alireza Najafi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Rahimi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Zeinab Baghernejadan
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Khorramdelazad
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Reza Falak
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
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18
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Cheng CC, Ho AS, Peng CL, Chang J, Sie ZL, Wang CL, Chen YL, Chen CY. Sorafenib suppresses radioresistance and synergizes radiotherapy-mediated CD8 + T cell activation to eradicate hepatocellular carcinoma. Int Immunopharmacol 2022; 112:109110. [PMID: 36037651 DOI: 10.1016/j.intimp.2022.109110] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 07/22/2022] [Accepted: 07/27/2022] [Indexed: 11/24/2022]
Abstract
Radiotherapy (RT) is applied to eradicate tumors in the clinic. However, hepatocellular carcinoma (HCC) exhibits resistance against RT. It is demonstrated that RT directly inhibits tumor growth but which induces type I interferons (IFNs) expression to phosphorylate STATs and increase STATs-downstream PD-L1 levels in the survival tumor cells. Since sorafenib is capable of suppressing STATs, we, therefore, hypothesize that sorafenib suppresses IFNs-mediated radioresistance and PD-L1 in the residual tumor cells and may synergistically enhance RT-mediated reactivation of CD8+ T immunological activity to eradicate HCC cells. We found that combined RT, sorafenib, and PBMCs significantly suppress the colony formation in the HCC cells, whereas CD8+ T cells expressed high granzyme B (GZMB) and perforin (PRF1) in co-cultured with RT-treated HCC cells. We demonstrated RT significantly inhibited HCC cell viability but induced IFNα and IL-6 expression in the RT-treated HCC cells, resulting in immune checkpoint PD-L1 and anti-apoptosis MCL1 and BCL2 overexpression in the non-RT HCC cells. We found that sorafenib decreased RT-PLC5 medium (RT-PLC5-m)-mediated cell growth by suppressing IFNα- and IL-6-mediated STAT1 and STAT3 phosphorylation. Sorafenib also reduced IFNα-mediated PD-L1 levels in HCC cells. Meanwhile, RT-PLC5-m reactivated CD8+ T cells and non-CD8+ PBMCs, resulting in high IFNγ and IL-2 levels in CD8+ T cells, and cytokines IFNα, IFNγ, IL-2, and IL-6 in non-CD8+ PBMCs. Particularly, CD8+ T cells expressed higher GZMB and PRF1 and non-CD8+ PBMCs expressed higher IFNα, IFNγ, IL-2, IL-6, CXCL9, and CXCL10 in co-cultured with RT-treated HCC cells compared to parental cells. Although we demonstrated that sorafenib slightly inhibited RT-mediated GZMB and PRF1 expression in CD8+ T cells, and cytokines levels in non-CD8+ PBMCs. Based on sorafenib significantly suppressed IFNα- and IL-6-mediated radioresistance and PD-L1 expression, we demonstrated that sorafenib synergized RT and immune surveillance for suppressing PLC5 cell viability in vitro. In conclusion, this study revealed that RT induced IFNα and IL-6 expression to phosphorylate STAT1 and STAT3 by autocrine and paracrine effect, leading to radioresistance and PD-L1 overexpression in HCC cells. Sorafenib not only suppressed IFNα- and IL-6-mediated PLC5 cell growth but also inhibited IFNα-mediated PD-L1 expression, synergistically enhancing RT-mediated CD8+ T cell reactivation against HCC cells.
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Affiliation(s)
- Chun-Chia Cheng
- Radiation Biology Research Center, Institute for Radiological Research, Chang Gung University, Taoyuan 333, Taiwan; Division of Pulmonary Oncology and Interventional Bronchoscopy, Department of Thoracic Medicine, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan
| | - Ai-Sheng Ho
- Division of Gastroenterology, Cheng Hsin General Hospital, Taipei 112, Taiwan.
| | - Cheng-Liang Peng
- Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan 325, Taiwan.
| | - Jungshan Chang
- Graduate Institute of Medical Sciences, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
| | - Zong-Lin Sie
- Radiation Biology Research Center, Institute for Radiological Research, Chang Gung University, Taoyuan 333, Taiwan
| | - Chih-Liang Wang
- Division of Pulmonary Oncology and Interventional Bronchoscopy, Department of Thoracic Medicine, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan
| | - Yi-Li Chen
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Cheng-Yi Chen
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
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19
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Bejjani AC, Finn RS. Hepatocellular Carcinoma: Pick the Winner-Tyrosine Kinase Inhibitor Versus Immuno-oncology Agent-Based Combinations. J Clin Oncol 2022; 40:2763-2773. [PMID: 35649192 DOI: 10.1200/jco.21.02605] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The treatment landscape for advanced hepatocellular carcinoma has changed dramatically over the past 4 years. We now have numerous options for patients in frontline, second-line, and beyond. The most significant impact has been the introduction of immunotherapy into our treatment paradigms. We now have regimens that induce consistent double-digit objective response rates and markedly improve overall survival (OS) with favorable side effect profiles. The combination of atezolizumab and bevacizumab has demonstrated that the combination of targeting programmed death-ligand 1 and the vascular endothelial growth factor axis can improve outcomes versus sorafenib in the IMBrave150 study. Results from the COSMIC-312 study evaluating the multikinase vascular endothelial growth factor receptor, hepatocyte growth factor receptor, and AXL tyrosine kinase receptor inhibitor cabozantinib in combination with atezolizumab improved progression-free survival versus sorafenib, but at this time, there is no improvement in OS and response rates were lower than expected. Additional data with similar combinations are awaited on the basis of encouraging early-phase data. In addition, the combination of cytotoxic T-lymphocyte-associated protein 4 and programmed cell death-1/programmed death-ligand 1 targeting is yielding similar promising early results, and the phase III HIMALAYA study met its primary end points of improving OS versus sorafenib for durvalumab plus tremelimumab and demonstrated noninferiority for single-agent durvalumab as well. However, this combination did not improve progression-free survival and objective response rates with this combination did not seem significantly different from that with single-agent durvalumab. Although there are still knowledge gaps in this rapidly changing landscape, we will address some of the important questions relevant to making therapeutic decisions in the management of advanced hepatocellular carcinoma in the modern era on the basis of our current knowledge of the safety and efficacy of these evolving regimens. The goal is to provide clinicians with the knowledge needed to optimize outcomes for their patients.
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Affiliation(s)
- Anthony C Bejjani
- Hematology-Oncology Division, Department of Medicine, Greater Los Angeles VA Healthcare Center, UCLA Medical Center, Jonsson Comprehensive Cancer Center, Los Angeles, CA
| | - Richard S Finn
- Division of Hematology/Oncology, Department of Medicine, Geffen School of Medicine at UCLA, Santa Monica, CA
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20
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Zhao Y, Kong LX, Feng FS, Yang J, Wei G. A simple CD4+ T cells to FIB-4 ratio for evaluating prognosis of BCLC-B hepatocellular carcinoma: a retrospective cohort study. BMC Cancer 2022; 22:311. [PMID: 35321670 PMCID: PMC8941753 DOI: 10.1186/s12885-022-09433-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 03/21/2022] [Indexed: 02/08/2023] Open
Abstract
Introduction Immunotherapy has become a new therapy for advanced hepatocellular carcinoma (HCC); however, its treatment results are considerably different. CD4+ T cells (CD4+) are the key to immunotherapy, but patients with HCC that have low CD4+ are rarely observed for clinical evidence. Hepatitis B virus-related HCC is often accompanied by cirrhosis and portal hypertension; therefore, CD4+ tend to be relatively low in number. TACE is the standard treatment for Barcelona Clinic Liver Cancer (BCLC)-B HCC, which may further reduce the number of CD4 + . Methods This retrospective cohort study further reduced CD4+ by including patients with human immunodeficiency virus (HIV) to observe the relationship between CD4+ and Chronic hepatitis B virus (CHB) induced HCC. A total of 170 BCLC-B HCC patients (42 HIV+) were included. Univariate and multivariate analyses, and artificial neural networks (ANNs) were used to evaluate the independent risk factors for the two-year survival. Results The statistical analysis of the two-year survival rate showed that the main factors influencing survival were liver function and immune indices, including CD4+, platelet, alanine aminotransferase, aspartate aminotransferase, aspartate aminotransferase-to-platelet ratio index, and fibrosis-4 (FIB-4) (P < 0.05). Compared with that in other indices, in logistic and ANN multivariate analysis, CD4 + -to-FIB-4 ratio (CD4+/FIB-4) had the highest importance with 0.716 C-statistic and 145.93 cut-off value. In terms of overall survival rate, HIV infection was not a risk factor (P = 0.589); however, CD4+/FIB-4 ≤ 145.93 significantly affected patient prognosis (P = 0.002). Conclusion HIV infection does not affect the prognosis of BCLC-B HCC, but CD4+ have a significant predictive value. CD4+ played a vital role in HCC and this deserves the attention from physicians. Further, the CD4+/FIB-4 is a clinically valuable effective prognostic indicator for these patients.
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Affiliation(s)
- Yong Zhao
- Department of General Surgery, Chengdu Public Health Clinical Medical Center, Sichuan Province, Chengdu, China
| | - Ling Xiang Kong
- Department of Liver Surgery and Liver transplantation Laboratory, West China Hospital of Sichuan University, Sichuan Province, Chengdu, China
| | - Feng Shi Feng
- Department of General Surgery, Chengdu Public Health Clinical Medical Center, Sichuan Province, Chengdu, China
| | - Jiayin Yang
- Department of Liver Surgery and Liver transplantation Laboratory, West China Hospital of Sichuan University, Sichuan Province, Chengdu, China.
| | - Guo Wei
- Department of General Surgery, Chengdu Public Health Clinical Medical Center, Sichuan Province, Chengdu, China.
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21
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Hao X, Sun G, Zhang Y, Kong X, Rong D, Song J, Tang W, Wang X. Targeting Immune Cells in the Tumor Microenvironment of HCC: New Opportunities and Challenges. Front Cell Dev Biol 2021; 9:775462. [PMID: 34869376 PMCID: PMC8633569 DOI: 10.3389/fcell.2021.775462] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 10/19/2021] [Indexed: 12/17/2022] Open
Abstract
Immune associated cells in the microenvironment have a significant impact on the development and progression of hepatocellular carcinoma (HCC) and have received more and more attention. Different types of immune-associated cells play different roles, including promoting/inhibiting HCC and several different types that are controversial. It is well known that immune escape of HCC has become a difficult problem in tumor therapy. Therefore, in recent years, a large number of studies have focused on the immune microenvironment of HCC, explored many mechanisms worth identifying tumor immunosuppression, and developed a variety of immunotherapy methods as targets, laying the foundation for the final victory in the fight against HCC. This paper reviews recent studies on the immune microenvironment of HCC that are more reliable and important, and provides a more comprehensive view of the investigation of the immune microenvironment of HCC and the development of more immunotherapeutic approaches based on the relevant summaries of different immune cells.
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Affiliation(s)
- Xiaopei Hao
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, China
| | - Guangshun Sun
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yao Zhang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, China
| | - Xiangyi Kong
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, China
| | - Dawei Rong
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, China
| | - Jinhua Song
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, China
| | - Weiwei Tang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, China
| | - Xuehao Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, China
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22
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Moldogazieva NT, Zavadskiy SP, Sologova SS, Mokhosoev IM, Terentiev AA. Predictive biomarkers for systemic therapy of hepatocellular carcinoma. Expert Rev Mol Diagn 2021; 21:1147-1164. [PMID: 34582293 DOI: 10.1080/14737159.2021.1987217] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Introduction: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the third cancer-related cause of death worldwide. In recent years, several systemic therapy drugs including sorafenib, lenvatinib, regorafenib, cabozantinib, ramucicurab, nivilumab, and pembrolizumab have been approved by FDA for advanced HCC. However, their insufficient efficacy, toxicity, and drug resistance require clinically applicable and validated predictive biomarkers.Areas covered: Our review covers the recent advancements in the identification of proteomic/genomic/epigenomic/transcriptomic biomarkers for predicting HCC treatment efficacy with the use of multi-kinase inhibitors (MKIs), CDK4/6 inhibitors, and immune checkpoint inhibitors (ICIs). Alpha-fetoprotein, des-carboxyprothrombin, vascular endothelial growth factor, angiopoietin-2, and dysregulated MTOR, VEGFR2, c-KIT, RAF1, PDGFRβ have the potential of proteomic/genomic biomarkers for sorafenib treatment. Alanine aminotransferase, aspartate aminotransferase, and albumin-bilirubin grade can predict the efficacy of other MKIs. Rb, p16, and Ki-67, and genes involved in cell cycle regulation, CDK1-4, CCND1, CDKN1A, and CDKN2A have been proposed for CD4/6 inhibitors, while dysregulated TERT, CTNNB1, TP53 FGF19, and TP53 are found to be predictors for ICI efficacy.Expert opinion: There are still limited clinically applicable and validated predictive biomarkers to identify HCC patients who benefit from systemic therapy. Further prospective biomarker validation studies for HCC personalized systemic therapy are required.
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Affiliation(s)
- Nurbubu T Moldogazieva
- Laboratory of Bioinformatics, Institute of Translational Medicine and Biotechnology, I.m. Sechenov First Moscow State Medical University (Sechenov University);, Moscow, Russia
| | - Sergey P Zavadskiy
- Department of Pharmacology, Nelyubin Institute of Pharmacy, I.m. Sechenov First Moscow State Medical University (Sechenov University), Russia, Russia
| | - Susanna S Sologova
- Department of Pharmacology, Nelyubin Institute of Pharmacy, I.m. Sechenov First Moscow State Medical University (Sechenov University), Russia, Russia
| | - Innokenty M Mokhosoev
- Department of Biochemistry and Molecular Biology, N.i. Pirogov Russian National Research Medical University, Moscow, Russia
| | - Alexander A Terentiev
- Department of Biochemistry and Molecular Biology, N.i. Pirogov Russian National Research Medical University, Moscow, Russia
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23
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Immune Responses Following Locoregional Treatment for Hepatocellular Carcinoma: Possible Roles of Adjuvant Immunotherapy. Pharmaceutics 2021; 13:pharmaceutics13091387. [PMID: 34575463 PMCID: PMC8471821 DOI: 10.3390/pharmaceutics13091387] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 08/29/2021] [Accepted: 08/30/2021] [Indexed: 12/22/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a common cause of cancer-related deaths worldwide. Unlike other types of cancer, HCC can be treated with locoregional treatments (LRTs) such as radiofrequency ablation (RFA) or transarterial chemoembolization (TACE). However, recurrences following LRTs are common, and strategies to improve long-term outcomes need to be developed. The exhaustion of anti-tumor immunity in HCC has been well established in many reports and the immunomodulatory effects of LRTs (enhancement of tumor antigen-specific T cell responses after RFA, reduction of effector regulatory T cells after TACE) have also been reported in several previous studies. However, a comprehensive review of previous studies and the possible roles of immunotherapy following LRTs in HCC are not known. In this review, we discuss the immunological evidence of current clinical trials using LRTs and combined immunotherapies, and the possible role of this strategy.
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24
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Zhu L, Guo W. Combined DNA Methylation and Transcriptomic Assessments to Determine a Prognostic Model for PD-1-Negative Hepatocellular Carcinoma. Front Cell Dev Biol 2021; 9:708819. [PMID: 34458266 PMCID: PMC8385720 DOI: 10.3389/fcell.2021.708819] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 07/23/2021] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) has the highest incidence and mortality of any malignancy in the world. Immunotherapy has been a major breakthrough for HCC treatment, but immune checkpoint inhibitors (ICIs) are effective in only a small percentage of HCC patients. In the present study, we screened programmed cell death protein 1 (PD-1) -negative HCC samples, which are frequently resistant to ICIs, and identified their methylation and transcription characteristics through the assessment of differential gene methylation and gene expression. We also screened for potential targeted therapeutic drugs using the DrugBank database. Finally, we used a LASSO (least absolute shrinkage and selection operator) regression analysis to construct a prognostic model based on three differentially methylated and expressed genes (DMEGs). The results showed that ESTIMATE (Estimation of Stromal and Immune Cells in Malignant Tumors using Expression Data) scores for the tumor samples were significantly lower compared to normal sample ESTIMATE scores. In addition, we identified 31 DMEGs that were able to distinguish PD-1-negative samples from normal samples. A functional enrichment analysis showed that these genes were involved in a variety of tumor-related pathways and immune-related pathways, and the DrugBank screening identified potential therapeutic drugs. Finally, the prognostic model based on three DMEGs (UBD, CD5L, and CD213A2) demonstrated good predictive power for HCC prognosis and was verified using an independent cohort. The present study demonstrated the methylation characteristics of PD-1-negative HCC samples, identified several potential therapeutic drugs, and proposed a prognostic model based on UBD, CD5L, and CD213A2 methylation expression. In conclusion, this work provides an in-depth understanding of methylation in HCC samples that are not sensitive to ICIs.
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Affiliation(s)
- Lixu Zhu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China.,Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China
| | - Wenzhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China.,Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China
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25
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Natural Killer Cells and T Cells in Hepatocellular Carcinoma and Viral Hepatitis: Current Status and Perspectives for Future Immunotherapeutic Approaches. Cells 2021; 10:cells10061332. [PMID: 34071188 PMCID: PMC8227136 DOI: 10.3390/cells10061332] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/13/2021] [Accepted: 05/22/2021] [Indexed: 02/06/2023] Open
Abstract
Natural killer (NK) cells account for 25–50% of the total number of hepatic lymphocytes, which implicates that NK cells play an important role in liver immunity. The frequencies of both circulating and tumor infiltrating NK cells are positively correlated with survival benefit in hepatocellular cancer (HCC) and have prognostic implications, which suggests that functional impairment in NK cells and HCC progression are strongly associated. In HCC, T cell exhaustion is accompanied by the interaction between immune checkpoint ligands and their receptors on tumor cells and antigen presenting cells (APC). Immune checkpoint inhibitors (ICIs) have been shown to interfere with this interaction and have altered the therapeutic landscape of multiple cancer types including HCC. Immunotherapy with check-point inhibitors, aimed at rescuing T-cells from exhaustion, has been applied as first-line therapy for HCC. NK cells are the first line effectors in viral hepatitis and play an important role by directly eliminating virus infected cells or by activating antigen specific T cells through IFN-γ production. Furthermore, chimeric antigen receptor (CAR)-engineered NK cells and T cells offer unique opportunities to create CAR-NK with multiple specificities learning from the experience gained with CAR-T cells with potentially less adverse effects. This review focus on the abnormalities of NK cells, T cells, and their functional impairment in patients with chronic viral hepatitis, which contributes to progression to hepatic malignancy. Furthermore, we discuss and summarize recent advances in the NK cell and T cell based immunotherapeutic approaches in HCC.
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26
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Bourhis M, Palle J, Galy-Fauroux I, Terme M. Direct and Indirect Modulation of T Cells by VEGF-A Counteracted by Anti-Angiogenic Treatment. Front Immunol 2021; 12:616837. [PMID: 33854498 PMCID: PMC8039365 DOI: 10.3389/fimmu.2021.616837] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 03/04/2021] [Indexed: 12/29/2022] Open
Abstract
Vascular endothelial growth factor A is known to play a central role in tumor angiogenesis. Several studies showed that VEGF-A is also an immunosuppressive factor. In tumor-bearing hosts, VEGF-A can modulate immune cells (DC, MDSC, TAM) to induce the accumulation of regulatory T-cells while simultaneously inhibiting T-cell functions. Furthermore, VEGFR-2 expression on activated T-cells and FoxP3high regulatory T-cells also allow a direct effect of VEGF-A. Anti-angiogenic agents targeting VEGF-A/VEGFR contribute to limit tumor-induced immunosuppression. Based on interesting preclinical studies, many clinical trials have been conducted to investigate the efficacy of anti-VEGF-A/VEGFR treatments combined with immune checkpoint blockade leading to the approvement of these associations in different tumor locations. In this review, we focus on the impact of VEGF-A on immune cells especially regulatory and effector T-cells and different therapeutic strategies to restore an antitumor immunity.
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Affiliation(s)
| | - Juliette Palle
- Université de Paris, PARCC, INSERM, Paris, France.,Department of GI Oncology, AP-HP, Hôpital Européen Georges-Pompidou, Paris, France
| | | | - Magali Terme
- Université de Paris, PARCC, INSERM, Paris, France
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27
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Jacobs CF, Eldering E, Kater AP. Kinase inhibitors developed for treatment of hematologic malignancies: implications for immune modulation in COVID-19. Blood Adv 2021; 5:913-925. [PMID: 33560402 PMCID: PMC7871903 DOI: 10.1182/bloodadvances.2020003768] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 12/28/2020] [Indexed: 02/07/2023] Open
Abstract
Tyrosine kinase inhibitors (TKIs) are used to target dysregulated signaling pathways in virtually all hematologic malignancies. Many of the targeted signaling pathways are also essential in nonmalignant immune cells. The current coronavirus severe acute respiratory syndrome coronavirus 2 pandemic catalyzed clinical exploration of TKIs in the treatment of the various stages of COVID-19, which are characterized by distinct immune-related complications. Most of the reported effects of TKIs on immune regulation have been explored in vitro, with different class-specific drugs having nonoverlapping target affinities. Moreover, many of the reported in vivo effects are based on artificial animal models or on observations made in symptomatic patients with a hematologic malignancy who often already suffer from disturbed immune regulation. Based on in vitro and clinical observations, we attempt to decipher the impact of the main TKIs approved or in late-stage development for the treatment of hematological malignancies, including inhibitors of Bruton's tyrosine kinase, spleen tyrosine kinase, BCR-Abl, phosphatidylinositol 3-kinase/ mammalian target of rapamycin, JAK/STAT, and FMS-like tyrosine kinase 3, to provide a rationale for how such inhibitors could modify clinical courses of diseases, such as COVID-19.
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Affiliation(s)
- Chaja F Jacobs
- Department of Experimental Immunology and
- Department of Hematology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam, The Netherlands
- Amsterdam Institute for Infection & Immunity, Amsterdam, The Netherlands; and
| | - Eric Eldering
- Department of Experimental Immunology and
- Cancer Center Amsterdam, Amsterdam, The Netherlands
- Amsterdam Institute for Infection & Immunity, Amsterdam, The Netherlands; and
- Lymphoma and Myeloma Center Amsterdam, Amsterdam, The Netherlands
| | - Arnon P Kater
- Department of Hematology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam, The Netherlands
- Amsterdam Institute for Infection & Immunity, Amsterdam, The Netherlands; and
- Lymphoma and Myeloma Center Amsterdam, Amsterdam, The Netherlands
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28
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Fountzilas C, Evans R, Alaklabi S, Iyer R. Immunotherapy in hepatocellular cancer. Adv Cancer Res 2021; 149:295-320. [PMID: 33579426 DOI: 10.1016/bs.acr.2020.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Hepatocellular carcinoma is a major global healthcare problem. It is closely related to chronic liver inflammation triggered by viral and non-viral insults, that can lead to exhaustion of effector T-cells. Furthermore, immune cells within the normal liver itself tend to be more immune tolerant in order to support the essential function of liver as the first processing station of molecules absorbed in the gastrointestinal tract. Dysregulation of the immune system is a hallmark of hepatocellular carcinoma. Immune checkpoint inhibitors targeting the programmed death-1 axis have shown promise as monotherapy in the management of advanced disease, but still most patients do not benefit from treatment. Most recently, combinatorial strategies with other immune checkpoint inhibitors or agents targeting the second hallmark of hepatocellular carcinoma, i.e., the activation of the vascular epithelial growth factor axis have been studied. In this paper, we review the current immunotherapy approaches for hepatocellular carcinoma and discuss novel immunotherapy approaches and optimal patient selection.
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Affiliation(s)
| | - Rachel Evans
- Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Sabah Alaklabi
- Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Renuka Iyer
- Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States.
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Sung PS, Shin EC. Immunological Mechanisms for Hepatocellular Carcinoma Risk after Direct-Acting Antiviral Treatment of Hepatitis C Virus Infection. J Clin Med 2021; 10:E221. [PMID: 33435135 PMCID: PMC7827927 DOI: 10.3390/jcm10020221] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 01/05/2021] [Accepted: 01/06/2021] [Indexed: 02/08/2023] Open
Abstract
Direct-acting antiviral agents (DAAs) that allow for rapid clearance of hepatitis C virus (HCV) may evoke immunological changes. Some cases of rapid de novo hepatocellular carcinoma (HCC) development or early recurrence of HCC after DAA treatment have been reported. During chronic HCV infection, natural killer (NK) cells exhibited a deviant functional phenotype with decreased production of antiviral cytokines and increased cytotoxicity; however, DAA treatment rapidly decreased their cytotoxic function. Effective DAA therapy also suppressed the intrahepatic activation of macrophages/monocytes. This was followed by a decrease in mucosal-associated invariant T (MAIT) cell cytotoxicity without normalization of cytokine production. Rapid changes in the phenotypes of NK and MAIT cells after DAA treatment may attenuate the cytotoxicity of these cells against cancer cells. Moreover, DAA treatment did not normalize the increased frequencies of regulatory T cells even after clearance of HCV infection. Thus, the persistently increased frequency of regulatory T cells may contribute to a local immunosuppressive milieu and hamper the clearance of cancer cells. This review will focus on recent studies describing the changes in innate and adaptive immune responses after DAA treatment in patients with chronic HCV infection in the context of de novo occurrence or recurrence of HCC.
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Affiliation(s)
- Pil Soo Sung
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul 06591, Korea
- The Catholic Liver Research Center, The Catholic University of Korea, Seoul 06591, Korea
| | - Eui-Cheol Shin
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
- The Center for Epidemic Preparedness, KAIST Institute, Daejeon 34141, Korea
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Bian J, Lin J, Long J, Yang X, Yang X, Lu X, Sang X, Zhao H. T lymphocytes in hepatocellular carcinoma immune microenvironment: insights into human immunology and immunotherapy. Am J Cancer Res 2020; 10:4585-4606. [PMID: 33415021 PMCID: PMC7783774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 11/12/2020] [Indexed: 06/12/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is characterized by poor outcome and shows limited drug-response in clinical trials. Tumor immune microenvironment (TIME) exerts a strong selection pressure on HCC, leading to HCC evolvement and recurrence after multiple therapies. T cell-mediated immunoreaction during cancer surveillance and clearance is central in cancer immunity. Heterogenous T cell subsets play multiple roles in HCC development and progression. The re-educated T cells in TIME usually lead to deteriorated T cell response and tumor progression. Investigation into immune system dysregulation during HCC development will shed light on how to turn immune suppressive state to immune activation and induce more efficient immune response. Emerging T cell-based treatment such as cancer vaccines, CAR-T cell therapy, adoptive cell therapy, and immune checkpoint inhibitors (ICIs), have been proved to cause tumor regression in some clinical and preclinical trials. In this review, we focused on recent studies that explored T cells involved in HCC and how they affect the course of disease. We also briefly outlined current T cell-based immunotherapies in HCC.
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Affiliation(s)
- Jin Bian
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC)Beijing, China
| | - Jianzhen Lin
- Pancreas Center, First Affiliated Hospital of Nanjing Medical UniversityNanjing, China
- Pancreas Institute, Nanjing Medical UniversityNanjing, Jiangsu, China
| | - Junyu Long
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC)Beijing, China
| | - Xu Yang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC)Beijing, China
| | - Xiaobo Yang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC)Beijing, China
| | - Xin Lu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC)Beijing, China
| | - Xinting Sang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC)Beijing, China
| | - Haitao Zhao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC)Beijing, China
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Sangro B, Melero I, Wadhawan S, Finn RS, Abou-Alfa GK, Cheng AL, Yau T, Furuse J, Park JW, Boyd Z, Tang H(T, Shen Y, Tschaika M, Neely J, El-Khoueiry A. Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma. J Hepatol 2020; 73:1460-1469. [PMID: 32710922 PMCID: PMC7751218 DOI: 10.1016/j.jhep.2020.07.026] [Citation(s) in RCA: 303] [Impact Index Per Article: 60.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 06/25/2020] [Accepted: 07/03/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Nivolumab, a programmed death (PD)-1 (PD-1) inhibitor, led to durable responses, manageable safety, and increased survival in patients with advanced hepatocellular carcinoma (HCC). In our retrospective analysis, we studied the immunobiology and potential associations between biomarkers and outcomes with nivolumab in HCC. METHODS Fresh and archival tumour samples from dose-escalation and dose-expansion phases of the CheckMate 040 trial were analysed by immunohistochemistry and RNA sequencing to assess several inflammatory gene expression signatures, including CD274 (PD-ligand 1 [PD-L1]), CD8A, LAG3, and STAT1. Biomarkers were assessed for association with clinical outcomes (best overall response by blinded independent central review per RECIST v1.1 and overall survival [OS]). RESULTS Complete or partial tumour responses were observed in PD-L1-positive and PD-L1-negative patients treated with nivolumab monotherapy. Median OS was 28.1 (95% CI 18.2-n.a.) vs. 16.6 months (95% CI 14.2-20.2) for patients with tumour PD-L1 ≥1% vs. <1% (p = 0.03). Increased CD3 and CD8 showed a non-significant trend towards improved OS (both p = 0.08), and macrophage markers were not associated with OS. Tumour PD-1 and PD-L1 expression were associated with improved OS (p = 0.05 and p = 0.03, respectively). An inflammatory gene signature consisting of 4 genes was associated with improved objective response rate (p = 0.05) and OS (p = 0.01). CONCLUSIONS PD-1 and PD-L1 expression, biomarkers of inflammation, and inflammatory gene signatures trended with improved survival and response. While further confirmation within a larger phase III trial is needed to evaluate predictive value of these biomarkers, these exploratory analyses suggest that anti-tumour immune response may play a role in the treatment benefit of nivolumab in HCC. LAY SUMMARY Certain tests may be used to provide a picture of how a tumour is escaping the immune system, allowing it to continue to grow and create more tumours. Therapies such as nivolumab are designed to help the immune system fight the tumour. These tests may be used to determine how effective such therapies will be in the treatment of advanced liver cancer. NCT NUMBER NCT01658878.
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Affiliation(s)
- Bruno Sangro
- Clinica Universidad de Navarra-IDISNA and CIBEREHD, Pamplona, Spain.
| | | | | | | | - Ghassan K. Abou-Alfa
- Memorial Sloan Kettering Cancer Center, New York, NY, USA,Weill Medical College at Cornell University, New York, NY, USA
| | | | - Thomas Yau
- University of Hong Kong, Hong Kong, China
| | - Junji Furuse
- Kyorin University Faculty of Medicine, Tokyo, Japan
| | | | | | | | - Yun Shen
- Bristol Myers Squibb, Princeton, NJ, USA
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Terashima T, Honda M, Toyama T, Shimakami T, Shimizu R, Takatori H, Arai K, Kawaguchi K, Kitamura K, Yamashita T, Sakai Y, Yamashita T, Mizukoshi E, Kaneko S. IL-28B variant as a predictor in patients with advanced hepatocellular carcinoma treated with hepatic arterial infusion chemotherapy. J Gastroenterol Hepatol 2020; 35:1813-1820. [PMID: 32180251 DOI: 10.1111/jgh.15035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Revised: 02/28/2020] [Accepted: 03/09/2020] [Indexed: 01/10/2023]
Abstract
BACKGROUND AND AIM Single-nucleotide polymorphisms (SNPs) of the interleukin-28B (IL-28B) gene are associated with the effectiveness of interferon therapy for chronic hepatitis C infection. Whether the IL-28B genotype affects the course of treatment and the outcomes of patients with advanced hepatocellular carcinoma (HCC) is unknown. METHODS We detected the IL-28B SNP (rs8099917) using TaqMan PreDesigned SNP Genotyping Assays to assess the effects of the IL-28B genotype on treatment efficacy and prognosis of patients with advanced HCC treated with hepatic arterial infusion chemotherapy (HAIC) between September 2003 and January 2015. RESULTS The study included 154 patients who received HAIC to treat advanced HCC, among which 27 (17.5%) had the minor genotype, IL-28B rs8099917 TG or GG, and the others had the major genotype, IL-28B rs8099917 TT. The objective response rates of patients with the minor or major genotype were 51.9% and 29.1% (P = 0.022), respectively. Multivariate analysis revealed that the minor genotype remained associated with the response to HAIC (odds ratio, 2.620; P = 0.026). The median overall survival of patients with major or minor genotypes was 14.1 and 16.9 months, respectively, and the overall survival of patients with the major genotype was significantly shorter than that of patients with the minor genotype (P = 0.027). Multivariate analysis revealed that the major genotype was an independent, unfavorable prognostic factor (hazard ratio, 1.720; P = 0.024). Consistent results were obtained in selected populations after propensity score matching analysis. CONCLUSIONS The IL-28B SNP (rs8099917) will serve as a useful predictor of the outcomes of patients with advanced HCC treated with HAIC.
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Affiliation(s)
- Takeshi Terashima
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
| | - Masao Honda
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
| | - Tadashi Toyama
- Innovative Clinical Research Center, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Tetsuro Shimakami
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
| | - Ryogo Shimizu
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
| | - Hajime Takatori
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
| | - Kuniaki Arai
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
| | - Kazunori Kawaguchi
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
| | - Kazuya Kitamura
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
| | - Taro Yamashita
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
| | - Yoshio Sakai
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
| | - Tatsuya Yamashita
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
| | - Eishiro Mizukoshi
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
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Kalathil SG, Wang K, Hutson A, Iyer R, Thanavala Y. Tivozanib mediated inhibition of c-Kit/SCF signaling on Tregs and MDSCs and reversal of tumor induced immune suppression correlates with survival of HCC patients. Oncoimmunology 2020; 9:1824863. [PMID: 33101775 PMCID: PMC7553535 DOI: 10.1080/2162402x.2020.1824863] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
The immune modulatory effect of tivozanib, a tyrosine kinase inhibitor, and the underlying immune mechanisms impacting survival of HCC patients have not been investigated. Pre-clinical studies have shown that tivozanib reduces Tregs and MDSCs accumulation through inhibition of c-Kit/SCF axis. We rationalized that c-Kit/SCF axis antagonism by tivozanib may reverse tumor-induced immune suppression in HCC patients. The frequency of circulating Tregs, MDSCs, CTLA-4+Tregs, PD-1+T cells, c-Kit+pERK-2+Tregs, and c-Kit+pERK-2+MDSCs were quantified in HCC patients at baseline and two time points during tivozanib treatment. We report for the first time that reduction in Tregs after tivozanib treatment and increased levels of baseline CD4+PD-1+T cells correlated with significant improvement in overall survival (OS) of the patients and these signatures may be potential biomarkers of prognostic significance. This immune modulation resulted from tivozanib-mediated blockade of c-Kit/SCF signaling, impacting ERK2 phosphorylation on Tregs and MDSCs. Low pre-treatment CD4+T cells: Treg ratio and reduction in the frequencies of Foxp3+c-Kit+pERK+Tregs after tivozanib treatment correlated significantly with progression free survival. In a comparative analysis of tivozanib vs sorafenib treatment in HCC patients, we demonstrate that decrease in the baseline numbers or frequencies of Foxp3+Tregs, MDSCs and exhausted T cells was significantly greater following tivozanib treatment. Additionally, greater increase in CD4+T cell: Treg ratio after tivozanib treatment was associated with significant improvement in OS compared to sorafenib treatment, highlighting the greater efficacy of tivozanib. These insights may help identify patients who likely would benefit from c-Kit/SCF antagonism and inform efforts to improve the efficacy of tivozanib in combination with immunotherapy.
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Affiliation(s)
- Suresh Gopi Kalathil
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, USA
| | - Katy Wang
- Department of Biostatistics & Bioinformatics Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, USA
| | - Alan Hutson
- Department of Biostatistics & Bioinformatics Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, USA
| | - Renuka Iyer
- Medicine, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, USA
| | - Yasmin Thanavala
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, USA
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Chinnadurai R, Scandolara R, Alese OB, Arafat D, Ravindranathan D, Farris AB, El-Rayes BF, Gibson G. Correlation Patterns Among B7 Family Ligands and Tryptophan Degrading Enzymes in Hepatocellular Carcinoma. Front Oncol 2020; 10:1632. [PMID: 33014820 PMCID: PMC7494748 DOI: 10.3389/fonc.2020.01632] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 07/27/2020] [Indexed: 12/30/2022] Open
Abstract
Mechanisms of dysfunctional T cell immunity in Hepatocellular Carcinoma (HCC) need to be well defined. B7 family molecules provide both co-stimulatory and co-inhibitory signals to T cells while tryptophan degrading enzymes like Indoleamine 2,3 dioxygenase (IDO) and Tryptophan 2,3 Dioxygenase (TDO) mediate tumor immune tolerance. It is necessary to identify their in situ correlative expression, which informs targets for combined immunotherapy approaches. We investigated B7 family molecules, IDO, TDO and immune responsive effectors in the tumor tissues of patients with HCC (n = 28) using a pathway-focused quantitative nanoscale chip real-time PCR. Four best correlative expressions, namely (1) B7-1 & PD-L2, (2) B7-H2 & B7-H3, (3) B7-2 & PD-L1, (4) PD-L1 & PD-L2, were identified among B7 family ligands, albeit they express at different levels. Although TDO expression is higher than IDO, PD-L1 correlates only with IDO but not TDO. Immune effector (Granzyme B) and suppressive (PD-1 and TGF-β) genes correlate with IDO and B7-1, B7-H5, PD-L2. Identification of the in situ correlation of PD-L1, PD-L2 and IDO suggest their cumulative immuno suppressive role in HCC. The distinct correlations among B7-1, B7-2, B7-H2, and B7-H3, correlation of PD-1 with non-cognate ligands such as B7-1 and B7-H5, and correlation of tumor lytic enzyme Granzyme B with IDO and PD-L2 suggest that HCC microenvironment is complexly orchestrated with both stimulatory and inhibitory molecules which together neutralize and blunt anti-HCC immunity. Functional assays demonstrate that both PDL-1 and IDO synergistically inhibit T cell responses. Altogether, the present data suggest the usage of combined immune checkpoint blocking strategies targeting co-inhibitory B7 molecules and IDO for HCC management.
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Affiliation(s)
- Raghavan Chinnadurai
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA, United States
| | - Rafaela Scandolara
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA, United States
| | - Olatunji B Alese
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, United States
| | - Dalia Arafat
- School of Biology, Georgia Institute of Technology, Atlanta, GA, United States
| | - Deepak Ravindranathan
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, United States
| | - Alton B Farris
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, United States
| | - Bassel F El-Rayes
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, United States
| | - Greg Gibson
- School of Biology, Georgia Institute of Technology, Atlanta, GA, United States
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Immunologic Features of Patients With Advanced Hepatocellular Carcinoma Before and During Sorafenib or Anti-programmed Death-1/Programmed Death-L1 Treatment. Clin Transl Gastroenterol 2020; 10:e00058. [PMID: 31295151 PMCID: PMC6708670 DOI: 10.14309/ctg.0000000000000058] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Today, a promising treatment strategy is focused on the enhancement of antitumor immune responses by immune checkpoint modification. However, as only 20% of patients with HCC are responders, identification of predictive factors is urgently required. Therefore, for the first time, the features of the intrahepatic and circulating immune system in patients with advanced-stage HCC, before and during the treatment, were analyzed. METHODS We collected fresh HCC biopsies, along with adjacent tumor-free liver tissues and peripheral blood samples, from 21 patients with advanced HCC. Furthermore, we performed an extensive immunomonitoring of patients with HCC treated with sorafenib or programmed death (PD)-1/PD-L1 pathway blockade using multiparametric flow cytometry. RESULTS We observed that regardless of the treatment, low baseline intratumoral CD4/CD8 T-cell ratio was associated with better overall survival (P = 0.0002). The baseline frequency of intratumoral PD-1 CD8 T cells was significantly lower in patients responding to sorafenib treatment than in the nonresponders (P = 0.0117), and the frequency of circulating PD-1 T cells increased with tumor progression (P = 0.0329). By contrast, responders to PD-1/PD-L1 pathway blockade showed a trend of high baseline frequency of intratumoral PD-1 CD8 T cells. Moreover, we observed a trend of LAG3 and TIM3 upregulation on circulating T cells in nonresponding patients to PD-1/PD-L1 pathway blockade. DISCUSSION Immunosuppressive state, characterized by an enhanced intratumoral CD4/CD8 T-cell ratio, was associated with poor prognosis. Additionally, our results suggest that the frequency of intratumoral PD-1 CD8 T cells may serve as a biomarker to identify which individuals will benefit from which treatment and support the use of combination strategies.
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Huang C, Li H, Feng Y, Li X, Zhang Z, Jiang C, Wang J, Yang C, Fu Y, Mu M, Zhao S, Wang Z, Kuang Y, Hou H, Wang Y, Guo W, Xu J, Yang H, Zhou L, Tong A, Guo G. Combination therapy with B7H3-redirected bispecific antibody and Sorafenib elicits enhanced synergistic antitumor efficacy. Theranostics 2020; 10:10498-10512. [PMID: 32929362 PMCID: PMC7482810 DOI: 10.7150/thno.49480] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Accepted: 08/05/2020] [Indexed: 02/05/2023] Open
Abstract
Rationale: Current traditional treatment options are frequently ineffective to fight against ovarian cancer due to late diagnosis and high recurrence. Therefore, there is a vital need for the development of novel therapeutic agents. B7H3, an immune checkpoint protein, is highly expressed in various cancers, representing it a promising target for cancer immunotherapy. Although targeting B7H3 by bispecific T cell-engaging antibodies (BiTE) has achieved successes in hematological malignancies during recent years, attempts to use them for the treatment of solid cancers are less favorable, in part due to the heterogeneity of tumors. Sorafenib is an unselective inhibitor of multiple kinases currently being tested in clinical trials for several tumors, including ovarian cancer which showed limited activity and inevitable side effect for ovarian cancer treatment. However, it is able to enhance antitumor immune response, which indicates sorafenib may improve the efficiency of immunotherapy. Methods: We evaluated the expression of B7H3 in ovarian cancer using online database and validated its expression of tumor tissues by immunohistochemistry staining. Then, B7H3 expression and the effects of sorafenib on ovarian cancer cell lines were determined by flow cytometry. In addition, 2D and 3D ovarian cancer models were established to test the combined therapeutic effect in vitro. Finally, the efficiency of B7H3×CD3 BiTE alone and its combination with sorafenib were evaluated both in vitro and in vivo. Results: Our data showed that B7H3 was highly expressed in ovarian cancer compared with normal samples. Treatment with sorafenib inhibited ovarian cancer cell proliferation and induced a noticeable upregulation of B7H3 expression level. Further study suggested that B7H3×CD3 BiTE was effective in mediating T cell killing to cancer cells. Combined treatment of sorafenib and B7H3×CD3 BiTE had synergistic anti-tumor effects in ovarian cancer models. Conclusions: Overall, our study indicates that combination therapy with sorafenib and B7H3×CD3 BiTE may be a new therapeutic option for the further study of preclinical treatment of OC.
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Cao D, Chen MK, Zhang QF, Zhou YF, Zhang MY, Mai SJ, Zhang YJ, Chen MS, Li XX, Wang HY. Identification of immunological subtypes of hepatocellular carcinoma with expression profiling of immune-modulating genes. Aging (Albany NY) 2020; 12:12187-12205. [PMID: 32544882 PMCID: PMC7343492 DOI: 10.18632/aging.103395] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 05/20/2020] [Indexed: 12/24/2022]
Abstract
Recent studies demonstrate that immune checkpoint inhibitor (ICI) therapy has achieved success in many types of advanced cancers including advanced hepatocellular carcinoma (HCC). However, ICI therapy is beneficial in only some HCC patients, suggesting that immune-responses are highly variable in HCCs. Therefore, understanding the immune status in HCC microenvironment will facilitate ICI immunotherapy and guide patient selection for the therapy. In this study, we first analyzed the expression profile of immune-modulating genes and their relationship with survival of HCC patients using the data downloaded from The Cancer Genome Atlas - Liver Hepatocellular Carcinoma (TCGA-LIHC) database, and found that the higher expressions of CD276 (B7-H3) and CD47 were significantly associated with poor survival. Then we identified 4 immune subtypes of HCCs with different survivals by using the combination expression of B7-H3 (or CD47) and CD8. Patients with B7-H3low/CD8high or CD47low/CD8high have the best survival while ones with B7-H3high/CD8low or CD47high/CD8low have the worst survival. The 4 immune subtypes were validated in another 72 HCC patients obtained from South China. In conclusion, our findings suggest that HCC patient prognosis is associated with immunophenotypes by T cell infiltration (CD8 expression) and the expression of the adaptive immune resistance gene (B7-H3 or CD47), and this immune classification system will facilitate HCC patient selection for ICI immunotherapy.
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Affiliation(s)
- Di Cao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Meng-Ke Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Qing-Feng Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yu-Feng Zhou
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Mei-Yin Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Shi-Juan Mai
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yao-Jun Zhang
- Department of Hepatobiliary Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Min-Shan Chen
- Department of Hepatobiliary Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Xiao-Xing Li
- Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Hui-Yun Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
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Zhang X, Fu X, Li T, Yan H. The prognostic value of myeloid derived suppressor cell level in hepatocellular carcinoma: A systematic review and meta-analysis. PLoS One 2019; 14:e0225327. [PMID: 31790437 PMCID: PMC6886785 DOI: 10.1371/journal.pone.0225327] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 11/01/2019] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND AND AIMS Many studies have investigated the association between the level of myeloid derived suppressor cells (MDSCs) and clinical features and prognosis of hepatocellular carcinoma (HCC), but the results remain controversial. This systematic review and meta-analysis was conducted to summarize all available data and estimate the relationship. METHODS A comprehensive literature review was carried out using Medline, Embase and Web of Science database through December 2018 to identify relevant studies. The standardized mean difference (SMD) and the hazard ratio (HR) with 95% confidence interval (CI) were utilized for evaluating continuous outcomes and survival analysis, respectively. All statistical analyses were performed by STATA 14.0 software. RESULTS A total of 13 studies with 1002 HCC patients were included in the meta-analysis. Overall, the proportion of MDSCs in HCC patients was higher than that in healthy controls (SMD = 4.49, 95% CI = 2.53-6.46, P<0.001), and patients with chronic liver disease (SMD = 3.41, 95% CI = 1.58-5.24, P<0.001). Subgroup analysis based on the phenotypes of MDSCs and geographical areas showed similar results. However, the frequency of MDSCs was not affected by the treatment with conventional approaches for HCC (SMD = -0.25, 95% CI = -0.57-0.06, P = 0.119). Moreover, increased MDSCs level was significantly associated with poorer overall survival (HR = 2.36, 95% CI = 1.70-3.29, P<0.001) and recurrence-free survival (HR = 2.72, 95% CI = 1.70-4.35, P<0.001), but not significantly correlated with any clinicopathological parameters. CONCLUSION The results of this systematic review suggest that elevated MDSCs level appears to be associated with an increased risk for disease progression and poor prognosis for HCC.
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Affiliation(s)
- Xinyu Zhang
- Graduate College of Hebei Medical University, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xin Fu
- Graduate College of Hebei Medical University, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Tianyu Li
- Graduate College of Hebei Medical University, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Huimin Yan
- Clinical Research Center, Shijiazhuang Fifth Hospital, Shijiazhuang, Hebei, China
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The role of vascular endothelial growth factor in the hypoxic and immunosuppressive tumor microenvironment: perspectives for therapeutic implications. Med Oncol 2019; 37:2. [PMID: 31713115 DOI: 10.1007/s12032-019-1329-2] [Citation(s) in RCA: 153] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 10/30/2019] [Indexed: 12/12/2022]
Abstract
The microvasculature and immune cells are major components of the tumor microenvironment (TME). Hypoxia plays a pivotal role in the TME through hypoxia-inducible factor 1-alpha (HIF-1α) which upregulates vascular endothelial growth factor (VEGF). VEGF, an angiogenesis stimulator, suppresses tumor immunity by inhibiting the maturation of dendritic cells, and induces immunosuppressive cells such as regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells. HIF-1α directly induces immune checkpoint molecules. VEGF/VEGF receptor (VEGFR)-targeted therapy as a cancer treatment has not only anti-angiogenic effects, but also immune-supportive effects. Anti-angiogenic therapy has the potential to change the immunological "cold tumors" into the "hot tumors". Glioblastoma (GB) is a hypervascular tumor with high VEGF expression which leads to development of an immuno suppressive TME. Therefore, in the last decade, several combination immunotherapies with anti-angiogenic agents have been developed for numerous tumors including GBs. In particular, combination therapy with an immune checkpoint inhibitor and VEGF/VEGFR-targeted therapy has been suggested as a synergic treatment strategy that may show favorable changes in the TME. In this article, we discuss the cross talk among immunosuppressive cells exposed to VEGF in the hypoxic TME of GBs. Current efficient combination strategies using VEGF/VEGFR-targeted therapy are reviewed and proposed as novel cancer treatments.
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Sanghera C, Teh JJ, Pinato DJ. The systemic inflammatory response as a source of biomarkers and therapeutic targets in hepatocellular carcinoma. Liver Int 2019; 39:2008-2023. [PMID: 31433891 DOI: 10.1111/liv.14220] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Revised: 08/10/2019] [Accepted: 08/13/2019] [Indexed: 12/12/2022]
Abstract
The pathogenesis of hepatocellular carcinoma (HCC) strongly relates to inflammation, with chronic up-regulation of pro-inflammatory mediators standing as a potential unifying mechanism that underscores the origin and progression of HCC independent of aetiology. Activation of the diverse pro-inflammatory mediators either within the tumour or its microenvironment is part of an active cross-talk between the progressive HCC and the host, which is known to influence clinical outcomes including recurrence after radical treatments and long-term survival. A number of clinical biomarkers to measure the severity of cancer-related inflammation are now available, most of which emerge from routine blood parameters including neutrophil, lymphocyte, platelet counts, as well as albuminaemia and C-reactive protein levels. In this review, we summarise the body of evidence supporting the biologic qualification of inflammation-based scores in HCC and review their potential in facilitating the prognostic assessment and treatment allocation in the individual patient. We also discuss the evidence to suggest modulation of tumour-promoting inflammation may act as a source of novel therapeutic strategies in liver cancer.
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Affiliation(s)
| | - Jhia J Teh
- Department of Medicine, Imperial College London, London, UK
| | - David J Pinato
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK
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Afifi AM, El-Husseiny AM, Tabashy RH, Khalil MA, El-Houseini ME. Sorafenib- Taurine Combination Model for Hepatocellular Carcinoma Cells: Immunological Aspects. Asian Pac J Cancer Prev 2019; 20:3007-3013. [PMID: 31653148 PMCID: PMC6982677 DOI: 10.31557/apjcp.2019.20.10.3007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Indexed: 12/29/2022] Open
Abstract
Sorafenib (Sor) is a multi-kinase inhibitor. It is recommended for the treatment of advanced hepatocellular carcinoma (HCC). However, Sor has severe and marked side effects. On the other hand, taurine (Tau) has been shown to enhance the therapeutic effects of cancer chemotherapy and also to enhance the function of leukocytes. Here, we aimed to investigate the enhancing efficacy of Sor as well as minimizing its marked side effects by using Tau in combination in an immunological aspect. We evaluated the influence of Sor and Tau combination on the expression pattern of FOXP3 gene in HepG2 cells compared to peripheral blood mononuclear leukocytes (PBMCs) as control normal cells. Also, the levels of TGF-β and IL-10 released in culture media of both cells were determined. Our results revealed that, Tau reduced cytotoxicity of Sor on PBMC indicated by lactic dehyrogenase (LDH) release assay. In addition, Sor-Tau combination led to FOXP3 down-regulation in hepatic cancer cells (HepG2). The results showed also that, TGF-β levels decreased significantly in their culture media. In contrary, the cytokine increased in PBMCs culture media. Moreover, IL-10 was significantly elevated in the culture media of both cells. This study could open new avenues for the improvement of therapeutic efficacy of Sorafenib treated HCC patients by using Tau in combination.
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Affiliation(s)
- Ahmed M Afifi
- Department of Zoology, Faculty of Science, Cairo University, Cairo, Egypt
| | - Ahmed M El-Husseiny
- Department of Zoology, Faculty of Science, Cairo University, Cairo, Egypt.,Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Reda H Tabashy
- Department of Diagnostic Radiology, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Mohamed A Khalil
- Department of Clinical Pathology, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Motawa E El-Houseini
- Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo, Egypt
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42
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Noda Y, Kawaguchi T, Korenaga M, Yoshio S, Komukai S, Nakano M, Niizeki T, Koga H, Kawaguchi A, Kanto T, Torimura T. High serum interleukin-34 level is a predictor of poor prognosis in patients with non-viral hepatocellular carcinoma. Hepatol Res 2019; 49:1046-1053. [PMID: 30993774 DOI: 10.1111/hepr.13350] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2019] [Revised: 04/10/2019] [Accepted: 04/11/2019] [Indexed: 12/30/2022]
Abstract
AIMS We aimed to investigate the impact of interleukin (IL)-34 and YKL-40, regulators of hepatic fibrosis and tumor growth, on the prognosis of patients with non-viral hepatocellular carcinoma (HCC). METHODS We enrolled 159 non-viral HCC patients (age, 70.8 ± 8.5 years; female/male, 43/116). Of these, 86 patients were alive and 73 patients had died at the censor time point. Serum IL-34 and YKL-40 levels were quantified by enzyme-linked immunosorbent assay. Patients were stratified by the median level of serum IL-34 to examine its effect on survival. Multivariate analysis and random forest analysis were used to evaluate the impact of IL-34 and YKL-40 on the prognosis of non-viral HCC patients. RESULTS Interleukin-34 (hazard ratio [HR] 1.30; 95% confidence interval [CI], 1.13-1.49; P ≤ 0.01), tumor size (HR 1.63; 95% CI, 1.37-1.94; P ≤ 0.01), and tumor number (HR 1.53; 95% CI, 1.25-1.87; P ≤ 0.01) were independent predictive factors for survival. Furthermore, the survival rates were significantly lower in the high IL-34 group than in the low IL-34 group (5-year survival rates, 34.7% vs. 59.8%, respectively; P < 0.05). In the random forest analysis for survival, IL-34 was the third-highest ranking factor, following tumor size and number. In a stratification analysis, serum α-fetoprotein level and Fibrosis-4 index were independent positive risk factors for high serum IL-34 level. YKL-40 was not associated with prognosis in either the multivariate or random forest analysis. CONCLUSION Interleukin-34 was an independent factor for survival of non-viral HCC patients. Interleukin-34 might be associated with prognosis through tumor and hepatic fibrosis factors.
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Affiliation(s)
- Yu Noda
- Division of Gastroenterology, Kurume University School of Medicine, Kurume, Japan
| | - Takumi Kawaguchi
- Division of Gastroenterology, Kurume University School of Medicine, Kurume, Japan
| | - Masaaki Korenaga
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Sachiyo Yoshio
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Sho Komukai
- Division of Biomedical Statistics, Department of Integrated Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Masahito Nakano
- Division of Gastroenterology, Kurume University School of Medicine, Kurume, Japan
| | - Takashi Niizeki
- Division of Gastroenterology, Kurume University School of Medicine, Kurume, Japan
| | - Hironori Koga
- Division of Gastroenterology, Kurume University School of Medicine, Kurume, Japan.,Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan
| | - Atsushi Kawaguchi
- Center for Comprehensive Community Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | - Tatsuya Kanto
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Takuji Torimura
- Division of Gastroenterology, Kurume University School of Medicine, Kurume, Japan.,Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan
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Lu C, Rong D, Zhang B, Zheng W, Wang X, Chen Z, Tang W. Current perspectives on the immunosuppressive tumor microenvironment in hepatocellular carcinoma: challenges and opportunities. Mol Cancer 2019; 18:130. [PMID: 31464625 PMCID: PMC6714090 DOI: 10.1186/s12943-019-1047-6] [Citation(s) in RCA: 298] [Impact Index Per Article: 49.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Accepted: 07/18/2019] [Indexed: 12/14/2022] Open
Abstract
Incidence of hepatocellular carcinoma (HCC) is on the rise due to the prevalence of chronic hepatitis and cirrhosis. Although there are surgical and chemotherapy treatment avenues the mortality rate of HCC remains high. Immunotherapy is currently the new frontier of cancer treatment and the immunobiology of HCC is emerging as an area for further exploration. The tumor microenvironment coexists and interacts with various immune cells to sustain the growth of HCC. Thus, immunosuppressive cells play an important role in the anti-tumor immune response. This review will discuss the current concepts of immunosuppressive cells, including tumor-associated macrophages, marrow-derived suppressor cells, tumor-associated neutrophils, cancer-associated fibroblasts, and regulatory T cell interactions to actively promote tumorigenesis. It further elaborates on current treatment modalities and future areas of exploration.
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Affiliation(s)
- Chen Lu
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Dawei Rong
- Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.,Key Laboratory of Living Donor Transplantation, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China
| | - Betty Zhang
- Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Wubin Zheng
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xuehao Wang
- Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China. .,Key Laboratory of Living Donor Transplantation, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China.
| | - Ziyi Chen
- Department of General Surgery, Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu, China.
| | - Weiwei Tang
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
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Kalathil SG, Hutson A, Barbi J, Iyer R, Thanavala Y. Augmentation of IFN-γ+ CD8+ T cell responses correlates with survival of HCC patients on sorafenib therapy. JCI Insight 2019; 4:130116. [PMID: 31391334 DOI: 10.1172/jci.insight.130116] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Accepted: 06/27/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUNDSorafenib has been shown to reduce the extent of immunosuppression in patients with hepatocellular carcinoma (HCC). The rationale of this investigation was to identify biomarkers that can predict treatment efficacy of sorafenib in HCC patients and to unravel the mechanism by which sorafenib impedes immune suppression mediated by distinct immunosuppressive cell subsets.METHODSWith informed consent, blood samples were collected from 30 patients with advanced HCC, at baseline and 2 time points after initiation of sorafenib treatment. The frequency of PD-1+ T cells, ERK2 phosphorylation on flt-3+ Tregs and MDSCs, and T effector cell function were quantified by using flow cytometry.RESULTSElevated levels of CD8+Ki67+ T cells producing IFN-γ were associated with improved progression-free survival and overall survival (OS). High frequencies of these T cells were correlated with significantly reduced risk of death over time. Patients with an increased pretreatment T effector/Treg ratio showed significant improvement in OS. ERK+flt-3+ Tregs and MDSCs were significantly decreased after sorafenib therapy. Increased numbers of baseline flt-3+p-ERK+ MDSCs were associated with survival benefit of patients.CONCLUSIONA high baseline CD4+ T effector/Treg ratio is a potential biomarker of prognostic significance in HCC. CD8+Ki67+ T cells producing IFN-γ are a key biomarker of response to sorafenib therapy resulting in survival benefit. The immune modulation resulted from sorafenib-mediated blockade of signaling through the VEGF/VEGFR/flt-3 pathway, affecting ERK phosphorylation. These insights may help identify patients who likely would benefit from VEGFR antagonism and inform efforts to improve the efficacy of sorafenib in combination with immunotherapy.TRIAL REGISTRATIONNCT02072486.FUNDINGNational Comprehensive Cancer Network Oncology Research Program from general research support provided by Bayer US LLC (NCCNSORA0002), National Cancer Institute grant P30CA016056, and pilot funds from Roswell Park Alliance Foundation.
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Affiliation(s)
| | - Alan Hutson
- Department of Biostatistics and Bioinformatics, and
| | | | - Renuka Iyer
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
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Cheng H, Sun G, Chen H, Li Y, Han Z, Li Y, Zhang P, Yang L, Li Y. Trends in the treatment of advanced hepatocellular carcinoma: immune checkpoint blockade immunotherapy and related combination therapies. Am J Cancer Res 2019; 9:1536-1545. [PMID: 31497341 PMCID: PMC6726979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2018] [Accepted: 07/03/2019] [Indexed: 06/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common liver cancer with high morbidity and mortality worldwide. Systemic treatments with several multi-targeted tyrosine kinase inhibitors (TKIs), including sorafenib, lenvatinib, regorafenib and cabozantinib, have been widely utilized int the treatment of HCC. However, with tolerable adverse events and relative low survival time, neo or optimized therapies for advanced HCC are still urgently needed. New developed immune checkpoint inhibitors therapy have been first demonstrated effective in metastatic melanoma through against CTLA-4 or PD-1/PD-L1 to renew T cell effector function. Preclinical data indicated that interference with immune checkpoint molecules results in HCC growth suppression, suggesting it may bring hope to the HCC treatment. Several clinical trials applying monoclonal antibodies to immune checkpoint molecules demonstrated that immune checkpoint inhibitors are safe and enable durable antitumor activity in advanced HCC patients. Several published immunotherapy trials in HCC using Anti-CTLA-4 agents (tremelimumab) or anit-PD-1 agents (Nivolumab) have showed promising results, in which have similar response rate (15%-30%) and disease control rate with TKIs therapies. This article will review the on-going clinical trials associated with immune checkpoint molecules monotherapy or co, and then discuss the optimal scheme of immune checkpoint therapy for advanced HCC.
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Affiliation(s)
- Huijuan Cheng
- Lanzhou University Second HospitalLanzhou 730030, Gansu Province, China
- The Key Laboratory of The Digestive System Tumors of Gansu ProvinceLanzhou 730030, Gansu Province, China
| | - Guodong Sun
- Lanzhou University Second HospitalLanzhou 730030, Gansu Province, China
| | - Hao Chen
- Lanzhou University Second HospitalLanzhou 730030, Gansu Province, China
- The Key Laboratory of The Digestive System Tumors of Gansu ProvinceLanzhou 730030, Gansu Province, China
| | - Yu Li
- Lanzhou University Second HospitalLanzhou 730030, Gansu Province, China
| | - Zhijian Han
- Lanzhou University Second HospitalLanzhou 730030, Gansu Province, China
- The Key Laboratory of The Digestive System Tumors of Gansu ProvinceLanzhou 730030, Gansu Province, China
| | - Yangbing Li
- Lanzhou University Second HospitalLanzhou 730030, Gansu Province, China
- The Key Laboratory of The Digestive System Tumors of Gansu ProvinceLanzhou 730030, Gansu Province, China
| | - Peng Zhang
- Lanzhou University Second HospitalLanzhou 730030, Gansu Province, China
| | - Luxi Yang
- Lanzhou University Second HospitalLanzhou 730030, Gansu Province, China
- The Key Laboratory of The Digestive System Tumors of Gansu ProvinceLanzhou 730030, Gansu Province, China
| | - Yumin Li
- Lanzhou University Second HospitalLanzhou 730030, Gansu Province, China
- The Key Laboratory of The Digestive System Tumors of Gansu ProvinceLanzhou 730030, Gansu Province, China
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Analysis of Tumor Angiogenesis and Immune Microenvironment in Non-Functional Pituitary Endocrine Tumors. J Clin Med 2019; 8:jcm8050695. [PMID: 31100921 PMCID: PMC6572068 DOI: 10.3390/jcm8050695] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 05/06/2019] [Accepted: 05/14/2019] [Indexed: 11/17/2022] Open
Abstract
Cavernous sinus (CS) invasion is an aggressive behavior exhibited by pituitary neuroendocrine tumors (PitNETs). The cause of CS invasion in PitNETs has not been fully elucidated. The tumor immune microenvironment, known to promote aggressive behavior in various types of tumors, has not been examined for PitNETs. Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) signaling is strongly associated with the tumor immune microenvironment. In the present study, these molecular and histopathological characteristics were examined in invasive non-functional PitNETs (NF-PitNETs). Twenty-seven patients with newly diagnosed NF-PitNETs (with CS invasion: 17, without CS invasion: 10) were analyzed by immunohistochemistry for VEGF-A/VEGFR1 and 2, hypoxia-inducible Factor (HIF), tumor-infiltrating lymphocytes, immunosuppressive cells including regulatory T cells (Tregs) and tumor-associated macrophages (TAMs), and immune checkpoint molecules. Previously validated tumor proliferation markers including mitotic count, Ki-67 index, and p53 were also analyzed for their expressions in NF-PitNETs. VEGF-A and VEGFR1 were expressed on not only vascular endothelial cells, but also on tumor cells. The expressions of VEGF-A and VEGFR1 were significantly higher in NF-PitNETs with CS invasion. The number of TAMs and the expression of PD-L1 were also significantly higher in NF-PitNETs with CS invasion than in NF-PitNETs without CS invasion. The high expression of VEGF-A and VEGFR1 and associated immunosuppressive microenvironment were observed in NF-PitNETs with CS invasion, suggesting that a novel targeted therapy can be applied.
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Iyer RV, Maguire O, Kim M, Curtin LI, Sexton S, Fisher DT, Schihl SA, Fetterly G, Menne S, Minderman H. Dose-Dependent Sorafenib-Induced Immunosuppression Is Associated with Aberrant NFAT Activation and Expression of PD-1 in T Cells. Cancers (Basel) 2019; 11:cancers11050681. [PMID: 31100868 PMCID: PMC6562672 DOI: 10.3390/cancers11050681] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Revised: 05/14/2019] [Accepted: 05/14/2019] [Indexed: 02/06/2023] Open
Abstract
The multikinase inhibitor sorafenib is the only standard first-line therapy for hepatocellular carcinoma (HCC). Here, we report the dose-dependent effects of sorafenib on the immune response, which is related to nuclear factor of activated T cells 1 (NFAT1) activity. In vitro and in vivo experiments were performed with low and high doses of sorafenib using human T cells and spontaneous developed woodchuck HCC models. In vitro studies demonstrated that following exposure to a high dose of sorafenib the baseline activity of NFAT1 in T cells was significantly increased. In a parallel event, high dose sorafenib resulted in a significant decrease in T cell proliferation and increased the proportion of PD-1 expressing CD8+ T cells with NFAT1 activation. In the in vivo model, smaller tumors were detected in the low-dose sorafenib treated group compared to the placebo and high-dose treated groups. The low-dose sorafenib group showed a significant tumor growth delay with significantly more CD3+ cells in tumor. This study demonstrates that sorafenib has immunomodulatory effects in a dose- and time-dependent manner. Higher dose of sorafenib treatment was associated with immunosuppressive action. This observed effect of sorafenib should be taken into consideration in the selection of optimum starting dose for future trials.
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Affiliation(s)
- Renuka V Iyer
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
| | - Orla Maguire
- Flow and Image Cytometry Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
| | - Minhyung Kim
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
| | - Leslie I Curtin
- Laboratory Animal Shared Resources, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
| | - Sandra Sexton
- Laboratory Animal Shared Resources, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
| | - Daniel T Fisher
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
| | - Sarah A Schihl
- Bioanalytics, Metabolomics, and Pharmacokinetics Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
| | - Gerald Fetterly
- Bioanalytics, Metabolomics, and Pharmacokinetics Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
| | - Stephan Menne
- Department of Microbiology & Immunology, Georgetown University, Washington, DC 20057, USA.
| | - Hans Minderman
- Flow and Image Cytometry Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
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Wu X, Luo H, Shi B, Di S, Sun R, Su J, Liu Y, Li H, Jiang H, Li Z. Combined Antitumor Effects of Sorafenib and GPC3-CAR T Cells in Mouse Models of Hepatocellular Carcinoma. Mol Ther 2019; 27:1483-1494. [PMID: 31078430 DOI: 10.1016/j.ymthe.2019.04.020] [Citation(s) in RCA: 117] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2019] [Revised: 04/17/2019] [Accepted: 04/23/2019] [Indexed: 02/07/2023] Open
Abstract
Our previous study indicated that GPC3-targeted chimeric antigen receptor (CAR) T cell therapy has a high safety profile in patients with hepatocellular carcinoma (HCC). However, the response rate requires further improvement. Here, we analyzed the combined effect of GPC3-CAR T cells and sorafenib in both immunocompetent and immunodeficient mouse models of hepatocellular carcinoma. In immunocompetent mouse model, mouse CAR (mCAR) T cells induced regression of small tumors (approximately 130 mm3 tumor volume) but had no effect on large, established tumors (approximately 400 mm3 tumor volume). Sorafenib, at a subpharmacologic but not a pharmacologic dose, augmented the antitumor effects of mCAR T cells, in part by promoting IL12 secretion in tumor-associated macrophages (TAMs) and cancer cell apoptosis. In an immunodeficient mouse model, both subpharmacologic and pharmacologic doses of sorafenib had limited impacts on the function of human CAR (huCAR) T cells in vitro and showed synergistic effects with huCAR T cells in vivo, which can at least partially be ascribed to the upregulated tumor cell apoptosis induced by the combined treatment. Thus, this study applied two of the most commonly used mouse models for CAR T cell research and demonstrated the clinical potential of combining sorafenib with GPC3-targeted CAR T cells against HCC.
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Affiliation(s)
- Xiuqi Wu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China
| | - Hong Luo
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China; State Key Laboratory of Oncogenes and Related Genes, Renji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Bizhi Shi
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China
| | - Shengmeng Di
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China
| | - Ruixin Sun
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China
| | - Jingwen Su
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China
| | - Ying Liu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China
| | - Hua Li
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China
| | - Hua Jiang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China.
| | - Zonghai Li
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China; CARsgen Therapeutics, Shanghai 200032, China.
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Tamura R, Tanaka T, Ohara K, Miyake K, Morimoto Y, Yamamoto Y, Kanai R, Akasaki Y, Murayama Y, Tamiya T, Yoshida K, Sasaki H. Persistent restoration to the immunosupportive tumor microenvironment in glioblastoma by bevacizumab. Cancer Sci 2019; 110:499-508. [PMID: 30467920 PMCID: PMC6361613 DOI: 10.1111/cas.13889] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 11/06/2018] [Accepted: 11/19/2018] [Indexed: 01/06/2023] Open
Abstract
Although vascular endothelial growth factor (VEGF) promotes the immunosuppressive microenvironment, the efficacy of bevacizumab (Bev) on tumor immunity has not been fully investigated. The present study used 47 glioblastoma tissues obtained at 3 different settings: tumors of initial resection (naïve Bev group), tumors resected following Bev therapy (effective Bev group), and recurrent tumors after Bev therapy (refractory Bev group). The paired samples of the initial and post-Bev recurrent tumors from 9 patients were included. The expression of programmed cell death-1 (PD-1)/PD ligand-1 (PD-L1), CD3, CD8, Foxp3, and CD163 was analyzed by immunohistochemistry. The PD-L1+ tumor cells significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (P < .01 for each). The PD-1+ cells significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (P < .01 for each). The amount of CD3+ and CD8+ T cell infiltration increased in the refractory Bev group compared with the naïve Bev group (CD3, P < .01; CD8, P = .06). Both Foxp3+ regulatory T cells and CD163+ tumor-associated macrophages significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (Foxp3, P < .01 for each; CD163, P < .01 for each). These findings were largely confirmed by comparing paired initial and post-Bev recurrent tumors. Bevacizumab restores the immunosupportive tumor microenvironment in glioblastomas, and this effect persists during long-term Bev therapy.
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Affiliation(s)
- Ryota Tamura
- Department of NeurosurgeryKeio University School of MedicineTokyoJapan
| | - Toshihide Tanaka
- Department of NeurosurgeryJikei University Kashiwa HospitalChibaJapan
| | - Kentaro Ohara
- Division of Diagnostic PathologyKeio University School of MedicineTokyoJapan
| | - Keisuke Miyake
- Department of NeurosurgeryKagawa University HospitalKagawaJapan
| | - Yukina Morimoto
- Department of NeurosurgeryKeio University School of MedicineTokyoJapan
| | - Yohei Yamamoto
- Department of NeurosurgeryJikei University Kashiwa HospitalChibaJapan
| | - Ryuichi Kanai
- Department of NeurosurgeryEiju General HospitalTokyoJapan
| | | | - Yuichi Murayama
- Department of NeurosurgeryJikei University HospitalTokyoJapan
| | - Takashi Tamiya
- Department of NeurosurgeryKagawa University HospitalKagawaJapan
| | - Kazunari Yoshida
- Department of NeurosurgeryKeio University School of MedicineTokyoJapan
| | - Hikaru Sasaki
- Department of NeurosurgeryKeio University School of MedicineTokyoJapan
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Rizell M, Sternby Eilard M, Andersson M, Andersson B, Karlsson-Parra A, Suenaert P. Phase 1 Trial With the Cell-Based Immune Primer Ilixadencel, Alone, and Combined With Sorafenib, in Advanced Hepatocellular Carcinoma. Front Oncol 2019; 9:19. [PMID: 30719425 PMCID: PMC6348253 DOI: 10.3389/fonc.2019.00019] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 01/07/2019] [Indexed: 12/12/2022] Open
Abstract
Several lines of evidence support immunotherapy in hepatocellular carcinoma (HCC). We have shown that intratumoral injections of the immune primer ilixadencel (pro-inflammatory allogeneic dendritic cells) are safe in renal-cell carcinoma. Here, we assessed ilixadencel as a single agent and combined with sorafenib in advanced HCC. Of 17 HCC patients enrolled, 12 patients received ilixadencel at the dose of 10 × 106 cells (six as monotherapy and six in combination with sorafenib), and five received ilixadencel at the dose of 20 × 106 cells as monotherapy. The primary objective was to evaluate tolerability. All patients had at least one adverse event, with 30% of such events considered as treatment-related, with one single treatment-related grade three event. The most common toxicity was grade 1 and 2 fever and chills. Eleven of 15 evaluable patients (73%) showed increased frequency of tumor-specific CD8+ T cells in peripheral blood. Overall one patient had a partial response (with ilixadencel as monotherapy), and five had stable disease as overall best response per mRECIST. The median time to progression was 5.5 months, and overall survival ranged from 1.6 to 21.4 months. Our study confirms the safety of ilixadencel as single agent or in combination with sorafenib and indicates tumor-specific immunological responses in advanced HCC. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT01974661.
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Affiliation(s)
- Magnus Rizell
- Transplantation Center, Sahlgrenska University Hospital, Gothenburg, Sweden.,Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Malin Sternby Eilard
- Transplantation Center, Sahlgrenska University Hospital, Gothenburg, Sweden.,Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Mats Andersson
- Department of Radiology, Sahlgrenska University Hospital and Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Radiology, Karolinska University Hospital, Huddinge, Sweden
| | - Bengt Andersson
- Department of Microbiology and Immunology, Sahlgrenska University Hospital and Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Alex Karlsson-Parra
- Immunicum AB, Stockholm, Sweden.,Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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