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Lu JL, Cheng Y, Xu ZL, Qian GX, Wei MT, Jia WD. Immune checkpoint inhibitors plus anti-angiogenesis in patients with resected high-risk hepatitis B virus-associated hepatocellular carcinoma. World J Gastrointest Oncol 2025; 17:101371. [DOI: 10.4251/wjgo.v17.i4.101371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 01/25/2025] [Accepted: 02/13/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Currently, there is a lack of effective adjuvant therapies for patients at high-risk of recurrent hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) after radical resection. Given the efficacy of anti-programmed death 1/anti-programmed death ligand 1 plus anti-vascular endothelial growth factor receptor agents in advanced HCC, we conducted this study to investigate the efficacy of this combination regimen in the postoperative adjuvant treatment of patients with HBV-HCC.
AIM To evaluate the value of postoperative combined therapy (PCT) with anti-programmed death 1/anti-programmed death ligand 1 and anti-vascular endothelial growth factor receptor agents in patients with HBV-HCC.
METHODS Patients with HBV-HCC who underwent radical resection surgery at Anhui Provincial Hospital Affiliated to Anhui Medical University between July 2020 and April 2023 were included. Recurrence-free survival (RFS) and overall survival were assessed using propensity score matching and inverse probability of treatment weighting. Cox regression analysis was used to identify factors affecting recurrence, and subgroup analysis was conducted to investigate the impact of medications on different populations. Treatment-related adverse events and liver function measurements were evaluated.
RESULTS A total of 150 patients were recruited, of whom 30 underwent PCT and 120 did not. After adjusting for confounders, patients who underwent PCT had better RFS at 6 and 12 months than those who did not (P > 0.05). Similar results were observed in the Kaplan-Meier curves after propensity score matching or inverse probability of treatment weighting, although the difference was not statistically significant (P > 0.05). A maximum diameter of > 5 cm, vascular invasion, satellite nodules, and high gamma-glutamyl transferase levels were independent risk factors for recurrence (P < 0.05). No significant interaction effects were observed in subgroup analyses. The most prevalent adverse event was hypertension (66.7%). PCT was associated with an increased risk of hepatic impairment which may predict RFS rates (P = 0.041).
CONCLUSION The recurrence rate was not significantly reduced in patients who underwent PCT. Hepatic impairment during treatment may indicate recurrence, and close monitoring of liver function and HBV infection is recommended.
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Affiliation(s)
- Jian-Lin Lu
- Department of Hepatic Surgery, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei 230001, Anhui Province, China
| | - Yuan Cheng
- Department of Hepatic Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230001, Anhui Province, China
| | - Zi-Ling Xu
- Department of Hepatic Surgery, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei 230001, Anhui Province, China
| | - Gui-Xiang Qian
- Department of Hepatic Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230001, Anhui Province, China
| | - Ming-Tong Wei
- Department of Hepatic Surgery, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei 230001, Anhui Province, China
| | - Wei-Dong Jia
- Department of Hepatic Surgery, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei 230001, Anhui Province, China
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Jiang Y, Li R, Li X, Zhang N. Risk Factors of Immune-Mediated Hepatotoxicity Induced by Immune Checkpoint Inhibitors in Cancer Patients: A Systematic Review and Meta-Analysis. Curr Oncol 2024; 31:7129-7143. [PMID: 39590156 PMCID: PMC11593173 DOI: 10.3390/curroncol31110525] [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: 09/25/2024] [Revised: 10/27/2024] [Accepted: 11/09/2024] [Indexed: 11/28/2024] Open
Abstract
Immune checkpoint inhibitors (ICIs) significantly improve survival, while immune-mediated hepatotoxicity (IMH) has been reported. To evaluate the incidence and potential risk factors of IMH among cancer patients treated by ICIs, PubMed/Medline, Web of Science, Cochrane, and Embase were searched before 30 March 2024 for systematic review and meta-analysis. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated. Quality assessment was completed using the Newcastle-Ottawa scale. Of 1217 articles identified, 24 consisting of 9076 patients were included, with one study being prospective and the rest retrospective. The overall incidence of any grade IMH and grade ≥ 3 secondary to ICIs was 14% and 7%, respectively. The cholestatic pattern was more prevalent than the hepatocellular and mixed patterns. The meta-analysis revealed that ICI treatment was related to reduced risk of IMH in older patients (SMD: -0.18; 95% CI: -0.33 to -0.04), individuals with higher body mass index (WMD: -2.15; 95% CI: -3.92 to -0.38), males (OR: 0.44; 95% CI: 0.27 to 0.72), and patients with lung cancer (OR: 0.58, 95%CI 0.41 to 0.83). On the other hand, patients with liver metastasis (OR: 1.80; 95% CI: 1.47 to 2.20), history of ICI treatment (OR: 3.09; 95% CI: 1.21 to 7.89), diabetes (OR: 2.19; 95% CI: 1.36 to 3.51), chronic HBV (OR: 3.06; 95% CI: 1.11 to 8.46), and concomitant use of ICIs (OR: 8.73; 95% CI: 2.41 to 31.59) increased the risk of developing IMH. This study will provide clinicians with information on potentially high-risk groups for IMH, who need to be cautiously monitored for liver function when receiving immunotherapy.
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Affiliation(s)
- Ying Jiang
- Department of Pharmacy, Zhongshan Hospital Fudan University, Shanghai 200032, China; (Y.J.); (R.L.)
| | - Ranyi Li
- Department of Pharmacy, Zhongshan Hospital Fudan University, Shanghai 200032, China; (Y.J.); (R.L.)
| | - Xiaoyu Li
- Department of Pharmacy, Zhongshan Hospital Fudan University, Shanghai 200032, China; (Y.J.); (R.L.)
| | - Ningping Zhang
- Department of Gastroenterology, Zhongshan Hospital Fudan University, Shanghai 200032, China
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Hwang SY, Hsieh P, Zhang W. Steroid-refractory immune checkpoint inhibitor (ICI) hepatitis and ICI rechallenge: A systematic review and meta-analysis. Hepatol Commun 2024; 8:e0525. [PMID: 39298568 PMCID: PMC11412713 DOI: 10.1097/hc9.0000000000000525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 07/31/2024] [Indexed: 09/22/2024] Open
Abstract
BACKGROUND In recent years, the use of immune checkpoint inhibitors (ICIs) has become a cornerstone in cancer treatment. However, this has also resulted in the emergence of immune-related adverse events, notably ICI hepatitis, posing a significant clinical challenge. While steroids are the primary treatment, there are increasing cases of steroid-refractory ICI hepatitis. Our objective is to investigate the management of ICI hepatitis and its response to steroid treatment. METHODS PubMed/MEDLINE, EMBASE, and CENTRAL databases were searched in July 2023 based on keywords including ICIs (anti-Programmed cell death protein 1/Programmed Death-Ligand 1, anti-CTLA-4, and anti-LAG3) and hepatitis. RESULTS A total of 4358 studies were screened, and 44 studies were included in this systematic review. One thousand eight hundred fifty-six patients with ICI hepatitis were included (grade 1-2: 31.7%, grade 3-4: 56.0%, and unknown: 12.3%) with 1184 patients who received corticosteroid treatment. The duration of treatment and dosage varied considerably across the studies. Mycophenolate mofetil was the predominant agent used in 68 out of 82 cases (82.9%), followed by infliximab and azathioprine. A summary estimate of the proportion of steroid-refractory hepatitis in a random effects model was 16% (95% CI: 11%-23%). An estimated 40% (95% CI: 30%-51%) of patients of all patients with ICI hepatitis were rechallenged with an ICI, and of those rechallenged, there was an estimated 22% (95% CI: 15%-30%) recurrence. CONCLUSIONS Corticosteroids are the primary treatment for ICI hepatitis, with mycophenolate mofetil used as a secondary option for steroids-refractory cases. Current practices mostly rely on expert consensus, highlighting the need for further research to validate and optimize these treatments, particularly for steroid-resistant cases.
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Affiliation(s)
- Soo Young Hwang
- Department of Internal Medicine, University of Maryland Midtown Campus, Baltimore, Maryland, USA
- Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Pinghsin Hsieh
- Department of Internal Medicine, University of Maryland Midtown Campus, Baltimore, Maryland, USA
| | - Wei Zhang
- Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Hiraizumi K, Honda C, Watanabe A, Nakao T, Midorikawa S, Abe H, Matsui N, Yamamoto T, Sakamoto T. Safety of nivolumab monotherapy in five cancer types: pooled analysis of post-marketing surveillance in Japan. Int J Clin Oncol 2024; 29:932-943. [PMID: 38844668 PMCID: PMC11196337 DOI: 10.1007/s10147-024-02515-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 03/13/2024] [Indexed: 06/25/2024]
Abstract
BACKGROUND Nivolumab has been approved for treating ≥ 10 cancer types. However, there is limited information on the incidence of rare, but potentially serious, treatment-related adverse events (TRAEs), as well as notable TRAEs in patients with certain medical disorders or older patients in Japan. METHODS We performed pooled analyses of data from published post-marketing surveillance in Japan of nivolumab monotherapy for patients with malignant melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancer, and gastric cancer to determine the frequencies of 20 categories of TRAEs of special interest overall and in patient groups with higher perceived safety risks (history of autoimmune disease, interstitial lung disease, tuberculosis, or hepatitis B/C; patients vaccinated during nivolumab treatment; and older patients [≥ 75 years]). RESULTS The overall population comprised 7421 patients treated with nivolumab. TRAEs were reported in 49.1% of patients, with grade ≥ 3 TRAEs in 16.7%. Endocrine disorders (14.4%), hepatobiliary disorders (10.9%), and interstitial lung disease (7.0%) were the three most common categories (any grade). The incidences of rare TRAEs with high risk of becoming serious, which occurred in < 1% of patients, were consistent with those in previous reports. The frequencies of TRAEs were not markedly increased in the specified patient groups relative to the overall population. CONCLUSION To our knowledge, this is the largest study examining the safety of nivolumab-treated patients in real-world clinical practice including rare but potentially serious TRAEs. We found no new signals in the safety of nivolumab among the patient groups relative to the overall population, and no additional safety measures are required in these groups. Trial registration UMIN000048892 (overall analysis), JapicCTI-163272 (melanoma), Japic-163271 (non-small cell lung cancer), JapicCTI-184071 (head and neck cancer), JapicCTI-184070 (gastric cancer), and JapicCTI-184069 (renal cell cancer).
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Affiliation(s)
- Kenji Hiraizumi
- Oncology Medical Affairs, Ono Pharmaceutical Co., Ltd., 1-8-2 Kyutaromachi, Chuo-ku, Osaka, 541-8564, Japan
| | - Chikara Honda
- PV Data Strategy, Pharmacovigilance Department, Ono Pharmaceutical Co., Ltd., 2-1-5 Dosho-machi, Chuo-ku, Osaka, 541-8526, Japan
| | - Ayu Watanabe
- Safety Management Pharmacovigilance Department, Ono Pharmaceutical Co., Ltd., 2-1-5 Dosho-machi, Chuo-ku, Osaka, 541-8526, Japan
| | - Takafumi Nakao
- Safety Management Pharmacovigilance Department, Ono Pharmaceutical Co., Ltd., 2-1-5 Dosho-machi, Chuo-ku, Osaka, 541-8526, Japan
| | - Shuichi Midorikawa
- Biometrics and Data Sciences, R&D Department, Bristol-Myers Squibb K.K., Otemachi One Tower, 1-2-1 Otemachi, Chiyoda-ku, Tokyo, 100-0004, Japan
| | - Hiromi Abe
- Oncology Medical, Bristol-Myers Squibb K.K., Otemachi One Tower, 1-2-1 Otemachi, Chiyoda-ku, Tokyo, 100-0004, Japan
| | - Nobuki Matsui
- Patient Safety Japan, Bristol-Myers Squibb K.K., Otemachi One Tower, 1-2-1 Otemachi, Chiyoda-ku, Tokyo, 100-0004, Japan
| | - Tsunehisa Yamamoto
- Oncology Medical, Bristol-Myers Squibb K.K., Otemachi One Tower, 1-2-1 Otemachi, Chiyoda-ku, Tokyo, 100-0004, Japan
| | - Takahiko Sakamoto
- Safety Management Pharmacovigilance Department, Ono Pharmaceutical Co., Ltd., 2-1-5 Dosho-machi, Chuo-ku, Osaka, 541-8526, Japan.
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Lasagna A, Sacchi P. The ABC of Immune-Mediated Hepatitis during Immunotherapy in Patients with Cancer: From Pathogenesis to Multidisciplinary Management. Cancers (Basel) 2024; 16:795. [PMID: 38398187 PMCID: PMC10886483 DOI: 10.3390/cancers16040795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 01/29/2024] [Accepted: 02/13/2024] [Indexed: 02/25/2024] Open
Abstract
Immune-mediated hepatotoxicity (IMH) is not-so-rare complication during treatment with immune checkpoint inhibitors (ICIs). This narrative review aims to report the current knowledge on hepatic immune-related adverse events (irAEs) during immunotherapy from pathogenesis to multidisciplinary management. The majority of cases of IMH are asymptomatic and only a few patients may have clinical conditions. The severity of IMH is usually stratified according to Common Terminology for Clinical Adverse Events (CTCAE) criteria, but these scores may overestimate the clinical severity of IMH compared to the Drug-Induced Liver Injury Network (DILIN) scale. The differential diagnosis of IMH is challenging because the elevated liver enzymes can be due to a number of etiologies such as viral infection, autoimmune and metabolic diseases, liver metastases, biliary diseases, and other drugs. The cornerstones of IMH management are represented by withholding or delaying ICI administration and starting immunosuppressive therapy. A multidisciplinary team, including oncologists, hepatologists, internists, and emergency medicine physicians, is essential for the management of IMH.
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Affiliation(s)
- Angioletta Lasagna
- Medical Oncology Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Paolo Sacchi
- Division of Infectious Diseases I, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
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Shen J, Wang X, Yang G, Li L, Fu J, Xu W, Zhang Q, Pan X. Liver Injury and Its Impact on Prognosis in Patients with HBV-Related Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization Combined with Tyrosine Kinase Inhibitors Plus Immune Checkpoint Inhibitors. J Hepatocell Carcinoma 2024; 11:207-217. [PMID: 38283694 PMCID: PMC10822136 DOI: 10.2147/jhc.s431191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Accepted: 01/13/2024] [Indexed: 01/30/2024] Open
Abstract
Purpose Recently, the triple therapy of transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) plus immune checkpoint inhibitors (ICIs) has become a new treatment option for advanced or unresectable hepatocellular carcinoma (HCC) patients. We aimed to explore the liver injury and its effect on overall survival (OS) in patients treated with this combination therapy. Patients and Methods Patients with HBV-related HCC who were treated with TACE-TKIs-ICIs from January 2020 to December 2021 were enrolled. Liver injury and survival time were the main endpoints of the study. Logistic regression analysis was used to analyze the factors associated with liver injury. Cox regression and Kaplan-Meier analysis were used to determine prognostic factors for OS. Results As of March 2022, 52 of the 119 enrolled patients developed any grade hepatotoxicity: 15 cases with grade 1, 19 cases with grade 2, 16 cases with grade 3 and 2 cases with grade 4. Our analysis indicated that lack of antiviral prevention was a risk factor for liver injury (OR = 0.149; 95% CI: 0.050-0.442; P = 0.001). The findings suggested that liver injury events (HR = 1.912; 95% CI: 1.031-3.546; P = 0.040) was associated with patient death. The median OS of patients without liver injury, grade 1-2 and grade 3-4 liver injury were undefined, 13.7 months and 11.1 months, respectively (log-rank P = 0.034). Conclusion Liver injury adverse events are common in HBV-related HCC patients treated with TACE-TKIs-ICIs. Patients who developed liver injury had a poor prognosis. For HBV-related HCC patients, effective prophylactic antiviral therapy and regular liver function testing are required before and during this triple therapy.
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Affiliation(s)
- Jiaming Shen
- Department of Gastroenterology, People’s Hospital of Jingjiang, Taizhou, People’s Republic of China
- Department of Infectious Disease, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China
| | - Xia Wang
- Department of Infectious Disease, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China
| | - Guangde Yang
- Department of Infectious Disease, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China
| | - Li Li
- Department of Infectious Disease, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China
| | - Juanjuan Fu
- Department of Infectious Disease, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China
| | - Wei Xu
- Department of Interventional Radiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China
| | - Qingqiao Zhang
- Department of Interventional Radiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China
| | - Xiucheng Pan
- Department of Infectious Disease, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China
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Li K, Lu E, Wang Q, Xu R, Yuan W, Wu R, Lu L, Li P. Serum vitamin D deficiency is associated with increased risk of γδ T cell exhaustion in HBV-infected patients. Immunology 2024; 171:31-44. [PMID: 37702282 DOI: 10.1111/imm.13696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Accepted: 09/04/2023] [Indexed: 09/14/2023] Open
Abstract
Previous studies have demonstrated that T cell exhaustion is associated with poor clearance of Hepatitis B virus (HBV). However, whether the expression of exhaustion markers on innate-like circulating γδ T cells derived from patients with HBV infection correlates with the serum level of vitamin D is not completely understood. In this study, we found that the frequency of circulating Vδ2+ T cell and serum levels of vitamin 25(OH)D3 were significantly decreased in patients with HBV. And serum 25(OH)D3 levels in HBV-infected patients were negatively correlated with HBV DNA load and PD-1 expression on γδ T cells. Interestingly, 1α,25(OH)2 D3 alleviated the exhaustion phenotype of Vδ2 T cells in HBV-infected patients and promoted IFN-β expression in human cytotoxic Vδ2 T cells in vitro. Collectively, these findings demonstrate that vitamin D plays a pivotal role in reversing γδ T-cell exhaustion and is highly promising target for ameliorating HBV infection.
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Affiliation(s)
- Ke Li
- Department of Geriatrics, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, Guangdong, China
| | - Eying Lu
- Department of Infectious Disease, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, China
| | - Qian Wang
- Department of Infectious Disease, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, China
| | - Ruirong Xu
- Department of Infectious Disease, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, China
| | - Wenhui Yuan
- The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou, Guangdong, China
| | - Ruan Wu
- Anhui Provincial Center for Disease Control and Prevention, Hefei, Anhui, China
| | - Ligong Lu
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai, Guangdong, China
| | - Peng Li
- The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai, Guangdong, China
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Zhou J, He X, Ou Y, Peng S, Li D, Zhou Q, Fu J, Long Y, Tan Y. Role of CXCR5 + CD8 + T cells in human hepatitis B virus infection. J Viral Hepat 2023; 30:638-645. [PMID: 37129474 DOI: 10.1111/jvh.13840] [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: 02/01/2023] [Revised: 04/05/2023] [Accepted: 04/15/2023] [Indexed: 05/03/2023]
Abstract
The replication of HBV in hepatocytes can be effectively inhibited by lifelong antiviral therapy. Because of the long-term presence of HBV reservoirs, the virus rebound frequently occurs once the treatment is stopped, which poses a considerable obstacle to the complete removal of the virus. In terms of gene composition, regulation of B cell action and function, CXCR5+ CD8+ T cells are similar to CXCR5+ CD4+ T follicular helper cells, while these cells are characterized by elevated programmed cell death 1 and cytotoxic-related proteins. CXCR5+ CD8+ T cells are strongly associated with progression in inflammatory and autoimmune diseases. In addition, CXCR5 expression on the surface of CD8+ T cells is mostly an indicator of memory stem cell-like failure in progenitor cells in cancer that are more responsive to immune checkpoint blocking therapy. Furthermore, the phenomena have also been demonstrated in some viral infections, highlighting the duality of the cellular immune response of CXCR5+ CD8+ T cells. This mini-review will focus on the function of CXCR5+ CD8+ T cells in HBV infection and discuss the function of these CD8+ T cells and the potential of associated co-stimulators or cytokines in HBV therapeutic strategies.
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Affiliation(s)
- Juan Zhou
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Xiaojing He
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Yangjing Ou
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Shuang Peng
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Dan Li
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Qing Zhou
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Jingli Fu
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Yunzhu Long
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Yingzheng Tan
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
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Wang J, Zhang B, Peng L, Liu X, Sun J, Su C, Wang H, Zhao Z, Si L, Duan J, Zhang H, Li M, Zhu B, Zhang L, Li J, Guo J, Luo R, Qiu W, Ye D, Chu Q, Cui J, Dong X, Fan Y, Gao Q, Guo Y, He Z, Li W, Lin G, Liu L, Liu Y, Qin H, Ren S, Ren X, Wang Y, Xue J, Yang Y, Yang Z, Yue L, Zhan X, Zhang J, Ma J, Qin S, Wang B. Chinese expert consensus recommendations for the administration of immune checkpoint inhibitors to special cancer patient populations. Ther Adv Med Oncol 2023; 15:17588359231187205. [PMID: 37484525 PMCID: PMC10357053 DOI: 10.1177/17588359231187205] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 06/21/2023] [Indexed: 07/25/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1, programmed cell death ligand 1, and cytotoxic T lymphocyte-associated antigen-4 have shown significantly durable clinical benefits and tolerable toxicities and have improved the survival of patients with various types of cancer. Since 2018, the National Medical Products Administration of China has approved 17 ICIs as the standard treatment for certain advanced or metastatic solid tumors. As ICIs represent a broad-spectrum antitumor strategy, the populations eligible for cancer immunotherapy are rapidly expanding. However, the clinical applications of ICIs in cancer patient populations with special issues, a term that refers to complex subgroups of patients with comorbidities, special clinical conditions, or concomitant medications who are routinely excluded from prospective clinical trials of ICIs or are underrepresented in these trials, represent a great real-world challenge. Although the Chinese Society of Clinical Oncology (CSCO) has provided recommendations for screening before the use of ICIs in special populations, the recommendations for full-course management remain insufficient. The CSCO Expert Committee on Immunotherapy organized leading medical oncology and multidisciplinary experts to develop a consensus that will serve as an important reference for clinicians to guide the proper application of ICIs in special patient populations. This article is a translation of a study first published in Chinese in The Chinese Clinical Oncology (ISSN 1009-0460, CN 32-1577/R) in May 2022 (27(5):442-454). The publisher of the original paper has provided written confirmation of permission to publish this translation in Therapeutic Advances in Medical Oncology.
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Affiliation(s)
- Jun Wang
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital; Shandong Key Laboratory of Rheumatic Disease and Translational Medicine; Shandong Lung Cancer Institute, Jinan 250014, China
| | - Bicheng Zhang
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Ling Peng
- Department of Pulmonary and Critical Care Medicine, Zhejiang Provincial People’s Hospital, Hangzhou, China
| | - Xiufeng Liu
- Department of Hepatobiliary Oncology, Qinhuai Medical District, Eastern Theater Command General Hospital, Nanjing, China
| | - Jianguo Sun
- Cancer Institute, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Chunxia Su
- Department of Oncology, Shanghai Pulmonary Hospital, Thoracic Cancer Institute, School of Medicine, Tongji University, Shanghai, China
| | - Huijuan Wang
- Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Zheng Zhao
- Department of Oncology, Shannxi Cancer Hospital, Xi’an, China
| | - Lu Si
- Department of Melanoma, Cancer Hospital and Institute, Peking University, Beijing, China
| | - Jianchun Duan
- Department of Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Hongmei Zhang
- Department of Oncology, Xijing Hospital, Air Force Medical University, Xian, China
| | - Mengxia Li
- Cancer Center, Daping Hospital and Research Institute of Surgery, Army Medical University, Chongqing, China
| | - Bo Zhu
- Cancer Institute, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Li Zhang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Jin Li
- Department of Oncology, Shanghai East Hospital, Tongji University, Shanghai, China
| | - Jun Guo
- Department of Melanoma, Cancer Hospital and Institute, Peking University, Beijing, China
| | - Rongcheng Luo
- Cancer Center, Jinshazhou Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wensheng Qiu
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Dingwei Ye
- Department of Urology, Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Qian Chu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiuwei Cui
- Department of Oncology, The First Hospital of Jilin University, Changchun, China
| | - Xiaorong Dong
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yun Fan
- Department of Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou, China
| | - Quanli Gao
- Department of Immunology, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Ye Guo
- Department of Oncology, Shanghai East Hospital, Tongji University, Shanghai, China
| | - Zhiyong He
- Department of Thoracic Oncology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, China
| | - Wenfeng Li
- Department of Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Gen Lin
- Department of Thoracic Oncology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, China
| | - Lian Liu
- Department of Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yutao Liu
- Department of Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Haifeng Qin
- Department of Oncology, Chinese People’s Liberation Army General Hospital, Beijing, China
| | - Shengxiang Ren
- Department of Oncology, Shanghai Pulmonary Hospital, Thoracic Cancer Institute, School of Medicine, Tongji University, Shanghai, China
| | - Xiubao Ren
- Department of Immunology and Biotherapy, Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
| | - Yongsheng Wang
- GCP Center/Institute of Clinical Pharmacology, West China Hospital, Sichuan University, Chengdu, China
| | - Junli Xue
- Department of Oncology, Shanghai East Hospital, Tongji University, Shanghai, China
| | - Yunpeng Yang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Zhenzhou Yang
- Department of Oncology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lu Yue
- Department of Oncology, Qingdao Municipal Hospital, Qingdao, China
| | - Xianbao Zhan
- Department of Oncology, Changhai Hospital, Navy Medical University, Shanghai, China
| | - Junping Zhang
- Department of Cancer Biotherapy, Shanxi Bethune Hospital, Taiyuan, China
| | - Jun Ma
- Harbin Institute of Hematology and Oncology, Harbin, China
| | - Shukui Qin
- Department of Hepatobiliary Oncology, Qinhuai Medical District, Eastern Theater Command General Hospital, Nanjing 210008, China
| | - Baocheng Wang
- Department of Oncology, The 960th Hospital, The People’s Liberation Army, Jinan 250031, China
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10
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Zhou J, Chen G, Wang J, Zhou B, Sun X, Wang J, Tang S, Xing X, Hu X, Zhao Y, Peng Y, Shi W, Zhao T, Wu Y, Zhong H, Hong N, Ruan Z, Zhang Y, Jin W. Anti-PD-1 therapy achieves favorable outcomes in HBV-positive non-liver cancer. Oncogenesis 2023; 12:22. [PMID: 37080999 PMCID: PMC10119302 DOI: 10.1038/s41389-023-00468-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 03/31/2023] [Accepted: 04/14/2023] [Indexed: 04/22/2023] Open
Abstract
Anti-PD-1 therapy has shown promising outcomes in the treatment of different types of cancer. It is of fundamental interest to analyze the efficacy of anti-PD-1 therapy in cancer patients infected with hepatitis B virus (HBV) since the comorbidity of HBV and cancer is widely documented. We designed a multicenter retrospective study to evaluate the efficacy of anti-PD-1 therapy on non-liver cancer patients infected with HBV. We found anti-PD-1 therapy achieved much better outcomes in HBV+ non-liver cancer patients than their HBV- counterparts. We performed single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells (PBMCs) from esophageal squamous cell carcinoma (ESCC) patients. We found both cytotoxicity score of T cells and MHC score of B cells significantly increased after anti-PD-1 therapy in HBV+ ESCC patients. We also identified CX3CR1high TEFF, a subset of CD8+ TEFF, associated with better clinical outcome in HBV+ ESCC patients. Lastly, we found CD8+ TEFF from HBV+ ESCC patients showing higher fraction of Exhaustionhi T than their HBV- counterpart. In summary, anti-PD-1 therapy on HBV+ non-liver cancer patients is safe and achieves better outcomes than that on HBV- non-liver cancer patients, potentially because HBV+ patients had higher fraction of Exhaustionhi T, which made them more efficiently respond to anti-PD-1 therapy.
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Affiliation(s)
- Jie Zhou
- Chongqing International Institute for Immunology, 400030, Chongqing, China
- Department of Oncology, Southwest Hospital, Army Medical University, 400038, Chongqing, China
| | - Guanming Chen
- School of Life Sciences, Southern University of Science and Technology, 518055, Shenzhen, China
| | - Jiuling Wang
- Chongqing International Institute for Immunology, 400030, Chongqing, China
- Institute of Immunology, PLA, Army Medical University, 400038, Chongqing, China
| | - Bo Zhou
- School of Life Sciences, Southern University of Science and Technology, 518055, Shenzhen, China
| | - Xuemin Sun
- Chongqing International Institute for Immunology, 400030, Chongqing, China
- Institute of Immunology, PLA, Army Medical University, 400038, Chongqing, China
| | - Jinsong Wang
- Chongqing International Institute for Immunology, 400030, Chongqing, China
- Institute of Immunology, PLA, Army Medical University, 400038, Chongqing, China
| | - Shu Tang
- Institute of Cancer, Xinqiao Hospital, Army Medical University, 400038, Chongqing, China
| | - Xiangju Xing
- Pulmonary and Critical Care Medicine, The Third Affiliated Hospital of Chongqing Medical University, 400038, Chongqing, China
| | - Xiaofei Hu
- Department of Radiology, Southwest Hospital, Army Medical University, 400038, Chongqing, China
| | - Yang Zhao
- Department of Oncology, Southwest Hospital, Army Medical University, 400038, Chongqing, China
| | - Yu Peng
- Department of Oncology, Southwest Hospital, Army Medical University, 400038, Chongqing, China
| | - Wenjiong Shi
- Chongqing International Institute for Immunology, 400030, Chongqing, China
| | - Tingting Zhao
- Chongqing International Institute for Immunology, 400030, Chongqing, China
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 400054, Chongqing, China
| | - Yuzhang Wu
- Institute of Immunology, PLA, Army Medical University, 400038, Chongqing, China
| | - Hanbing Zhong
- School of Life Sciences, Southern University of Science and Technology, 518055, Shenzhen, China
| | - Ni Hong
- School of Life Sciences, Southern University of Science and Technology, 518055, Shenzhen, China
| | - Zhihua Ruan
- Department of Oncology, Southwest Hospital, Army Medical University, 400038, Chongqing, China.
| | - Yi Zhang
- Chongqing International Institute for Immunology, 400030, Chongqing, China.
- School of Pharmacy and Bioengineering, Chongqing University of Technology, 400054, Chongqing, China.
| | - Wenfei Jin
- School of Life Sciences, Southern University of Science and Technology, 518055, Shenzhen, China.
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11
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Pan J, Liu Y, Guo X, Bai Z, Levi Sandri GB, Méndez-Sánchez N, Qi X. Risk factors for immune-mediated hepatotoxicity in patients with cancer treated with immune checkpoint inhibitors: A systematic review and meta-analysis. Expert Opin Drug Saf 2022; 21:1275-1287. [PMID: 36214583 DOI: 10.1080/14740338.2022.2134854] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Immune checkpoint inhibitors (ICIs) are effective for the treatment of various cancers, but can lead to immune-mediated hepatotoxicity (IMH). The aim of this study was to analyze the risk factors for IMH in cancer patients treated with ICIs. AREAS COVERED The PubMed, EMBASE, and Cochrane Library databases were searched. Eligible studies should compare the difference between patients who developed and did not develop IMH. Odds ratio (OR) and weighted mean difference (WMD) with 95% confidence interval (CI) were calculated. EXPERT OPINION Among the 5030 papers initially identified, 13 studies were included. Meta-analyses indicated that age (WMD: -5.200, 95%CI: -7.481 to -2.919), history of ICIs treatment (OR: 4.491, 95%CI: 2.205 to 9.145), ICIs combination therapy (OR: 5.353, 95%CI: 1.663 to 17.232), and AST level (WMD: 5.039, 95%CI: 1.220 to 8.857) were significantly associated with the risk of any grade IMH; and age (WMD: -5.193; 95%CI: -9.669 to -0.718) was significantly associated with the risk of grade ≥3 IMH. These findings provide the evidence for identifying patients at a high risk of IMH. Appropriate intervention may be given to prevent from IMH in high-risk patients, thereby enabling ICIs to achieve an expected tumor response.
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Affiliation(s)
- Jiahui Pan
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China.,Postgraduate College, Shenyang Pharmaceutical University, Shenyang, China
| | - Yuwei Liu
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China.,Postgraduate College, Shenyang Pharmaceutical University, Shenyang, China
| | - Xiaozhong Guo
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China
| | - Zhaohui Bai
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China.,Postgraduate College, Shenyang Pharmaceutical University, Shenyang, China
| | | | | | - Xingshun Qi
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China
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12
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Hepatitis B virus reactivation in patients undergoing immune checkpoint inhibition: systematic review with meta-analysis. J Cancer Res Clin Oncol 2022; 149:1993-2008. [PMID: 35767193 DOI: 10.1007/s00432-022-04133-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 06/10/2022] [Indexed: 10/17/2022]
Abstract
PURPOSE Immune checkpoint inhibitors (ICIs) have been explored as first-line treatment in various types of previously untreatable malignancies, while limited evidence is available on the management of hepatitis B virus (HBV) in patients undergoing immunotherapy. We systematically reviewed data concerning challenges of hepatic adverse events including HBV reactivation and hepatitis in patients with chronic HBV infection undergoing immunotherapy. METHODS A systematic search was conducted in Medline, web of science, Embase and Cochrane library up to May 31, 2022. Studies reporting the safety profile of ICIs in patients with HBV infection were eligible. Meta-analyses were conducted to generate odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS A total of 13 studies including 2561 patients were included for meta-analysis. The overall incidence rates of HBV reactivation in patients with chronic HBV infection and past HBV infection were 1.0% (95% CI 0-3%) and 0% (95% CI 0-0%), respectively. Among patients with chronic HBV infection, the incidence rates of HBV reactivation were 1.0% (95% CI 0-2%) and 10.0% (95% CI 4-18%) for patients with and without antiviral prophylaxis, respectively. Patients with chronic HBV infection were at a higher risk of HBV reactivation compared with those with past HBV infection [OR = 8.69, 95% CI (2.16-34.99)]. Antiviral prophylaxis significantly reduced the risk of HBV reactivation [OR = 0.12, 95% CI (0.02-0.67)] and HBV-associated hepatitis [OR = 0.05, 95% CI (0.01-0.28)] in patients with chronic HBV infection. CONCLUSIONS Prophylactic antiviral therapy should be administered to patients with chronic HBV infection undergoing anticancer immunotherapy. Patients with past HBV infection are at lower risk of HBV reactivation compared with those with chronic HBV infection, they could be initiated with antiviral prophylaxis or monitored with the intent of on-demand antiviral therapy.
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