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Rao S, Prince SP, Gaddipati S, Feun L, Ezenwajiaku N, Martin P, Jones PD. Looking Toward the Future: Emerging Therapies for Hepatocellular Carcinoma. Gastroenterol Hepatol (N Y) 2025; 21:286-297. [PMID: 40416920 PMCID: PMC12100529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/27/2025]
Abstract
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related deaths worldwide. Despite the decreasing prevalence of hepatitis C, the burden of HCC is expected to rise owing to the increasing prevalence of metabolic syndrome and increased global alcohol consumption. Guideline-concordant screening with ultrasound every 6 months has been associated with increased rates of early-stage detection and receipt of curative treatment. However, most patients with cirrhosis do not undergo screening, with HCC often diagnosed only at an advanced stage when curative resection or ablation is not feasible. Systemic medical therapy is indicated in patients diagnosed with infiltrative or advanced HCC, or when early-stage disease progresses or recurs after resection, transplant, or other locoregional therapy. Sorafenib was approved as first-line therapy for HCC in 2007. Since 2017, there has been an exponential rate of approval of novel agents targeting HCC, including lenvatinib, regorafenib, and cabozantinib. Checkpoint inhibitors, including pembrolizumab, nivolumab, ipilimumab, and combination therapy with atezolizumab plus bevacizumab and durvalumab plus tremelimumab, have expanded treatment options. This article describes treatment for all HCC stages, with a brief discussion of locoregional therapy for context, as some emerging treatment regimens combine locoregional and systemic therapies. The article highlights approved systemic therapies that are guideline-endorsed and emerging therapies for advanced HCC.
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Affiliation(s)
- Sanjana Rao
- University of Miami/Jackson Health System Internal Medicine Residency, University of Miami Miller School of Medicine, Miami, Florida
| | - Sean-Patrick Prince
- University of Miami/Holy Cross Health Internal Medicine Program, Fort Lauderdale, Florida
| | - Sirisha Gaddipati
- University of Miami/Jackson Health System Internal Medicine Residency, University of Miami Miller School of Medicine, Miami, Florida
| | - Lynn Feun
- Department of Medicine, Division of Medical Oncology, University of Miami Miller School of Medicine, Miami, Florida
| | - Nkiruka Ezenwajiaku
- Department of Medicine, Division of Medical Oncology, University of Miami Miller School of Medicine, Miami, Florida
| | - Paul Martin
- Department of Medicine, Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida
| | - Patricia D. Jones
- Department of Medicine, Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida
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Di Marco L, Romanzi A, Pivetti A, De Maria N, Ravaioli F, Salati M, Villa E, Di Benedetto F, Magistri P, Dominici M, Colecchia A, Di Sandro S, Spallanzani A. Suppressing, stimulating and/or inhibiting: The evolving management of HCC patient after liver transplantation. Crit Rev Oncol Hematol 2025; 207:104607. [PMID: 39725094 DOI: 10.1016/j.critrevonc.2024.104607] [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: 05/23/2024] [Revised: 12/20/2024] [Accepted: 12/22/2024] [Indexed: 12/28/2024] Open
Abstract
Liver transplantation (LT) is a curative strategy for hepatocellular carcinoma (HCC), but the risk of HCC recurrence remains a challenging problem. In patients with HCC recurrence after LT (HCC-R_LT), the locoregional and surgical approaches are complex, and the guidelines do not report evidence-based strategies for the management of immunosuppression. In recent years, immunotherapy has become an effective option for patients with advanced HCC in pre-transplant settings. However, due to the risk of potentially fatal allograft rejection, the use of immunotherapy is avoided in post-transplant settings. Combining immunosuppressants with immunotherapy in transplant patients is also challenging due to the complex tumor microenvironment and immunoreactivity. The fear of acute liver rejection and the lack of predictive factors hinder the successful clinical application of immunotherapy for post-liver transplantation HCC recurrence. This review aims to comprehensively summarize the risk of HCC-R_LT, the available evidence for the efficacy of immunotherapy in patients with HCC-R_LT, and the clinical issues regarding the innovative management of this patient population.
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Affiliation(s)
- Lorenza Di Marco
- Department of Oncology and Hematology, Oncology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41124, Italy; Department of Biomedical, Metabolic and Neural Sciences, Clinical and Experimental Medicine Program, University of Modena and Reggio Emilia, Modena 41124, Italy.
| | - Adriana Romanzi
- Chimomo Department, Gastroenterology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy.
| | - Alessandra Pivetti
- Chimomo Department, Gastroenterology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy.
| | - Nicola De Maria
- Chimomo Department, Gastroenterology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy.
| | - Federico Ravaioli
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum University of Bologna, Bologna 40138, Italy.
| | - Massimiliano Salati
- Department of Oncology and Hematology, Oncology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41124, Italy.
| | - Erica Villa
- Chimomo Department, Gastroenterology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy; National Institute of Gastroenterology IRCCS "Saverio de Bellis", Research Hospital, Castellana Grotte 70013, Italy.
| | - Fabrizio Di Benedetto
- Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy.
| | - Paolo Magistri
- Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy.
| | - Massimo Dominici
- Department of Oncology and Hematology, Oncology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41124, Italy.
| | - Antonio Colecchia
- Chimomo Department, Gastroenterology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy.
| | - Stefano Di Sandro
- Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41125, Italy.
| | - Andrea Spallanzani
- Department of Oncology and Hematology, Oncology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, Modena 41124, Italy.
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Lau G, Obi S, Zhou J, Tateishi R, Qin S, Zhao H, Otsuka M, Ogasawara S, George J, Chow PKH, Cai J, Shiina S, Kato N, Yokosuka O, Oura K, Yau T, Chan SL, Kuang M, Ueno Y, Chen M, Cheng AL, Cheng G, Chuang WL, Baatarkhuu O, Bi F, Dan YY, Gani RA, Tanaka A, Jafri W, Jia JD, Kao JH, Hasegawa K, Lau P, Lee JM, Liang J, Liu Z, Lu Y, Pan H, Payawal DA, Rahman S, Seong J, Shen F, Shiha G, Song T, Sun HC, Masaki T, Sirachainan E, Wei L, Yang JM, Sallano JD, Zhang Y, Tanwandee T, Dokmeci AK, Zheng SS, Fan J, Fan ST, Sarin SK, Omata M. APASL clinical practice guidelines on systemic therapy for hepatocellular carcinoma-2024. Hepatol Int 2024; 18:1661-1683. [PMID: 39570557 DOI: 10.1007/s12072-024-10732-z] [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: 07/11/2024] [Accepted: 09/16/2024] [Indexed: 11/22/2024]
Abstract
In Asia-Pacific region, hepatocellular carcinoma is a serious health threat attributing to over 600,000 deaths each year and account for over 70% of global cases. Clinically, the major unmet needs are recurrence after curative-intent surgery, liver transplantation or local ablation and disease progression in those with hepatocellular carcinoma not eligible for resection or failed locoregional therapy. In the recent few years, new targeted therapy and immune-checkpoint inhibitors have been registered as systemic therapy to address these issues. Notably, new forms of systemic therapy, either as first-line or second-line therapy for unresectable hepatocellular or those not eligible for locoregional therapy, are now available. New data is also emerging with the use of systemic therapy to prevent hepatocellular carcinoma recurrence after curative-intent resection or local ablation therapy and to retard disease progression after locoregional therapy. In the future, further implementation of immune-checkpoint inhibitors and other forms of immunotherapy are expected to bring a new paradigm to the management of hepatocellular carcinoma. New insight related to immune-related adverse events with the use of immunotherapy has allso enabled optimization of the therapeutic approach to patients with hepatocellular carcinoma. The purpose of this clinical practice guideline is to provide an up-to-date recommendation based on clinical evidence and experience from expert Asia-Pacific key opinion leaders in the field of hepatocellular carcinoma. Three key questions will be addressed, namely: (1) Which patients with hepatocellular carcinoma should be considered for systemic therapy? (2) Which systemic therapy should be used? (3) How should a patient planned for immune checkpoint-based systemic therapy be managed and monitored?
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Affiliation(s)
- George Lau
- Humanity and Health Clinical Trial Center, Humanity and Health Medical Group, Zhongshan Hospital, Fudan University, Hong Kong SAR, Shanghai, China.
| | - Shuntaro Obi
- Department of Internal Medicine, Teikyo University Chiba Medical Center, Chiba, Japan
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai Key Laboratory of Organ Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ryosuke Tateishi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Shukui Qin
- Cancer Centre of Jinling Hospital, Nanjing University of Chinese Medicine, Nanjing, 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
| | - Motoyuki Otsuka
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, 700-8558, Japan
| | - Sadahisa Ogasawara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, NSW, 2145, Australia
| | - Pierce K H Chow
- Department of HPB Surgery and Transplantation, Duke-NUS Medical School, National Cancer Center Singapore and Singapore General Hospital, Surgery Academic Clinical Program, Singapore, Singapore
| | - Jianqiang Cai
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shuichiro Shiina
- Department of Gastroenterology, Juntendo University, 2-1-1, Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Naoya Kato
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Kita, Miki, Kagawa, 761-0793, Japan
| | - Thomas Yau
- Department of Medicine, The University of Hong Kong, Hong Kong, China
| | - Stephen L Chan
- Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Ming Kuang
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yoshiyuki Ueno
- Faculty of Medicine, Department of Gastroenterology, Faculty of Medicine, Yamagata University, 2-2-2 Iida-Nishi, Yamagata, 990-9585, Japan
| | - Minshan Chen
- Department of Liver Surgery, Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China
| | - Ann-Lii Cheng
- Department of OncologyDepartment of Medical OncologyGraduate Institute of OncologyDepartment of Internal Medicine, National Taiwan University Cancer CenterNational Taiwan University HospitalNational Taiwan University College of Medicine, Taipei, Taiwan
| | - Gregory Cheng
- Humanity and Health Clinical Trial Center, Humanity & Health Medical Group, Hong Kong SAR, China
- Faculty of Health Science, Macau University, Macau SAR, China
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, and Hepatitis Center, Center for Infectious Disease and Cancer Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Oidov Baatarkhuu
- School of Medicine, Mongolian National University of Medical Sciences, Ulan Bator, Mongolia
| | - Feng Bi
- Department of Medical Oncology, Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Yock Young Dan
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore
| | - Rino A Gani
- Hepatobiliary Division, Staff Medic Group of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Dr. Cipto Mangunkusumo Hospital, Jakarta, 10430, Indonesia
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Wasim Jafri
- The Aga Khan University Hospital, Karachi, Pakistan
| | - Ji-Dong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Jia-Horng Kao
- Department of Internal Medicine Division of Gastroenterology and Hepatology, Department of Internal MedicineHepatitis Research Center, Graduate Institute of Clinical Medicine, National Taiwan University Hospital Bei-Hu BranchNational Taiwan University HospitalNational Taiwan University College of Medicine, Taipei, Taiwan
| | - Kiyoshi Hasegawa
- Department of Surgery, Graduate School of Medicine, Hepato-Biliary-Pancreatic Surgery Division, The University of Tokyo, Tokyo, Japan
| | - Patrick Lau
- Humanity and Health Clinical Trial Center, Humanity & Health Medical Group, Hong Kong SAR, China
| | - Jeong Min Lee
- Department of Radiology, Seoul National University College of Medicine, Seoul, Korea
| | - Jun Liang
- Department of Medical Oncology, Peking University International Hospital, Beijing, China
| | - Zhenwen Liu
- Senior Department of Hepatology, The Fifth Medical Center of Chinese People's Liberation, Army General Hospital, Beijing, China
| | - Yinying Lu
- Department of Comprehensive Liver Cancer Center, The Fifth Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Hongming Pan
- Department of Medical Oncology, College of Medicine, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Diana A Payawal
- Department of Medicine, Fatima University Medical Center, Manila, Philippines
| | - Salimur Rahman
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, 1000, Bangladesh
| | - Jinsil Seong
- Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Feng Shen
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China
| | - Gamal Shiha
- European Liver Patients' Association (ELPA), Brussels, Belgium
- World Hepatitis Alliance, London, UK
- African Liver Patient Association (ALPA), Cairo, Egypt
- The Association of Liver Patients Care (ALPC), Hepatology and Gastroenterology Unit, Internal Medicine Department, Faculty of Medicine, Mansoura University, Egyptian Liver Research Institute and Hospital (ELRIAH), Sherbin, El Mansoura, Egypt
| | - Tianqiang Song
- Department of Hepatobiliary, HCC Research Center for Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China
| | - Hui-Chuan Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Kita, Miki, Kagawa, 761-0793, Japan
| | - Ekaphop Sirachainan
- Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Lai Wei
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Jin Mo Yang
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Jose D Sallano
- Section of Gastroenterology, University of Santo Tomas, Manila, Philippines
| | - Yanqiao Zhang
- Department of Gastrointestinal Medical Oncology, Institute of Prevention and Treatment of Cancer of Heilongjiang Province, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Tawesak Tanwandee
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - AKadir Dokmeci
- Department of Medicine, Ankara University School of Medicine, Ankara, Turkey
| | - Shu-Sen Zheng
- Department of Hepatobiliary and Pancreatic Surgery, Department of Liver Transplantation, Shulan (Hangzhou) Hospital, Zhejiang Shuren University School of Medicine, Hangzhou, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Sheung-Tat Fan
- Liver Surgery and Transplant Centre, Hong Kong Sanatorium and Hospital, Hong Kong, Japan
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Masao Omata
- Department of Gastroenterology, Yamanashi Prefectural Center Hospital, Kofu-City, Yamanashi, Japan
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De Stefano N, Patrono D, Colli F, Rizza G, Paraluppi G, Romagnoli R. Liver Transplantation for Hepatocellular Carcinoma in the Era of Immune Checkpoint Inhibitors. Cancers (Basel) 2024; 16:2374. [PMID: 39001436 PMCID: PMC11240403 DOI: 10.3390/cancers16132374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Revised: 06/26/2024] [Accepted: 06/27/2024] [Indexed: 07/16/2024] Open
Abstract
Hepatocellular carcinoma (HCC) remains the leading oncological indication for liver transplantation (LT), with evolving and broadened inclusion criteria. Immune checkpoint inhibitors (ICIs) gained a central role in systemic HCC treatment and showed potential in the peri-transplant setting as downstaging/bridging therapy before LT or as a treatment for HCC recurrence following LT. However, the antagonistic mechanisms of action between ICIs and immunosuppressive drugs pose significant challenges, particularly regarding the risk of acute rejection (AR). This review analyzes the main signaling pathways targeted by ICI therapies and summarizes current studies on ICI therapy before and after LT. The literature on this topic is limited and highly heterogeneous, precluding definitive evidence-based conclusions. The use of ICIs before LT appears promising, provided that a sufficient wash-out period is implemented. In contrast, the results of post-LT ICI therapy do not support its wide clinical application due to high AR rates and overall poor response to treatment. In the future, modern graft preservation techniques might support the selection of good ICI responders, but data from high-level studies are urgently needed.
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Affiliation(s)
| | | | | | | | | | - Renato Romagnoli
- General Surgery 2U-Liver Transplant Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, University of Torino, Corso Bramante 88-90, 10126 Torino, Italy; (N.D.S.); (D.P.); (F.C.); (G.R.); (G.P.)
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Gordan JD, Kennedy EB, Abou-Alfa GK, Beal E, Finn RS, Gade TP, Goff L, Gupta S, Guy J, Hoang HT, Iyer R, Jaiyesimi I, Jhawer M, Karippot A, Kaseb AO, Kelley RK, Kortmansky J, Leaf A, Remak WM, Sohal DPS, Taddei TH, Wilson Woods A, Yarchoan M, Rose MG. Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline Update. J Clin Oncol 2024; 42:1830-1850. [PMID: 38502889 DOI: 10.1200/jco.23.02745] [Citation(s) in RCA: 69] [Impact Index Per Article: 69.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 12/28/2023] [Indexed: 03/21/2024] Open
Abstract
PURPOSE To update an evidence-based guideline to assist in clinical decision-making for patients with advanced hepatocellular carcinoma (HCC). METHODS ASCO convened an Expert Panel to update the 2020 guideline on systemic therapy for HCC. The panel updated the systematic review to include randomized controlled trials (RCTs) published through October 2023 and updated recommendations. RESULTS Ten new RCTs met the inclusion criteria and were added to the evidence base. RECOMMENDATIONS Atezolizumab + bevacizumab (atezo + bev) or durvalumab + tremelimumab (durva + treme) may be offered first-line for patients with advanced HCC, Child-Pugh class A liver disease, and Eastern Cooperative Oncology Group performance status 0-1. Where there are contraindications to these therapies, sorafenib, lenvatinib, or durvalumab may be offered first-line. Following first-line treatment with atezo + bev, second-line therapy with a tyrosine kinase inhibitor (TKI), ramucirumab (for patients with alpha-fetoprotein [AFP] ≥400 ng/mL), durva + treme, or nivolumab + ipilimumab (nivo + ipi) may be recommended for appropriate candidates. Following first-line therapy with durva + treme, second-line therapy with a TKI is recommended. Following first-line treatment with sorafenib or lenvatinib, second-line therapy options include cabozantinib, regorafenib for patients who previously tolerated sorafenib, ramucirumab (AFP ≥400 ng/mL), nivo + ipi, or durvalumab; atezo + bev or durva + treme may be considered for patients who did not have access to these therapies in the first-line setting, and do not have contraindications. Pembrolizumab or nivolumab are also options for appropriate patients following sorafenib or lenvatinib. Third-line therapy may be considered in Child-Pugh class A patients with good PS, using one of the agents listed previously that has a nonidentical mechanism of action with previously received therapy. A cautious approach to systemic therapy is recommended for patients with Child-Pugh class B advanced HCC. Further guidance on choosing between options is included within the guideline.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.
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Affiliation(s)
- John D Gordan
- University of California, San Francisco, San Francisco, CA
| | | | - Ghassan K Abou-Alfa
- Memorial Sloan Kettering Cancer Center and Weill Medical College at Cornell University, New York, NY
- Trinity College Dublin Medical School, Dublin, Ireland
| | | | | | | | - Laura Goff
- Vanderbilt Ingram Cancer Center, Nashville, TN
| | | | | | | | - Renuka Iyer
- Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | | | | | | | | | - R Kate Kelley
- University of California, San Francisco, San Francisco, CA
| | | | - Andrea Leaf
- VA New York Harbor Healthcare System, Brooklyn, NY
| | - William M Remak
- California Hepatitis C Task Force, California Chronic Care Coalition, FAIR Foundation, San Francisco, CA
| | | | - Tamar H Taddei
- Yale University School of Medicine and VA Connecticut Healthcare System, West Haven, CT
| | | | | | - Michal G Rose
- Yale Cancer Center and VA Connecticut Healthcare System, West Haven, CT
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Tabrizian P, Zeitlhoefler M, Hassan AT, Marino R. Immunotherapy for transplantation of hepatocellular carcinoma: the next frontier in adjunctive therapy. Curr Opin Organ Transplant 2024; 29:144-154. [PMID: 38164882 DOI: 10.1097/mot.0000000000001133] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2024]
Abstract
PURPOSE OF REVIEW The increasing success of liver transplantation in hepatocellular carcinoma (HCC) drives an ever-evolving search for innovative strategies to broaden eligible patients' pools. Recent advances in immuno-oncology have turned the spotlight on immune checkpoint inhibitors (ICIs). This review offers an updated overview of ICIs in liver transplantation for HCC, exploring neoadjuvant and adjuvant approaches and addressing unanswered questions on safety, patients' selection, and response predictors. RECENT FINDINGS ICIs have transitioned from being a last-chance therapeutic hope to becoming an integral cornerstone in the treatment of advanced HCC, holding great promise as a compelling option not only to downstage patients for transplantation but also as an alternative strategy in addressing posttransplantation disease recurrence. Despite ongoing refinements in immunotherapeutic agents, the complex molecular pathways involved emphasize the need for a comprehensive approach to integrate immunotherapy in liver transplantation. SUMMARY Initial concerns about graft rejection, with ICIs as a bridging therapy to liver transplantation, were successfully addressed using adequate immunosuppressants strategies and minimized with a sufficient washout period. Post-liver transplantation disease recurrence remains challenging, requiring a balance between effective therapy and preserving graft function. Emphasis should be placed on clinical trials validating the risk-benefit ratio of ICIs for liver transplantation, guiding appropriate patients' selection, and establishing clear management pathways.
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Affiliation(s)
- Parissa Tabrizian
- Liver Transplant and Hepatobiliary Surgery, Recanati-Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Wang J, Yang L, Wang HX, Cui SP, Gao Y, Hu B, Zhou L, Lang R. Anti-PD-1 therapy reverses TIGIT +CD226 +NK depletion in immunotherapy resistance of hepatocellular carcinoma through PVR/TIGIT pathway. Int Immunopharmacol 2024; 130:111681. [PMID: 38368771 DOI: 10.1016/j.intimp.2024.111681] [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: 12/07/2023] [Revised: 02/05/2024] [Accepted: 02/08/2024] [Indexed: 02/20/2024]
Abstract
Immunotherapy resistance conducts the main reason for failure of PD-1-based immune checkpoint inhibitors (ICIs) in patients with hepatocellular carcinoma (HCC). This study aims to clarify the mechanism of nature kill cells (NK) depletion in immunotherapy resistance of HCC. Cancerous /paracancerous tissues and peripheral blood (PB) of 55 HCC patients were collected and grouped according to differentiation degree, FCM, IHC and lymphocyte culture drug intervention experiments were used to determine NK cell depletion degree. Furthermore, a mouse model of HCC in situ was constructed and divided into different groups according to intervention measures of ICIs. Immunofluorescence thermography was used to observe changes in tumor burden. NK cells in cancerous tissues significantly up-regulated TIGIT expression (P < 0.001). Intervention experiments revealed that TIGIT and PD-1 expression decreased gradually with increased PD-1 inhibitor dose in moderately-highly differentiated patients (P < 0.05). Animal experiment showed that tumors proliferation in experimental group was inhibited after PD-1 blockage, WB indicated that ICIs decreased TIGIT and PVRL1 protein expression while increased CD226 and PVRL3 protein expression. We concluded that TIGIT+NK cells competitively bind to PVR with CD226 and promote NK cell depletion. Anti-PD-1 decreases PVRL1 expression through PD-1/PD-L1 pathway, reducing the PVR/TIGIT inhibitory signal pathway, and enhancing function of PVR/CD226 activation signal.
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Affiliation(s)
- Jing Wang
- Department of Thoracic Surgery, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Lin Yang
- Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
| | - Han-Xuan Wang
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing ChaoYang Hospital, Capital Medical University, Beijing, China
| | - Song-Ping Cui
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing ChaoYang Hospital, Capital Medical University, Beijing, China
| | - Ya Gao
- Department of Thoracic Surgery, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Bin Hu
- Department of Thoracic Surgery, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Lin Zhou
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing ChaoYang Hospital, Capital Medical University, Beijing, China.
| | - Ren Lang
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing ChaoYang Hospital, Capital Medical University, Beijing, China.
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8
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Tabrizian P, Yu A, Debnath N, Myers B, Marron T. Immunotherapy and Liver Transplantation: The Future or the Failure? Surg Clin North Am 2024; 104:163-182. [PMID: 37953034 DOI: 10.1016/j.suc.2023.07.009] [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: 11/14/2023]
Abstract
A quarter century has passed since the milestone study by Mazzaferro and colleagues on liver transplantation (LT) for hepatocellular carcinoma (HCC). The increasing demand for LT for HCC has led to the continued efforts to expand LT indications. Downstaging to within Milan criteria has been incorporated into the organ allocation policy for HCC in the United States in 2017 and provides acceptable long-term survival. The present review focuses on the rationale of neoadjuvant immune checkpoint inhibitor (ICI) in HCC, the experience of ICI in the pre- and posttransplant setting.
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Affiliation(s)
- Parissa Tabrizian
- Liver Transplant and Hepatobiliary Surgery, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy, New York, NY 10029, USA.
| | - Allen Yu
- Liver Transplant and Hepatobiliary Surgery, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy, New York, NY 10029, USA
| | - Neha Debnath
- Liver Transplant and Hepatobiliary Surgery, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy, New York, NY 10029, USA
| | - Bryan Myers
- Liver Transplant and Hepatobiliary Surgery, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy, New York, NY 10029, USA
| | - Thomas Marron
- Liver Transplant and Hepatobiliary Surgery, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy, New York, NY 10029, USA
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9
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Wassmer CH, El Hajji S, Papazarkadas X, Compagnon P, Tabrizian P, Lacotte S, Toso C. Immunotherapy and Liver Transplantation: A Narrative Review of Basic and Clinical Data. Cancers (Basel) 2023; 15:4574. [PMID: 37760542 PMCID: PMC10526934 DOI: 10.3390/cancers15184574] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 09/12/2023] [Accepted: 09/13/2023] [Indexed: 09/29/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) have improved the management of patients with intermediate- and advanced-stage HCC, even making some of them potential candidates for liver transplantation. However, acute rejection has been observed after ICI therapy, challenging its safety in transplant settings. We summarize the key basic impact of immune checkpoints on HCC and liver transplantation. We analyze the available case reports and case series on the use of ICI therapy prior to and after liver transplantation. A three-month washout period is desirable between ICI therapy and liver transplantation to reduce the risk of acute rejection. Whenever possible, ICIs should be avoided after liver transplantation, and especially so early after a transplant. Globally, more robust prospective data in the field are required.
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Affiliation(s)
- Charles-Henri Wassmer
- Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland; (S.E.H.); (X.P.); (S.L.); (C.T.)
| | - Sofia El Hajji
- Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland; (S.E.H.); (X.P.); (S.L.); (C.T.)
| | - Xenofon Papazarkadas
- Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland; (S.E.H.); (X.P.); (S.L.); (C.T.)
| | - Philippe Compagnon
- Division of Transplantation, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland;
| | - Parissa Tabrizian
- Mount Sinai Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10019, USA;
| | - Stéphanie Lacotte
- Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland; (S.E.H.); (X.P.); (S.L.); (C.T.)
| | - Christian Toso
- Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland; (S.E.H.); (X.P.); (S.L.); (C.T.)
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10
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Hsu YC, Chen CH, Huang HF, Lee YT, Wu MC, Su CW, Chou HC, Wang LF, Lee HS, Lin SW, Hsu PN, Wu YM, Sheu JC, Weng MT. Therapeutic Effects of Anti-PD1 Immunotherapy on Hepatocellular Carcinoma Under Administration of Tacrolimus. Transplantation 2023; 107:1492-1501. [PMID: 36380450 DOI: 10.1097/tp.0000000000004425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND Liver transplantation (LT) is the treatment of choice for patients with hepatocellular carcinoma (HCC). Recurrence of HCC after LT occurs in 10% to 20% of cases. Preclinical studies to evaluate immune checkpoint inhibitors in conjunction with immunosuppressant treatment in transplant recipients have been lacking. Here, we evaluated the efficacy, safety, and mechanism of programmed cell death-1 (PD1) blockade under tacrolimus treatment in transplant recipients. METHODS We used a murine allogeneic skin transplantation model and murine syngeneic subcutaneous and orthotopic HCC models and measured the tumor volume and the change in tumor-infiltrating lymphocytes under PD1 blockade and tacrolimus treatment. RESULTS Tacrolimus treatment prolonged allograft survival in the allogeneic transplantation model and enhanced tumor growth in both subcutaneous and orthotopic HCC models. PD1 blockade suppressed tumor growth and lung metastasis in correlation with the number of infiltrating CD8 + T cells. Under tacrolimus treatment, PD1 blockade still resulted in an antitumor effect accompanied by a significant increase in tumor-infiltrating CD8 + T cells, natural killer cells, dendritic cells, and natural killer T cells. Tacrolimus treatment rescued the acceleration of transplant rejection induced by PD1 blockade in the allogeneic transplantation model. CONCLUSIONS Our data suggest that treatment with high-dose tacrolimus in conjunction with PD1 blockade has an antitumor effect and reduces transplant rejection in mouse models of allograft skin transplantation and HCC. Thus, these results suggest that a clinical trial of PD1 inhibitors for HCC in LT merits consideration.
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Affiliation(s)
- Yu-Chen Hsu
- Liver Disease Prevention and Treatment Research Foundation, Taiwan, Republic of China
| | - Chien-Hung Chen
- Department of Medicine, National Taiwan University Cancer Center, Taipei, Taiwan, Republic of China
- Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China
- Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China
| | - Hui-Fu Huang
- Department of Surgery, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China
| | - Ying-Te Lee
- Liver Disease Prevention and Treatment Research Foundation, Taiwan, Republic of China
| | - Meng-Chuan Wu
- Liver Disease Prevention and Treatment Research Foundation, Taiwan, Republic of China
| | - Chien-Wen Su
- Liver Disease Prevention and Treatment Research Foundation, Taiwan, Republic of China
| | - Huei-Chi Chou
- Liver Disease Prevention and Treatment Research Foundation, Taiwan, Republic of China
| | - Li-Fang Wang
- Liver Disease Prevention and Treatment Research Foundation, Taiwan, Republic of China
| | - Hsuan-Shu Lee
- Liver Disease Prevention and Treatment Research Foundation, Taiwan, Republic of China
- Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China
| | - Shu-Wha Lin
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China
- Department of Laboratory Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China
| | - Ping-Ning Hsu
- Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China
| | - Yao-Ming Wu
- Department of Surgery, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China
- Department of Surgery, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China
| | - Jin-Chuan Sheu
- Liver Disease Prevention and Treatment Research Foundation, Taiwan, Republic of China
- Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China
| | - Meng-Tzu Weng
- Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China
- Department of Medical Research, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan, Republic of China
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11
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Montano-Loza AJ, Rodríguez-Perálvarez ML, Pageaux GP, Sanchez-Fueyo A, Feng S. Liver transplantation immunology: Immunosuppression, rejection, and immunomodulation. J Hepatol 2023; 78:1199-1215. [PMID: 37208106 DOI: 10.1016/j.jhep.2023.01.030] [Citation(s) in RCA: 72] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 12/30/2022] [Accepted: 01/30/2023] [Indexed: 05/21/2023]
Abstract
Outcomes after liver transplantation have continuously improved over the past decades, but long-term survival rates are still lower than in the general population. The liver has distinct immunological functions linked to its unique anatomical configuration and to its harbouring of a large number of cells with fundamental immunological roles. The transplanted liver can modulate the immunological system of the recipient to promote tolerance, thus offering the potential for less aggressive immunosuppression. The selection and adjustment of immunosuppressive drugs should be individualised to optimally control alloreactivity while mitigating toxicities. Routine laboratory tests are not accurate enough to make a confident diagnosis of allograft rejection. Although several promising biomarkers are being investigated, none of them is sufficiently validated for routine use; hence, liver biopsy remains necessary to guide clinical decisions. Recently, there has been an exponential increase in the use of immune checkpoint inhibitors due to the unquestionable oncological benefits they provide for many patients with advanced-stage tumours. It is expected that their use will also increase in liver transplant recipients and that this might affect the incidence of allograft rejection. Currently, the evidence regarding the efficacy and safety of immune checkpoint inhibitors in liver transplant recipients is limited and cases of severe allograft rejection have been reported. In this review, we discuss the clinical relevance of alloimmune disease, the role of minimisation/withdrawal of immunosuppression, and provide practical guidance for using checkpoint inhibitors in liver transplant recipients.
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Affiliation(s)
- Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, AB, Canada.
| | - Manuel L Rodríguez-Perálvarez
- Department of Hepatology and Liver Transplantation, Hospital Universitario Reina Sofía, Universidad de Córdoba, IMIBIC, Córdoba, Spain; CIBER de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - George-Philippe Pageaux
- Liver Transplantation Unit, Digestive Department, Saint Eloi University Hospital, University of Montpellier, 34295, Montpellier Cedex 5, France
| | - Alberto Sanchez-Fueyo
- Institute of Liver Studies, King's College London University and King's College Hospital, London, United Kingdom
| | - Sandy Feng
- Department of Surgery, University of California San Francisco, San Francisco, CA, USA
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12
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Abboud K, Umoru G, Esmail A, Abudayyeh A, Murakami N, Al-Shamsi HO, Javle M, Saharia A, Connor AA, Kodali S, Ghobrial RM, Abdelrahim M. Immune Checkpoint Inhibitors for Solid Tumors in the Adjuvant Setting: Current Progress, Future Directions, and Role in Transplant Oncology. Cancers (Basel) 2023; 15:1433. [PMID: 36900226 PMCID: PMC10000896 DOI: 10.3390/cancers15051433] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 02/16/2023] [Accepted: 02/20/2023] [Indexed: 02/26/2023] Open
Abstract
The rationale for administering immune checkpoint inhibitors (ICIs) in the adjuvant setting is to eradicate micro-metastases and, ultimately, prolong survival. Thus far, clinical trials have demonstrated that 1-year adjuvant courses of ICIs reduce the risk of recurrence in melanoma, urothelial cancer, renal cell carcinoma, non-small cell lung cancer, and esophageal and gastroesophageal junction cancers. Overall survival benefit has been shown in melanoma while survival data are still not mature in other malignancies. Emerging data also show the feasibility of utilizing ICIs in the peri-transplant setting for hepatobiliary malignancies. While ICIs are generally well-tolerated, the development of chronic immune-related adverse events, typically endocrinopathies or neurotoxicities, as well as delayed immune-related adverse events, warrants further scrutiny regarding the optimal duration of adjuvant therapy and requires a thorough risk-benefit determination. The advent of blood-based, dynamic biomarkers such as circulating tumor DNA (ctDNA) can help detect minimal residual disease and identify the subset of patients who would likely benefit from adjuvant treatment. In addition, the characterization of tumor-infiltrating lymphocytes, neutrophil-to-lymphocyte ratio, and ctDNA-adjusted blood tumor mutation burden (bTMB) has also shown promise in predicting response to immunotherapy. Until additional, prospective studies delineate the magnitude of overall survival benefit and validate the use of predictive biomarkers, a tailored, patient-centered approach to adjuvant ICIs that includes extensive patient counseling on potentially irreversible adverse effects should be routinely incorporated into clinical practice.
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Affiliation(s)
- Karen Abboud
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Godsfavour Umoru
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Abdullah Esmail
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA
| | - Ala Abudayyeh
- Section of Nephrology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Naoka Murakami
- Division of Renal Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Humaid O. Al-Shamsi
- Department of Oncology, Burjeel Cancer Institute, Burjeel Medical City, Abu Dhabi P.O. Box 92510, United Arab Emirates
| | - Milind Javle
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ashish Saharia
- JC Walter Jr Center for Transplantation and Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA
| | - Ashton A. Connor
- JC Walter Jr Center for Transplantation and Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA
| | - Sudha Kodali
- JC Walter Jr Center for Transplantation and Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA
| | - Rafik M. Ghobrial
- JC Walter Jr Center for Transplantation and Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA
| | - Maen Abdelrahim
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA
- Cockrell Center of Advanced Therapeutics Phase I Program, Houston Methodist Research Institute, Houston, TX 77030, USA
- Department of Internal Medicine, Weill Cornell Medical College, New York, NY 14853, USA
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13
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Jiang J, Huang H, Chen R, Lin Y, Ling Q. Immunotherapy for hepatocellular carcinoma recurrence after liver transplantation, can we harness the power of immune checkpoint inhibitors? Front Immunol 2023; 14:1092401. [PMID: 36875077 PMCID: PMC9978931 DOI: 10.3389/fimmu.2023.1092401] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 02/03/2023] [Indexed: 02/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death globally and liver transplantation (LT) can serve as the best curative treatment option. However, HCC recurrence after LT remains the major obstacle to the long-term survival of recipients. Recently, immune checkpoint inhibitors (ICIs) have revolutionized the treatment of many cancers and provided a new treatment strategy for post-LT HCC recurrence. Evidence has been accumulated with the real-world application of ICIs in patients with post-LT HCC recurrence. Notably, the use of these agents as immunity boosters in recipients treated with immunosuppressors is still controversial. In this review, we summarized the immunotherapy for post-LT HCC recurrence and conducted an efficacy and safety evaluation based on the current experience of ICIs for post-LT HCC recurrence. In addition, we further discussed the potential mechanism of ICIs and immunosuppressive agents in regulating the balance between immune immunosuppression and lasting anti-tumor immunity.
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Affiliation(s)
- Jingyu Jiang
- Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Health Commission (NHC) Key Laboratory of Combined Multi-Organ Transplantation, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Haitao Huang
- Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Health Commission (NHC) Key Laboratory of Combined Multi-Organ Transplantation, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Ruihan Chen
- Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Health Commission (NHC) Key Laboratory of Combined Multi-Organ Transplantation, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Yimou Lin
- Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Health Commission (NHC) Key Laboratory of Combined Multi-Organ Transplantation, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Qi Ling
- Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Health Commission (NHC) Key Laboratory of Combined Multi-Organ Transplantation, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
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14
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Xu X. State of the art and perspectives in liver transplantation. Hepatobiliary Pancreat Dis Int 2023; 22:1-3. [PMID: 36528548 DOI: 10.1016/j.hbpd.2022.12.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Accepted: 12/02/2022] [Indexed: 02/04/2023]
Affiliation(s)
- Xiao Xu
- Institute of Organ Transplantation, Zhejiang University, Hangzhou 310003, China.
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15
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Lominadze Z, Hill K, Shaik MR, Canakis JP, Bourmaf M, Adams-Mardi C, Abutaleb A, Mishra L, Shetty K. Immunotherapy for Hepatocellular Carcinoma in the Setting of Liver Transplantation: A Review. Int J Mol Sci 2023; 24:2358. [PMID: 36768686 PMCID: PMC9917203 DOI: 10.3390/ijms24032358] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/07/2023] [Accepted: 01/18/2023] [Indexed: 01/27/2023] Open
Abstract
The emerging field of immuno-oncology has brought exciting developments in the treatment of hepatocellular carcinoma (HCC). It has also raised urgent questions about the role of immunotherapy in the setting of liver transplantation, both before and after transplant. A growing body of evidence points to the safety and efficacy of immunotherapeutic agents as potential adjuncts for successful down-staging of advanced HCCs to allow successful transplant in carefully selected patients. For patients with recurrent HCC post-transplant, immunotherapy has a limited, yet growing role. In this review, we describe optimal regimens in the setting of liver transplantation.
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Affiliation(s)
- Zurabi Lominadze
- Division of Gastroenterology & Hepatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Kareen Hill
- Department of Medicine, University of Maryland Medical Center, Baltimore, MD 21201, USA
| | - Mohammed Rifat Shaik
- Department of Medicine, University of Maryland Medical Center Midtown Campus, Baltimore, MD 21201, USA
| | - Justin P. Canakis
- Department of Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA
| | - Mohammad Bourmaf
- Department of Medicine, University of Maryland Medical Center, Baltimore, MD 21201, USA
| | - Cyrus Adams-Mardi
- Department of Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA
| | - Ameer Abutaleb
- Department of Surgery, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA
| | - Lopa Mishra
- Cold Spring Harbor Laboratory, Feinstein Institutes for Medical Research, Division of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY 11030, USA
| | - Kirti Shetty
- Division of Gastroenterology & Hepatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
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16
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Kayali S, Pasta A, Plaz Torres MC, Jaffe A, Strazzabosco M, Marenco S, Giannini EG. Immune checkpoint inhibitors in malignancies after liver transplantation: A systematic review and pooled analysis. Liver Int 2023; 43:8-17. [PMID: 36102312 PMCID: PMC10087158 DOI: 10.1111/liv.15419] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 08/13/2022] [Accepted: 09/06/2022] [Indexed: 01/04/2023]
Abstract
BACKGROUND AND AIMS Treatment of de novo malignancies and recurrent hepatocellular carcinoma with immune checkpoint inhibitors (ICI) in liver transplant recipients (LT) is an attractive strategy that is infrequently pursued because of the lack of strong evidence regarding their safety and efficacy. In this systematic review with pooled analysis, we aimed to assess safety and efficacy of ICI therapy following LT. METHODS We performed a systematic search of case reports and series published until January 2022. We included 31 publications reporting a total of 52 patients treated with ICIs after LT and assessed in a pooled analysis the risk of graft rejection and the outcome of ICI therapy. RESULTS Acute graft rejection occurred in 15 patients (28.8%) and 7 patients (13.4% of the total cohort) died because of graft loss. Rejection was associated with shorter overall survival (OS) (17.2 months, confidence interval [CI] 12.1-22.2 vs. 3.5 months, CI 1.6-5.4, p < 0.001). Disease control rate was 44.2% (n = 23), and in these patients, OS was longer than in non-responders (26.4 months, CI 20.8-32.0 vs. 3.4 months, CI 2.1-4.7, p < 0.001). CONCLUSIONS Observational, off-label experience suggests that treatment with ICI for advanced malignancies in LT recipients might not be discarded a priori. This notwithstanding, ICI treatment in these patients is associated with a substantial risk of graft rejection and mortality. Prospective studies are needed to provide adequate safety and efficacy figures of ICI treatment in this fragile population.
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Affiliation(s)
- Stefano Kayali
- Gastroenterology Unit, Department of Internal Medicine, IRCCS Ospedale Policlinico San Martino, University of Genoa, Genoa, Italy
| | - Andrea Pasta
- Gastroenterology Unit, Department of Internal Medicine, IRCCS Ospedale Policlinico San Martino, University of Genoa, Genoa, Italy
| | - Maria Corina Plaz Torres
- Gastroenterology Unit, Department of Internal Medicine, IRCCS Ospedale Policlinico San Martino, University of Genoa, Genoa, Italy
| | - Ariel Jaffe
- Liver Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.,Smilow Cancer Hospital and Liver Cancer Program, New Haven, Connecticut, USA
| | - Mario Strazzabosco
- Liver Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.,Smilow Cancer Hospital and Liver Cancer Program, New Haven, Connecticut, USA
| | - Simona Marenco
- Gastroenterology Unit, Department of Internal Medicine, IRCCS Ospedale Policlinico San Martino, University of Genoa, Genoa, Italy
| | - Edoardo G Giannini
- Gastroenterology Unit, Department of Internal Medicine, IRCCS Ospedale Policlinico San Martino, University of Genoa, Genoa, Italy
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17
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Jin X, Ma X, Zhao D, Yang L, Ma N. Immune microenvironment and therapeutic progress of recurrent hepatocellular carcinoma after liver transplantation. Transl Oncol 2022; 28:101603. [PMID: 36542991 PMCID: PMC9794975 DOI: 10.1016/j.tranon.2022.101603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 12/07/2022] [Accepted: 12/07/2022] [Indexed: 12/23/2022] Open
Abstract
HCC is a highly lethal tumor, and orthotopic liver transplantation, as one of the radical treatment methods for HCC, has opened-up a new therapeutic approach for the treatment of primary liver cancer. However, tumor recurrence after liver transplantation is the main reason that affects the long-term survival of recipients. At present, the application of ICIs has brought dawn to patients with refractory HCC. However, because of the special immune tolerance state created by long-term oral immunosuppressants in patients with HCC after liver transplantation, the current focus is how to regulate the immune balance of such patients and simultaneously maximize the anti-tumor effect. This article reviews the relationship between liver cancer and immunity, immune tolerance of liver transplantation, immune microenvironment after liver transplantation for HCC, and the application of immunotherapy in the recurrence of liver transplantation for HCC.
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Affiliation(s)
- Xin Jin
- Division of Liver Surgery and Organ Transplantation Center, Shenzhen Third People's Hospital, Second Affiliated Hospital of Southern University of Science and Technology, National Clinical Research Center for Infectious Disease, No.29 Bulan Road, Longgang District, Shenzhen, 518112, Guangdong Province, China
| | - Xiaoting Ma
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Dong Zhao
- Division of Liver Surgery and Organ Transplantation Center, Shenzhen Third People's Hospital, Second Affiliated Hospital of Southern University of Science and Technology, National Clinical Research Center for Infectious Disease, No.29 Bulan Road, Longgang District, Shenzhen, 518112, Guangdong Province, China
| | - Lin Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China,Corresponding authors.
| | - Nan Ma
- Division of Liver Surgery and Organ Transplantation Center, Shenzhen Third People's Hospital, Second Affiliated Hospital of Southern University of Science and Technology, National Clinical Research Center for Infectious Disease, No.29 Bulan Road, Longgang District, Shenzhen, 518112, Guangdong Province, China,Corresponding authors.
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18
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Zhang P, Zhu G, Li L, Lai G, Wang Z, Sun C, Xia W, Wu L. Immune checkpoint inhibitor therapy for malignant tumors in liver transplantation recipients: A systematic review of the literature. Transplant Rev (Orlando) 2022; 36:100712. [PMID: 35870411 DOI: 10.1016/j.trre.2022.100712] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 05/29/2022] [Accepted: 07/01/2022] [Indexed: 02/05/2023]
Abstract
BACKGROUND Treatment for de novo or recurrent tumors of liver transplantation (LT) recipients is challenging and immune checkpoint inhibitor (ICI) is recently well developed and could be a potentially effective option for this population. There remains limited evidence on the safety and efficacy of ICI therapy in LT recipients. METHODS A systematic literature search was conducted on PubMed database through April 1, 2022, to identify publications reporting ICI treatment for malignant tumors in LT recipients. We summarized the allograft rejection, mortality, and tumor response of ICI treatment. RESULTS 24 articles with 41 LT recipients were identified. The age of LT recipients ranged from 14 to 78, 76.2% were male, 56.1% had recurrent HCC, and 87.8% received anti-PD-1 therapy. Allograft rejection occurred in 31.7% of patients, death was reported in 46.3% and 6 cases died secondary to allograft rejection. Progressive disease rate of this population was 48.8% and 10 patients responded to immunotherapy. Half of recipients with positive PD-L1 staining (4/8) experienced allograft rejection. CONCLUSIONS ICI therapy has potential therapeutic value on malignant tumors for LT recipients, accompanied by a high rate of allograft rejection and mortality. PD-L1 expression, type of ICI, and immunosuppression agent should be taken into consideration before initiation of immunotherapy. Further studies are needed to optimize this anticancer treatment approach in these patients.
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Affiliation(s)
- Pinzhe Zhang
- Department of Organ Transplantation, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China; Shantou University Medical College, Shantou, China
| | - Guanghao Zhu
- Department of Organ Transplantation, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China; The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Leping Li
- Department of Organ Transplantation, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China; Shantou University Medical College, Shantou, China
| | - Guanzhi Lai
- Department of Organ Transplantation, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China; Shantou University Medical College, Shantou, China
| | - Zekang Wang
- Department of Organ Transplantation, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Chengjun Sun
- Department of Organ Transplantation, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Wuzheng Xia
- Department of Organ Transplantation, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Linwei Wu
- Department of Organ Transplantation, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Shantou University Medical College, Shantou, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
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19
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Immune checkpoint blockade for organ-transplant recipients with cancer: A review. Eur J Cancer 2022; 175:326-335. [DOI: 10.1016/j.ejca.2022.08.010] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/02/2022] [Accepted: 08/05/2022] [Indexed: 11/24/2022]
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20
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Jin X, Zhang K, Fang T, Zeng X, Yan X, Tang J, Liang Z, Xie L, Zhao D. Low-dose PD-1 inhibitor combined with lenvatinib for preemptive treatment of recurrence after liver transplantation for hepatocellular carcinoma: Case report and literature review. Front Oncol 2022; 12:951303. [PMID: 36119543 PMCID: PMC9478730 DOI: 10.3389/fonc.2022.951303] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 08/10/2022] [Indexed: 11/18/2022] Open
Abstract
Orthotopic liver transplantation (OLT), as one of the curative methods for the treatment of hepatocellular carcinoma (HCC), has brought hope to patients with HCC. However, treatment options for HCC recurrence and metastasis after liver transplantation are limited. Immune checkpoint inhibitor (ICI), such as programmed cell death protein 1 (PD-1) inhibitor, have been successfully used in advanced or metastatic HCC, but the data on the safety of PD-1 inhibitor after liver transplantation is limited. In this article, we report a 47-year-old patient with acute-on-chronic liver failure and multiple HCC who was successfully treated with liver transplantation. On the 45th day after OLT, the patient’s alpha fetoprotein (AFP) and lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) were increased, and imaging examination showed no residual tumor. The patient had high risk factors for tumor recurrence before operation, so the possibility of tumor recurrence was considered. When the tumor markers showed an upward trend, we immediately treated the patient with lenvatinib 8 mg, after half a month, the AFP and AFP-L3 continued to increase compared with before. Then we used low-dose nivolumab 40mg, the patient’s AFP and AFP-L3 gradually decreased. One month later, a second low-dose nivolumab 40mg was given, and the patient’s tumor markers gradually decreased to normal. No acute rejection and other complications occurred during the treatment. So far, we have followed up this patient for 2 years, and no tumor recurrence was observed. To our knowledge, this is the first reported case using a low dose of nivolumab in combination with lenvatinib to prevent recurrence of HCC after liver transplantation.
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21
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Xie M, Dang ZP, Sun XG, Zhang B, Zhang Q, Tian QJ, Cai JZ, Rao W. An analysis report on the application of immune checkpoint inhibitors after liver transplantation. Ther Adv Chronic Dis 2022; 13:20406223221099334. [PMID: 35620187 PMCID: PMC9127875 DOI: 10.1177/20406223221099334] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 04/21/2022] [Indexed: 01/05/2023] Open
Abstract
Up to now, a variety of immune checkpoint inhibitors (ICIs) have been proved to have good therapeutic effects in the treatment of hepatocellular carcinoma (HCC). However, the effects of their applications in liver transplant (LT) recipients are still unclear. In this analysis report, the clinical applications and therapeutic effects of ICIs on LT recipients with hepatic tumor recurrence or de novo carcinoma based on eight databases, including PubMed, EMBASE, Web of Science, Google Scholar, China National Knowledge Infrastructure, Wanfang Data, and CQVIP, were investigated. And the prior treatment, disease response, adverse reactions, and prognosis of patients with malignant tumors after LT and receiving ICI treatments were analyzed. After screening, a total of 28 articles with 47 recipients on the application of ICIs after LT were included. In these patients, their median age was 57 (14–71) years and the main type of tumor after LT was HCC (59.6%). The overall remission rate following ICI treatment was 29.8% (14/47) and the disease progression rate was 68.1% (32/47). Among all these patients, 31.9% (15/47) of patients had immune rejection; the median survival time was 6.5 (0.3–48) months, and the fatality rate was 61.7% (29/47). Considering that the therapeutic effect of ICIs in LT recipients with HCC recurrence or de novo carcinoma is not ideal, ICI treatment should be carefully considered for LT patients, and further research is needed.
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Affiliation(s)
- Man Xie
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zhi-ping Dang
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xue-guo Sun
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Bei Zhang
- Department of Immunology, Medical College of Qingdao University, Qingdao, China
| | - Qun Zhang
- Division of Hepatology, Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China
- Department of Organ Transplantation, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Qiu-ju Tian
- Division of Hepatology, Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China
- Department of Organ Transplantation, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jin-zhen Cai
- Division of Hepatology, Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China
- Department of Organ Transplantation, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wei Rao
- Division of Hepatology, Liver Disease Center, Department of Organ Transplantation, The Affiliated Hospital of Qingdao University, No. 59 Hai’er Road, Laoshan District, Qingdao City 266600, Shandong Province, China
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22
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Luo Y, Teng F, Fu H, Ding GS. Immunotherapy in liver transplantation for hepatocellular carcinoma: Pros and cons. World J Gastrointest Oncol 2022; 14:163-180. [PMID: 35116109 PMCID: PMC8790424 DOI: 10.4251/wjgo.v14.i1.163] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 06/30/2021] [Accepted: 12/08/2021] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation (LT) has emerged as a curative strategy for hepatocellular carcinoma (HCC), but contributes to a higher predisposition to HCC recurrence in the immunosuppression context, especially for tumors beyond the Milan criteria. Although immunotherapy has dramatically improved survival for immunocompetent patients and has become the standard of care for a variety of tumors, including HCC, it is mainly used outside the scope of organ transplantation owing to potentially fatal allograft rejection. Nevertheless, accumulative evidence has expanded the therapeutic paradigms of immunotherapy for HCC, from downstaging or bridging management in the pretransplant setting to the salvage or adjuvant strategy in the posttransplant setting. Generally, immunotherapy mainly includes immune checkpoint inhibitors (ICIs), adoptive cell transfer (ACT) and vaccine therapy. ICIs, followed by ACT, have been most investigated in LT, with some promising results. Because of the complex tumor microenvironment and immunoreactivity when immunosuppressants are combined with immunotherapy, it is difficult to reach formulations for immunosuppressant adjustment and the optimal selection of immunotherapy as well as patients. In addition, the absence of effective biomarkers for identifying rejection and tumor response is still an unresolved barrier to successful clinical immunotherapy applications for LT. In this review, we comprehensively summarize the available evidence of immunotherapy used in LT that is specific to HCC. Moreover, we discuss clinically concerning issues regarding the concurrent goals of graft protection and antitumor response.
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Affiliation(s)
- Yi Luo
- Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Fei Teng
- Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Hong Fu
- Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Guo-Shan Ding
- Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
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23
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Lyu N, Yi JZ, Zhao M. Immunotherapy in older patients with hepatocellular carcinoma. Eur J Cancer 2021; 162:76-98. [PMID: 34954439 DOI: 10.1016/j.ejca.2021.11.024] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 10/31/2021] [Accepted: 11/21/2021] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common types of cancer globally and is currently the third leading cause of cancer-related deaths. Recently, immunotherapy using immune checkpoint inhibitors (ICIs) has been shown with encouraging anticancer activity and safety in clinical trials. To reverse the phenomenon of tumours evading immune response, ICIs can be used to stimulate the natural antitumour potential of cancer cells by blocking the relevant checkpoints to activate T cells. However, the components and functions of the immune system may undergo a series of changes with ageing, known as 'immunosenescence,' potentially affecting the antitumour effect and safety of immunotherapy. In the current phase III clinical trials of ICIs including nivolumab, pembrolizumab and atezolizumab, the proportion of patients with HCC older than 65 years in CheckMate 459, KEYNOTE-240 and IMbrave150 is 51%, 58% and 50%, respectively, which is less than 70%-73% of epidemiological investigation. Therefore, the elderly population recruited in clinical trials may not accurately represent the real-world elderly patients with HCC, which affects the extrapolation of the efficacy and safety profile obtained in clinical trials to the elderly population in the real world. This review provides the latest advances in ICIs immuno-treatment available for HCC and relevant information about their therapeutic effects and safety on elderly patients. We discuss the benefits of ICIs for older HCC patients, and relevant recommendations about conducting further clinical trials are proposed for more complete answers to this clinical issue.
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Affiliation(s)
- Ning Lyu
- Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jun-Zhe Yi
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Ming Zhao
- Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
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24
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Ao H, Xin Z, Jian Z. Liquid biopsy to identify biomarkers for immunotherapy in hepatocellular carcinoma. Biomark Res 2021; 9:91. [PMID: 34930486 PMCID: PMC8686238 DOI: 10.1186/s40364-021-00348-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 11/03/2021] [Indexed: 12/12/2022] Open
Abstract
The past years have witnessed the vigorous development of immunotherapy, mainly immune checkpoint inhibitors (ICIs) targeting the programmed cell death-1 (PD-1) protein and its ligand, PD-L1, and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). Indeed, ICIs have largely revolutionized the management and improved the prognosis of patients with intermediate and advanced hepatocellular carcinoma (HCC). However, biomarker-based stratification of HCC patients for optimal response to ICI treatment is still of unmet need and again, there exists the necessity to dynamically monitor treatment effect in real-time manner. The role of conventional biomarkers in immunotherapy surveillance is largely limited by spatial and temporal tumor heterogeneity whereas liquid biopsy seems to be promising to circumvent tumor heterogeneity to identify candidate patients who may response to immunotherapy, to dynamically monitor treatment effect and to unveil resistance mechanism. Herein, we provide a thorough review about the potential utility of liquid biopsy in immunotherapy for HCC and discuss its future perspectives.
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Affiliation(s)
- Huang Ao
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education; Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Zhang Xin
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education; Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Zhou Jian
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education; Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Institute of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
- State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China.
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, China.
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25
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Halma J, Pierce S, McLennan R, Bradley T, Fischer R. Natural killer cells in liver transplantation: Can we harness the power of the immune checkpoint to promote tolerance? Clin Transl Sci 2021; 15:1091-1103. [PMID: 34866338 PMCID: PMC9099129 DOI: 10.1111/cts.13208] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 08/30/2021] [Accepted: 11/14/2021] [Indexed: 11/29/2022] Open
Abstract
The roles that natural killer (NK) cells play in liver disease and transplantation remain ill‐defined. Reports on the matter are often contradictory, and the mechanisms elucidated are complex and dependent on the context of the model tested. Moreover, NK cell attributes, such as receptor protein expression and function differ among species, make study of primate or rodent transplant models challenging. Recent insights into NK function and NK‐mediated therapy in the context of cancer therapy may prove applicable to transplantation. Of specific interest are immune checkpoint molecules and the mechanisms by which they modulate NK cells in the tumor micro‐environment. In this review, we summarize NK cell populations in the peripheral blood and liver, and we explore the data regarding the expression and function of immune checkpoint molecules on NK cells. We also hypothesize about the roles they could play in liver transplantation and discuss how they might be harnessed therapeutically in transplant sciences.
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Affiliation(s)
- Jennifer Halma
- Pediatric Gastroenterology, Children's Mercy Kansas City, Kansas City, Missouri, USA
| | - Stephen Pierce
- Genomic Medicine Center, Children's Mercy Kansas City, Kansas City, Missouri, USA
| | - Rebecca McLennan
- Genomic Medicine Center, Children's Mercy Kansas City, Kansas City, Missouri, USA
| | - Todd Bradley
- Genomic Medicine Center, Children's Mercy Kansas City, Kansas City, Missouri, USA.,Pediatrics, University of Missouri-Kansas City, Kansas City, Missouri, USA
| | - Ryan Fischer
- Pediatric Gastroenterology, Children's Mercy Kansas City, Kansas City, Missouri, USA.,Pediatrics, University of Missouri-Kansas City, Kansas City, Missouri, USA
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26
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Vogel A, Sterneck M, Vondran F, Waidmann O, Klein I, Lindig U, Nadalin S, Settmacher U, Tacke F, Schlitt HJ, Wege H. [The use of immuno-oncologic therapy in hepatocellular carcinoma in the context of liver transplantation. An interdisciplinary benefit/risk assessment]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2021; 60:184-191. [PMID: 34670296 DOI: 10.1055/a-1649-8643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
BACKGROUND Multiple systemic therapy options have been recently approved for the treatment of hepatocellular carcinoma (HCC). In particular, immuno-oncology combination therapies can now achieve impressive response rates and significantly prolonged survival with good tolerability. These immuno-oncology (IO)-based combinations are currently not only evaluated for the therapy of advanced HCC, but increasingly also in earlier stages in terms of peri-interventional therapy concepts and also for down-sizing to local therapies. In the context of liver transplantation (LTx), a particularly critical benefit/risk assessment must be made before the use of immunotherapeutics in the context of multimodal concepts, since the risk of a potentially lethal rejection can be significantly increased by immunotherapy. METHODS This review is based on a selective literature search performed between December 2020 and April 2021 in the PubMed and Cochrane Library databases. Guidelines, expert opinions, and recommendations from professional societies were given special consideration. RESULTS Nearly one in five LTx in Germany are performed due to HCCs. In this context, LTx is a curative therapy option not only for the underlying liver disease but also for the malignant tumor. Individual case reports indicate that IO therapy prior to LTx may increase the risk of rejection or liver failure after subsequent liver transplantation. Since 2015, immunotherapeutics have also been widely used for tumor therapy in patients after LTx. In small case series, rejection rates of 36%, associated with rejection-related mortality of 20% of treated patients, have been described. A similar incidence of rejection has also been described following the use of immunotherapeutics in patients after other organ transplantations. CONCLUSION In the context of organ transplantation, IO therapy carries the risk of graft rejection, which can lead to graft loss and also patient death. However, from today's point of view, IO-based therapy can be considered in the context of organ transplantation with a careful benefit/risk assessment.
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Affiliation(s)
- Arndt Vogel
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Deutschland
| | - Martina Sterneck
- I. Medizinische Klinik und Poliklinik, UKE Hamburg, Hamburg, Deutschland
| | - Florian Vondran
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Medizinische Hochschule Hannover, Hannover, Deutschland
| | - Oliver Waidmann
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Ingo Klein
- Klinik und Poliklinik für Allgemein-, Viszeral-, Transplantations-, Gefäß- und Kinderchirurgie, Universitätsklinikum Würzburg, Würzburg, Deutschland
| | - Udo Lindig
- Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Deutschland
| | - Silvio Nadalin
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - Utz Settmacher
- Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Jena, Deutschland
| | - Frank Tacke
- Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Charité - Universitätsmedizin Berlin, Berlin, Deutschland
| | - Hans Jürgen Schlitt
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg, Regensburg, Deutschland
| | - Henning Wege
- I. Medizinische Klinik und Poliklinik, UKE Hamburg, Hamburg, Deutschland.,Cancer Center Esslingen, Klinikum Esslingen, Esslingen, Deutschland
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27
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L R, T I, Mpaw C, H M, G S. THE MANAGEMENT OF POST-TRANSPLANTATION RECURRENCE OF HEPATOCELLULAR CARCINOMA. Clin Mol Hepatol 2021; 28:1-16. [PMID: 34610652 PMCID: PMC8755475 DOI: 10.3350/cmh.2021.0217] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 10/03/2021] [Indexed: 11/15/2022] Open
Abstract
The annual incidence of hepatocellular carcinoma (HCC) continues to rise. Over the last two decades, liver transplantation (LT) has become the preferable treatment of HCC, when feasible and strict selection criteria are met. With the rise in HCC-related LT, compounded by downstaging techniques and expansion of transplant selection criteria, a parallel increase in number of post-transplantation HCC recurrence is expected. Additionally, in the context of an immunosuppressed transplant host, recurrences may behave aggressively and more challenging to manage, resulting in poor prognosis. Despite this, no consensus or best practice guidelines for post-transplantation cancer surveillance and recurrence management for HCC currently exist. Studies with adequate population sizes and high-level evidence are lacking, and the role of systemic and locoregional therapies for graft and extrahepatic recurrences remains under debate. This review seeks to summarize the existing literature on post-transplant HCC surveillance and recurrence management. It highlights the value of early tumour detection, re-evaluating the immunosuppression regimen, and staging to differentiate disseminated recurrence from intrahepatic or extrahepatic oligo-recurrence. This ultimately guides decision-making and maximizes treatment effect. Treatment recommendations specific to recurrence type are provided based on currently available locoregional and systemic therapies.
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Affiliation(s)
- Rajendran L
- Division of General Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Ivanics T
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada.,Department of Surgery, Henry Ford Hospital, Detroit, MI, USA.,Department of Surgical Sciences, Akademiska Sjukhuset, Uppsala University, Uppsala, Sweden
| | - Claasen Mpaw
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada.,Department of Surgery, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands
| | - Muaddi H
- Division of General Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Sapisochin G
- Division of General Surgery, University of Toronto, Toronto, Ontario, Canada.,Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
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28
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Maggiore U, Palmisano A, Buti S, Claire Giudice G, Cattaneo D, Giuliani N, Fiaccadori E, Gandolfini I, Cravedi P. Chemotherapy, targeted therapy and immunotherapy: Which drugs can be safely used in the solid organ transplant recipients? Transpl Int 2021; 34:2442-2458. [PMID: 34555228 PMCID: PMC9298293 DOI: 10.1111/tri.14115] [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: 06/10/2021] [Revised: 08/04/2021] [Accepted: 09/03/2021] [Indexed: 11/29/2022]
Abstract
In solid organ transplant recipients, cancer is associated with worse prognosis than in the general population. Among the causes of increased cancer‐associated mortality, are the limitations in selecting the optimal anticancer regimen in solid organ transplant recipients, because of the associated risks of graft toxicity and rejection, drug‐to‐drug interactions, reduced kidney or liver function, and patient frailty and comorbid conditions. The advent of immunotherapy has generated further challenges, mainly because checkpoint inhibitors increase the risk of rejection, which may have life‐threatening consequences in recipients of life‐saving organs. In general, there are no safe or unsafe anticancer drugs. Rather, the optimal choice of the anticancer regimen results from a careful risk/benefit assessment, from the awareness of potential pharmacokinetic and pharmacodynamic drug‐to‐drug interactions, and of the risk of drug overexposure in patients with kidney or liver dysfunction. In this review, we summarize general principles that may help the oncologists and transplant physicians in the multidisciplinary management of recipients of solid organ transplantation with cancer who are candidates for chemotherapy, targeted therapy, or immunotherapy.
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Affiliation(s)
- Umberto Maggiore
- Department of Medicine and Surgery, University of Parma, Parma, Italy.,Nephrology Unit, University Hospital of Parma, Parma, Italy
| | | | - Sebastiano Buti
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | | | - Dario Cattaneo
- Unit of Clinical Pharmacology, ASST Fatebenefratelli Sacco University Hospital, Milan, Italy
| | - Nicola Giuliani
- Department of Medicine and Surgery, University of Parma, Parma, Italy.,Hematology Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Enrico Fiaccadori
- Department of Medicine and Surgery, University of Parma, Parma, Italy.,Nephrology Unit, University Hospital of Parma, Parma, Italy
| | - Ilaria Gandolfini
- Department of Medicine and Surgery, University of Parma, Parma, Italy.,Nephrology Unit, University Hospital of Parma, Parma, Italy
| | - Paolo Cravedi
- Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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29
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Qiao ZY, Zhang ZJ, Lv ZC, Tong H, Xi ZF, Wu HX, Chen XS, Xia L, Feng H, Zhang JJ, Xia Q. Neoadjuvant Programmed Cell Death 1 (PD-1) Inhibitor Treatment in Patients With Hepatocellular Carcinoma Before Liver Transplant: A Cohort Study and Literature Review. Front Immunol 2021; 12:653437. [PMID: 34349755 PMCID: PMC8326904 DOI: 10.3389/fimmu.2021.653437] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 06/25/2021] [Indexed: 12/12/2022] Open
Abstract
Programmed cell death 1 (PD-1) blockade is considered contraindicated in liver transplant (LT) recipients due to potentially lethal consequences of graft rejection and loss. Though post-transplant PD-1 blockade had already been reported, pre-transplant use of PD-1 blockade has not been thoroughly investigated. This study explores the safety and efficacy of neoadjuvant PD-1 blockade in patients with hepatocellular carcinoma (HCC) after registration on the waiting list. Seven transplant recipients who underwent neoadjuvant PD-1 blockade combined with lenvatinib and subsequent LT were evaluated. The objective response rate (ORR) and disease control rate (DCR) was 71% and 85% according to the mRECIST criteria. Additionally, a literature review contained 29 patients were conducted to summarize the PD-1 blockade in LT for HCC. Twenty-two LT recipients used PD-1 inhibitors for recurrent HCC. 9.1% (2/22) and 4.5% (1/22) recipients achieved complete remission (CR) and partial remission (PR), respectively; 40.9% (9/22) recipients had progressive disease (PD). Allograft rejection occurred in 45% of patients. In total, seven patients from our center and three from the literature used pretransplant anti-PD-1 antibodies, eight patients (80%) had a PR, and the disease control rate was 100%. Biopsy-proven acute rejection (BPAR) incidence was 30% (3 in 10 patients), two patients died because of BPAR. This indicated that neoadjuvant PD-1-targeted immunotherapy plus tyrosine kinase inhibitors (TKI) exhibited promising efficacy with tolerable mortality in transplant recipients under close clinical monitoring.
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Affiliation(s)
- Zi-Yun Qiao
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zi-Jie Zhang
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zi-Cheng Lv
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Huan Tong
- Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Shanghai, China
| | - Zhi-Feng Xi
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hao-Xiang Wu
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiao-Song Chen
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Engineering Research Centre of Transplantation and Immunology, Shanghai, China
| | - Lei Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Engineering Research Centre of Transplantation and Immunology, Shanghai, China
| | - Hao Feng
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Engineering Research Centre of Transplantation and Immunology, Shanghai, China.,Shanghai Institute of Transplantation, Shanghai, China
| | - Jian-Jun Zhang
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Engineering Research Centre of Transplantation and Immunology, Shanghai, China.,Shanghai Institute of Transplantation, Shanghai, China
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Miao K, Zhang L. Application of Immune Checkpoint Inhibitors in Solid Organ Transplantation Recipients: A Systematic Review. Interdiscip Sci 2021; 13:801-814. [PMID: 34152556 DOI: 10.1007/s12539-021-00437-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 04/29/2021] [Accepted: 05/06/2021] [Indexed: 01/26/2023]
Abstract
BACKGROUND Solid organ transplantation (SOT) is a treatment method for end-stage organ diseases and improve their life quality, while using long-term immunosuppressant drugs (ISD) is needed to suppress the function of the immune system. Immune checkpoint inhibitors (ICIs) are a class of anti-tumor drugs that kill tumors by activating the autoimmune system. The primary objective of our systematic review is to investigate the risk factors for organ rejection and the efficacy of ICIs in solid organ transplantation recipients (SOTRs). METHODS We searched four databases to find relevant articles up to January 2021. A total of 61 articles involving 106 SOTRs met the screening criteria and were included in our systematic review. The collected data were statistical described, and the risk factors were analyzed by logistic regression. RESULTS Forty-four patients (41.5%) developed host-versus-graft response (HVGR) after ICIs. mTOR inhibitors (pre-ICIs) (p = 0.069, OR = 0.377, 95% CI 0.132-1.078) and calcineurin inhibitors (post-ICIs) (p = 0.056, OR = 0.375, 95%CI 0.137-1.025) may help reduce the incidence of HVGR. Hormones (pre-ICIs) (p = 0.026, OR = 3.150, 95%CI 1.150-8.628) and anti-metabolites (pre-ICIs) (p = 0.022, OR = 3.214, 95%CI 1.185-8.720) may adversely affect the efficacy of ICIs. Only 35.6% of patients both responded well to ICIs treatment and did not develop HVGR. CONCLUSIONS Our systematic review summarizes the use of ICIs in SOTRs and evaluates the efficacy of ICIs and the risk factors that induce HVGR. Through risk factor analysis, we found that mTOR inhibitors and calcineurin inhibitors may help to reduce the occurrence of HVGR; hormones and anti-metabolic drugs may have adverse effects on the efficacy of ICIs. In addition, there is a contradictory relationship between the occurrence of HVGR and the efficacy of ICIs.
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Affiliation(s)
- Kang Miao
- Department of Pulmonary and Critical Care Medicine, Peking Union Medical Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 53 Dongdan North Avenue, Dongcheng District, Beijing, China
| | - Li Zhang
- Department of Pulmonary and Critical Care Medicine, Peking Union Medical Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 53 Dongdan North Avenue, Dongcheng District, Beijing, China.
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31
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Ziogas IA, Evangeliou AP, Giannis D, Hayat MH, Mylonas KS, Tohme S, Geller DA, Elias N, Goyal L, Tsoulfas G. The Role of Immunotherapy in Hepatocellular Carcinoma: A Systematic Review and Pooled Analysis of 2,402 Patients. Oncologist 2021; 26:e1036-e1049. [PMID: 33314549 PMCID: PMC8176986 DOI: 10.1002/onco.13638] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 12/03/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Immune checkpoints inhibitors (ICIs) have emerged as a treatment option for several malignancies. Nivolumab, pembrolizumab, nivolumab plus ipilimumab, and atezolizumab plus bevacizumab have been approved for the management of advanced-stage hepatocellular carcinoma (HCC). We aimed to systematically review the literature and summarize the characteristics and outcomes of patients with HCC treated with ICIs. METHODS A systematic literature search of PubMed, the Cochrane Library, and ClinicalTrials.gov was performed according to the PRISMA statement (end of search date: November 7, 2020). Quality of evidence assessment was also performed. RESULTS Sixty-three articles including 2,402 patients were analyzed, 2,376 of whom received ICIs for unresectable HCC. Response to ICIs could be evaluated in 2,116 patients; the overall objective response rate (ORR) and disease control rate (DCR) were 22.7% and 60.7%, respectively, and the mean overall survival (OS) was 15.8 months. The ORR, DCR, and OS for nivolumab (n = 846) were 19.7%, 51.1%, and 18.7 months, respectively; for pembrolizumab (n = 435) they were 20.7%, 64.6% and 13.3 months, respectively. The combination of atezolizumab/bevacizumab (n = 460) demonstrated an ORR and DCR of 30% and 77%, respectively. The overall rate of treatment discontinuation because of adverse events was 14.9%. Fifteen patients received ICIs in the liver transplant (LT) setting (one pre-LT for bridging, 14 for post-LT recurrence); fatal graft rejection was reported in 40.0% (n = 6/15) and mortality in 80.0% (n = 12/15). CONCLUSION ICIs are safe and effective against unresectable HCC, but caution is warranted regarding their use in the LT setting because of the high graft rejection rate. IMPLICATIONS FOR PRACTICE This systematic review pooled the outcomes from studies reporting on the use of immune checkpoint inhibitors (ICIs) for the management of 2,402 patients with advanced-stage hepatocellular carcinoma (HCC), 2,376 of whom had unresectable HCC. The objective response rate and disease control rate were 22.7% and 60.7%, respectively, and the mean overall survival was 15.8 months. The overall rate of treatment discontinuation because of adverse events was 14.9%. Fifteen patients received ICIs in the liver transplant (LT) setting (one pre-LT for bridging, 14 for post-LT recurrence). Six of these patients experienced graft rejection (40.0%).
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Affiliation(s)
- Ioannis A. Ziogas
- First Department of Surgery, Aristotle University of ThessalonikiThessalonikiGreece
- Surgery Working Group, Society of Junior DoctorsAthensGreece
| | | | - Dimitrios Giannis
- Surgery Working Group, Society of Junior DoctorsAthensGreece
- Institute of Health Innovations and Outcomes Research, The Feinstein Institute for Medical ResearchManhasset, New YorkUSA
| | - Muhammad H. Hayat
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical CenterNashvilleTennesseeUSA
| | | | - Samer Tohme
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, University of Pittsburgh Medical CenterPittsburghPennsylvaniaUSA
| | - David A. Geller
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, University of Pittsburgh Medical CenterPittsburghPennsylvaniaUSA
| | - Nahel Elias
- Transplantation Unit, Department of Surgery, Massachusetts General Hospital and Harvard Medical SchoolBostonMassachusettsUSA
| | - Lipika Goyal
- Department of Medicine, Division of Medical Oncology, Massachusetts General Hospital and Harvard Medical SchoolBostonMassachusettsUSA
| | - Georgios Tsoulfas
- First Department of Surgery, Aristotle University of ThessalonikiThessalonikiGreece
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Bittner A, Radke J, Eurich D, Wiener E, Denker S, Anagnostopoulos I, Na IK, Heppner FL, Bullinger L, Schmitt CA. Cerebral EBV-positive PTLD controlled by PD-1 checkpoint blockade in a liver transplant patient. Leuk Lymphoma 2021; 62:2026-2029. [PMID: 33612072 DOI: 10.1080/10428194.2021.1889537] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Affiliation(s)
- Aitomi Bittner
- Department of Hematology, Oncology and Tumor Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Josefine Radke
- Berlin Institute of Health (BIH), Berlin, Germany.,German Cancer Consortium (DKTK), Berlin, Germany.,Department of Neuropathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Dennis Eurich
- Department of Surgery, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Edzard Wiener
- Institute of Neuroradiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Sophy Denker
- Department of Hematology, Oncology and Tumor Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | | | - Il-Kang Na
- Department of Hematology, Oncology and Tumor Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.,Berlin Institute of Health (BIH), Berlin, Germany.,German Cancer Consortium (DKTK), Berlin, Germany.,Experimental and Clinical Research Center (ECRC), Berlin, Germany.,BIH Centre for Regenerative Therapies, Berlin, Germany
| | - Frank L Heppner
- Berlin Institute of Health (BIH), Berlin, Germany.,Department of Neuropathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.,Cluster of Excellence, NeuroCure, Berlin, Germany.,German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany
| | - Lars Bullinger
- Department of Hematology, Oncology and Tumor Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.,Berlin Institute of Health (BIH), Berlin, Germany.,German Cancer Consortium (DKTK), Berlin, Germany.,Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Clemens A Schmitt
- Department of Hematology, Oncology and Tumor Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.,German Cancer Consortium (DKTK), Berlin, Germany.,Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.,Department of Hematology and Oncology, Kepler University Hospital, Johannes Kepler University, Linz, Austria
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33
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Patel K, Lamm R, Altshuler P, Dang H, Shah AP. Hepatocellular Carcinoma-The Influence of Immunoanatomy and the Role of Immunotherapy. Int J Mol Sci 2020; 21:ijms21186757. [PMID: 32942580 PMCID: PMC7555667 DOI: 10.3390/ijms21186757] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 09/09/2020] [Accepted: 09/14/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related morbidity and mortality worldwide. Most patients are diagnosed with advanced disease, limiting their options for treatment. While current treatments are adequate for lower staged disease, available systemic treatments are limited, with marginal benefit at best. Chimeric antigen receptor (CAR) T cell therapy, effective in treating liquid tumors such as B-cell lymphoma, presents a potentially promising treatment option for advanced HCC. However, new challenges specific to solid tumors, such as tumor immunoanatomy or the immune cell presence and position anatomically and the tumor microenvironment, need to be defined and overcome. Immunotherapy currently in use must be re-engineered and re-envisioned to treat HCC with the hopes of ushering in an answer to advanced stage solid tumor disease processes. Future therapy options must address the uniqueness of the tumors under the umbrella of HCC. This review strives to summarize HCC, its staging system, current therapy and immunotherapy medications currently being utilized or studied in the treatment of HCC with the hopes of highlighting what is being done and suggesting what needs to be done in the future to champion this therapy as an effective option.
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Affiliation(s)
- Keyur Patel
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19144, USA; (K.P.); (R.L.); (P.A.)
| | - Ryan Lamm
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19144, USA; (K.P.); (R.L.); (P.A.)
| | - Peter Altshuler
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19144, USA; (K.P.); (R.L.); (P.A.)
| | - Hien Dang
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19144, USA; (K.P.); (R.L.); (P.A.)
- Sidney Kimmel Cancer Center, Philadelphia, PA 19107, USA
- Correspondence: (H.D.); (A.P.S.)
| | - Ashesh P. Shah
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19144, USA; (K.P.); (R.L.); (P.A.)
- Correspondence: (H.D.); (A.P.S.)
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