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Liu TH, Chen SC, Rau KM, Lu LC, Lin PT, Su YY, Teng W, Lai SW, Yeh RH, Kao TM, Lee PC, Wu CJ, Chen CH, Hsu CH, Lin SM, Huang YH, Chen LT, Cheng AL, Shen YC. Outcomes of Post-Immunotherapy Durable Responders of Advanced Hepatocellular Carcinoma- with Emphasis on Locoregional Therapy for Oligoprogression. Liver Cancer 2024; 13:509-521. [PMID: 39435270 PMCID: PMC11493387 DOI: 10.1159/000536549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Accepted: 01/29/2024] [Indexed: 10/23/2024] Open
Abstract
Introduction The progression patterns, dispositions, and outcomes of patients with advanced hepatocellular carcinoma (HCC) who achieved durable responses with immunotherapy remain poorly characterized. Methods Patients with advanced HCC who received immune checkpoint inhibitor (ICI)-based immunotherapy and achieved durable responses were retrospectively included. A durable response was defined as partial response (PR) or stable disease (SD) per RECIST 1.1 for more than 8 months after initiation of immunotherapy. Oligoprogression and polyprogression were defined as progression at ≤3 and >3 lesions, respectively. Results A total of 91 durable responders (63 PR and 28 SD) were identified. The majority had chronic viral hepatitis (n = 69, 75.8%). Forty-seven (51.6%) and 44 (48.4%) patients received the index immunotherapy as first-line and second- or beyond-line therapy, respectively. Fifty-four (59.3%) patients subsequently developed progression, with a predominant pattern of oligoprogression (66.7%). The median overall survival (OS) was 46.2 months (95% CI: 34.1-58.3). For patients with subsequent progression, employment of locoregional therapy (LRT) for progression was associated with prolonged OS (univariate analysis: hazard ratio [HR] 0.397, p = 0.009; multivariate analysis: HR 0.363, p = 0.050). Patients with oligoprogression who received LRT showed longer median OS than those who did not (48.4 vs. 20.5 months, p < 0.001). In contrast, the median OS of patients with polyprogression who received LRT was not different from those without LRT (27.7 vs. 25.5 months, p = 0.794). Conclusion Approximately 60% of the post-immunotherapy durable responders of HCC subsequently develop progression. Proactive LRT may further rescue patients who develop subsequent oligoprogression. Prospective studies are mandatory to clarify the proper management of durable responders with subsequent progression.
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Affiliation(s)
- Tsung-Hao Liu
- Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei City, Taiwan
| | - San-Chi Chen
- Division of Medical Oncology, Center of Immuno-Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei City, Taiwan
| | - Kun-Ming Rau
- Department of Hematology-Oncology, E-Da Cancer Hospital, Kaohsiung City, Taiwan
| | - Li-Chun Lu
- Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei City, Taiwan
| | - Po-Ting Lin
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yung-Yeh Su
- National Institute of Cancer Research, National Health Research Institute, Zhunan, Miaoli County, Taiwan
| | - Wei Teng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Shiue-Wei Lai
- Division of Hematology and Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei City, Taiwan
| | - Ren-Hua Yeh
- Division of Hematology and Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei City, Taiwan
| | - Tsui-Mai Kao
- Department of Oncology, National Taiwan University Hospital Yunlin Branch, Douliu City, Taiwan
| | - Pei-Chang Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei City, Taiwan
| | - Chi-Jung Wu
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei City, Taiwan
| | - Chien-Hung Chen
- Department of Medicine, National Taiwan University Cancer Center, Taipei City, Taiwan
| | - Chih-Hung Hsu
- Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei City, Taiwan
| | - Shi-Ming Lin
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei City, Taiwan
- Health Care and Service Center, Taipei Veterans General Hospital, Taipei City, Taiwan
- Institute of Clinical Medicine, Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei City, Taiwan
| | - Li-Tzong Chen
- National Institute of Cancer Research, National Health Research Institute, Zhunan, Miaoli County, Taiwan
- Division of Hematology and Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei City, Taiwan
| | - Ann-Lii Cheng
- Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei City, Taiwan
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei City, Taiwan
| | - Ying-Chun Shen
- Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei City, Taiwan
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei City, Taiwan
| | - on behalf of Taiwan Liver Cancer Association Research Group (TRG)
- Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei City, Taiwan
- Division of Medical Oncology, Center of Immuno-Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei City, Taiwan
- Department of Hematology-Oncology, E-Da Cancer Hospital, Kaohsiung City, Taiwan
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- National Institute of Cancer Research, National Health Research Institute, Zhunan, Miaoli County, Taiwan
- Division of Hematology and Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei City, Taiwan
- Department of Oncology, National Taiwan University Hospital Yunlin Branch, Douliu City, Taiwan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei City, Taiwan
- Department of Medicine, National Taiwan University Cancer Center, Taipei City, Taiwan
- Health Care and Service Center, Taipei Veterans General Hospital, Taipei City, Taiwan
- Institute of Clinical Medicine, Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei City, Taiwan
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei City, Taiwan
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Dai R, Uppot R, Arellano R, Kalva S. Image-guided Ablative Procedures. Clin Oncol (R Coll Radiol) 2024; 36:484-497. [PMID: 38087706 DOI: 10.1016/j.clon.2023.11.037] [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: 08/12/2023] [Revised: 09/19/2023] [Accepted: 11/21/2023] [Indexed: 07/09/2024]
Abstract
Various image-guided ablative procedures include chemical and thermal ablation techniques and irreversible electroporation. These have been used for curative intent for small tumours and palliative intent for debulking, immunogenicity and pain control. Understanding these techniques is critical to avoiding complications and achieving superior clinical outcomes. Additionally, combination with immunotherapy and chemotherapies is rapidly evolving. There are numerous opportunities in interventional radiology to advance ablation techniques and seamlessly integrate into current treatment regimens for both benign and malignant tumours.
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Affiliation(s)
- R Dai
- Massachusetts General Hospital, Department of Radiology, Division of Intervention Radiology, Boston, Massachusetts, USA.
| | - R Uppot
- Massachusetts General Hospital, Department of Radiology, Division of Intervention Radiology, Boston, Massachusetts, USA
| | - R Arellano
- Massachusetts General Hospital, Department of Radiology, Division of Intervention Radiology, Boston, Massachusetts, USA
| | - S Kalva
- Massachusetts General Hospital, Department of Radiology, Division of Intervention Radiology, Boston, Massachusetts, USA
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Salem R, Greten TF. Interventional radiology meets immuno-oncology for hepatocellular carcinoma. J Hepatol 2024; 80:967-976. [PMID: 35988688 DOI: 10.1016/j.jhep.2022.08.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 07/28/2022] [Accepted: 08/05/2022] [Indexed: 12/04/2022]
Abstract
Locoregional and systemic therapies are the most used treatment options for patients with hepatocellular carcinoma (HCC). Interventional radiologists have improved and developed novel protocols and devices for both intratumoural ablative approaches with curative intent and various transarterial intrahepatic treatment options, which have continuously improved patient outcomes. Two large phase III randomised clinical trials have demonstrated the efficacy of different immune checkpoint inhibitors either as single agents or in combination in the first-line setting and immunotherapy has become the standard first-line treatment option for patients with advanced HCC. Herein, we discuss advances and perspectives in the area of interventional radiology (IR) and immune-oncology (IO). We summarise results from recent studies and provide an overview of ongoing studies in IR and IO. Based on the significant advances in both areas, we propose that IR and IO need to cover the emerging "discipline" of IR-IO, in which we develop and test novel approaches to combine locoregional therapies with immunotherapy, in order to develop sufficient evidence for them to be considered standard of care for patients with HCC in the near future.
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Affiliation(s)
- Riad Salem
- Department of Radiology, Northwestern Feinberg School of Medicine, Chicago, IL, USA.
| | - Tim F Greten
- Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, Bethesda MD, USA; NCI CCR Liver Cancer Program, Center for Cancer Research, NCI, Bethesda MD, USA
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Charles J, Vrionis A, Mansur A, Mathias T, Shaikh J, Ciner A, Jiang Y, Nezami N. Potential Immunotherapy Targets for Liver-Directed Therapies, and the Current Scope of Immunotherapeutics for Liver-Related Malignancies. Cancers (Basel) 2023; 15:2624. [PMID: 37174089 PMCID: PMC10177356 DOI: 10.3390/cancers15092624] [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: 04/12/2023] [Revised: 05/01/2023] [Accepted: 05/03/2023] [Indexed: 05/15/2023] Open
Abstract
Liver cancer, including hepatocellular carcinoma and intrahepatic cholangiocarcinoma, is increasing in incidence and mortality across the globe. An improved understanding of the complex tumor microenvironment has opened many therapeutic doors and led to the development of novel pharmaceuticals targeting cellular signaling pathways or immune checkpoints. These interventions have significantly improved tumor control rates and patient outcomes, both in clinical trials and in real-world practice. Interventional radiologists play an important role in the multidisciplinary team given their expertise in minimally invasive locoregional therapy, as the bulk of these tumors are usually in the liver. The aim of this review is to highlight the immunological therapeutic targets for primary liver cancers, the available immune-based approaches, and the contributions that interventional radiology can provide in the care of these patients.
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Affiliation(s)
- Jonathan Charles
- Morsani College of Medicine, University of South Florida, 560 Channelside Drive, Tampa, FL 33602, USA; (J.C.); (A.V.); (J.S.)
| | - Andrea Vrionis
- Morsani College of Medicine, University of South Florida, 560 Channelside Drive, Tampa, FL 33602, USA; (J.C.); (A.V.); (J.S.)
| | - Arian Mansur
- Harvard Medical School, Harvard University, Boston, MA 02115, USA;
| | - Trevor Mathias
- School of Medicine, University of Maryland, Baltimore, MD 21201, USA;
| | - Jamil Shaikh
- Morsani College of Medicine, University of South Florida, 560 Channelside Drive, Tampa, FL 33602, USA; (J.C.); (A.V.); (J.S.)
- Department of Radiology, Tampa General Hospital, University of South Florida Health, Tampa General Cir, Tampa, FL 33606, USA
| | - Aaron Ciner
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (A.C.); (Y.J.)
| | - Yixing Jiang
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (A.C.); (Y.J.)
| | - Nariman Nezami
- Division of Vascular and Interventional Radiology, Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Experimental Therapeutics Program, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA
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Xie L, Meng Z. Immunomodulatory effect of locoregional therapy in the tumor microenvironment. Mol Ther 2023; 31:951-969. [PMID: 36694462 PMCID: PMC10124087 DOI: 10.1016/j.ymthe.2023.01.017] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 11/15/2022] [Accepted: 01/19/2023] [Indexed: 01/26/2023] Open
Abstract
Cancer immunotherapy appears to be a promising treatment option; however, only a subset of patients with cancer responds favorably to treatment. Locoregional therapy initiates a local antitumor immune response by disrupting immunosuppressive components, releasing immunostimulatory damage-associated molecular patterns, recruiting immune effectors, and remodeling the tumor microenvironment. Many studies have shown that locoregional therapy can produce specific antitumor immunity alone; nevertheless, the effect is relatively weak and transient. Furthermore, increasing research efforts have explored the potential synergy between locoregional therapy and immunotherapy to enhance the long-term systemic antitumor immune effect and improve survival. Therefore, further research is needed into the immunomodulatory effects of locoregional therapy and immunotherapy to augment antitumor effects. This review article summarizes the key components of the tumor microenvironment, discusses the immunomodulatory role of locoregional therapy in the tumor microenvironment, and emphasizes the therapeutic potential of locoregional therapy in combination with immune checkpoint inhibitors.
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Affiliation(s)
- Lin Xie
- Department of Minimally Invasive Therapy Center, Fudan University Shanghai Cancer Center, Shanghai 200032, P. R. China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P. R. China
| | - Zhiqiang Meng
- Department of Minimally Invasive Therapy Center, Fudan University Shanghai Cancer Center, Shanghai 200032, P. R. China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P. R. China.
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How Biology Guides the Combination of Locoregional Interventional Therapies and Immunotherapy for Hepatocellular Carcinoma: Cytokines and Their Roles. Cancers (Basel) 2023; 15:cancers15041324. [PMID: 36831664 PMCID: PMC9954096 DOI: 10.3390/cancers15041324] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 02/13/2023] [Accepted: 02/14/2023] [Indexed: 02/22/2023] Open
Abstract
As most patients with hepatocellular carcinoma (HCC) are diagnosed at the intermediate or advanced stage and are no longer eligible for curative treatment, the overall survival rate of HCC remains unsatisfactory. Locoregional interventional therapies (LITs), and immune checkpoint inhibitor (ICI)-based immunotherapy, focus on treating HCC, but the efficacy of their individual application is limited. Therefore, the purpose of this review was to discuss the biological roles of cytokines and their therapeutic potential in the combination therapy of LITs and ICI-based immunotherapy. The two common techniques of LITs are ablative and transarterial therapies. Whether LITs are complete or incomplete can largely affect the antitumor immune response and tumor progression. Cytokines that induce both local and systemic responses to LITs, including interferons, interleukins, chemokines, TNF-α, TGF-β, VEGF, and HGF, and their roles are discussed in detail. In addition, specific cytokines that can be used as therapeutic targets to reduce immune-related adverse events (irAEs) are introduced. Overall, incomplete LITs in a tumor, combined with specific cytokines, are thought to be effective at improving the therapeutic efficacy and reducing treatment-induced irAEs, and represent a new hope for managing unresectable HCC.
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Wang HY, Cui XW, Zhang YH, Chen Y, Lu NN, Sheng SP, Gao WF, Yang XZ, Duan ZP. Comparison of NK cell subsets, receptors and functions induced by radiofrequency ablation and microwave ablation in HBV-associated primary hepatocellular carcinoma. Front Oncol 2023; 13:1048049. [PMID: 37205189 PMCID: PMC10185829 DOI: 10.3389/fonc.2023.1048049] [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: 09/19/2022] [Accepted: 04/05/2023] [Indexed: 05/21/2023] Open
Abstract
Background Topical therapy has been shown to induce an immune response in patients with hepatocellular carcinoma (HCC). In this study, a prospective parallel group control experiment was conducted to compare the differences between radiofrequency ablation and microwave ablation in inducing the immune regulation of NK cells. Methods Sixty patients with clinically and pathologically confirmed hepatitis B-associated hepatocellular carcinoma (HCC) were selected for thermal ablation. Patients were randomly assigned into the MWA group (n = 30) and the RFA group (n = 30). Patient's peripheral blood was isolated on days D0, D7, and month M1. NK cell subsets, receptors, and killing function were detected by flow cytometry and LDH. Student t test and rank sum test were used to compare the statistical differences between the RFA (radio frequency) and MWA (microwave) groups. The Kaplan-Meier curve and log-rank test were used to calculate the difference between the two survival curves. Results Comparison of the frequency of CD3-CD56+ and CD3-CD56+CD16+ in NK cells between the RFA and WMA groups showed that there was no difference in the D0, D7, M1, D7-D0, M1-D0, and M1-D7 groups. The changes of the inhibitory NK cell receptor CD159A were significantly different at D7 (P<0.05). CD107a were compared between the RFA and WMA groups, indicating that CD107a changes induced by NK cells were significantly different at D7-D0 (P<0.05). Comparison of NK cell lysis activity of target K562 cells between the RFA and WMA groups showed that there was no difference at D0, D7, D7-D0. There was no difference in recurrence-free survival (RFS) between the RFA and WMA groups (P=0.11). Conclusions The difference between MWA and RFA-induced NK cell changes was mainly manifested in the inhibitory receptors CD159a and CD107a 1 week after surgery, with microwave-induced changes being more severe. Comparison of the NK cell lysis activity of the target K562 cells between the RFA and WMA groups showed that there was no difference in D0, D7, D7- D0. Survival analysis showed that these differences did not affect the recurrence-free survival (RFS) in the two groups.
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Yu L, Xie H, Wang L, Cheng M, Liu J, Xu J, Wei Z, Ye X, Xie Q, Liang J. Microwave ablation induces abscopal effect via enhanced systemic antitumor immunity in colorectal cancer. Front Oncol 2023; 13:1174713. [PMID: 37182153 PMCID: PMC10174442 DOI: 10.3389/fonc.2023.1174713] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 04/10/2023] [Indexed: 05/16/2023] Open
Abstract
Background Thermal ablation is the primary procedure for the local treatment of lung metastases. It is known that radiotherapy and cryoablation can stimulate an abscopal effect, while the occurrence of abscopal effect induced by microwave ablation is less; the cellular and molecular mechanisms involved in the abscopal effect after microwave ablation should be further elucidated. Methods CT26 tumor-bearing Balb/c mice were treated with microwave ablation with several combinations of ablation power and time duration. The growth of primary or abscopal tumors and the survival of mice were both monitored; moreover, immune profiles in abscopal tumors, spleens, and lymph nodes were examined by flow cytometry. Results Microwave ablation suppressed tumor growth in both primary and abscopal tumors. Both local and systemic T-cell responses were induced by microwave ablation. Furthermore, the mice exhibiting significant abscopal effect after microwave ablation markedly elevated Th1 cell proportion both in the abscopal tumors and spleens. Conclusions Microwave ablation at 3 w-3 min not only suppressed tumor growth in the primary tumors but also stimulated an abscopal effect in the CT26-bearing mice via the improvement of systemic and intratumoral antitumor immunity.
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Affiliation(s)
- Lu Yu
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China
| | - Hairong Xie
- Department of Oncology, Feicheng People’s Hospital, Feicheng, China
| | - Linping Wang
- Department of Gerontology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Min Cheng
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China
| | - Jie Liu
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China
- School of Clinical Medicine, Weifang Medical University, Weifang, China
| | - Jiamei Xu
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China
| | - Zhigang Wei
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China
| | - Xin Ye
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China
| | - Qi Xie
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China
- *Correspondence: Qi Xie, ; Jing Liang,
| | - Jing Liang
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China
- *Correspondence: Qi Xie, ; Jing Liang,
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Garg T, Weiss CR, Sheth RA. Techniques for Profiling the Cellular Immune Response and Their Implications for Interventional Oncology. Cancers (Basel) 2022; 14:3628. [PMID: 35892890 PMCID: PMC9332307 DOI: 10.3390/cancers14153628] [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: 07/08/2022] [Revised: 07/19/2022] [Accepted: 07/20/2022] [Indexed: 12/07/2022] Open
Abstract
In recent years there has been increased interest in using the immune contexture of the primary tumors to predict the patient's prognosis. The tumor microenvironment of patients with cancers consists of different types of lymphocytes, tumor-infiltrating leukocytes, dendritic cells, and others. Different technologies can be used for the evaluation of the tumor microenvironment, all of which require a tissue or cell sample. Image-guided tissue sampling is a cornerstone in the diagnosis, stratification, and longitudinal evaluation of therapeutic efficacy for cancer patients receiving immunotherapies. Therefore, interventional radiologists (IRs) play an essential role in the evaluation of patients treated with systemically administered immunotherapies. This review provides a detailed description of different technologies used for immune assessment and analysis of the data collected from the use of these technologies. The detailed approach provided herein is intended to provide the reader with the knowledge necessary to not only interpret studies containing such data but also design and apply these tools for clinical practice and future research studies.
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Affiliation(s)
- Tushar Garg
- Division of Vascular and Interventional Radiology, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (T.G.); (C.R.W.)
| | - Clifford R. Weiss
- Division of Vascular and Interventional Radiology, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (T.G.); (C.R.W.)
| | - Rahul A. Sheth
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Biondetti P, Saggiante L, Ierardi AM, Iavarone M, Sangiovanni A, Pesapane F, Fumarola EM, Lampertico P, Carrafiello G. Interventional Radiology Image-Guided Locoregional Therapies (LRTs) and Immunotherapy for the Treatment of HCC. Cancers (Basel) 2021; 13:5797. [PMID: 34830949 PMCID: PMC8616392 DOI: 10.3390/cancers13225797] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 11/16/2021] [Accepted: 11/16/2021] [Indexed: 12/12/2022] Open
Abstract
Image-guided locoregional therapies (LRTs) are a crucial asset in the treatment of hepatocellular carcinoma (HCC), which has proven to be characterized by an impaired antitumor immune status. LRTs not only directly destroy tumor cells but also have an immunomodulating role, altering the tumor microenvironment with potential systemic effects. Nevertheless, the immune activation against HCC induced by LRTs is not strong enough on its own to generate a systemic significant antitumor response, and it is incapable of preventing tumor recurrence. Currently, there is great interest in the possibility of combining LRTs with immunotherapy for HCC, as this combination may result in a mutually beneficial and synergistic relationship. On the one hand, immunotherapy could amplify and prolong the antitumoral immune response of LRTs, reducing recurrence cases and improving outcome. On the other hand, LTRs counteract the typical immunosuppressive HCC microenvironment and status and could therefore enhance the efficacy of immunotherapy. Here, after reviewing the current therapeutic options for HCC, we focus on LRTs, describing for each of them the technique and data on its effect on the immune system. Then, we describe the current status of immunotherapy and finally report the recently published and ongoing clinical studies testing this combination.
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Affiliation(s)
- Pierpaolo Biondetti
- Diagnostic and Interventional Radiology Department, IRCCS Cà Granda Fondazione Ospedale Maggiore Policlinico, Università degli Studi di Milano, 20122 Milan, Italy; (A.M.I.); (G.C.)
| | - Lorenzo Saggiante
- Postgraduate School in Radiodiagnostics, Università degli Studi di Milano, 20122 Milan, Italy;
| | - Anna Maria Ierardi
- Diagnostic and Interventional Radiology Department, IRCCS Cà Granda Fondazione Ospedale Maggiore Policlinico, Università degli Studi di Milano, 20122 Milan, Italy; (A.M.I.); (G.C.)
| | - Massimo Iavarone
- Gastroenterology Department, IRCCS Cà Granda Fondazione Ospedale Maggiore Policlinico, Università degli Studi di Milano, 20122 Milan, Italy; (M.I.); (A.S.); (P.L.)
| | - Angelo Sangiovanni
- Gastroenterology Department, IRCCS Cà Granda Fondazione Ospedale Maggiore Policlinico, Università degli Studi di Milano, 20122 Milan, Italy; (M.I.); (A.S.); (P.L.)
| | - Filippo Pesapane
- Radiology Department, IEO European Institute of Oncology IRCCS, 20122 Milan, Italy;
| | - Enrico Maria Fumarola
- Diagnostic and Interventional Radiology Department, ASST Santi Paolo e Carlo, 20122 Milan, Italy;
| | - Pietro Lampertico
- Gastroenterology Department, IRCCS Cà Granda Fondazione Ospedale Maggiore Policlinico, Università degli Studi di Milano, 20122 Milan, Italy; (M.I.); (A.S.); (P.L.)
| | - Gianpaolo Carrafiello
- Diagnostic and Interventional Radiology Department, IRCCS Cà Granda Fondazione Ospedale Maggiore Policlinico, Università degli Studi di Milano, 20122 Milan, Italy; (A.M.I.); (G.C.)
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Zhang X, Melzer A. Image guided ablation. Scott Med J 2021; 66:175-177. [PMID: 34743636 PMCID: PMC8573691 DOI: 10.1177/0036933020973637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Affiliation(s)
- Xinrui Zhang
- Scientist, ICCAS, Faculty of Medicine, University Leipzig, Germany
| | - Andreas Melzer
- Director, ICCAS, Faculty of Medicine, University Leipzig, Germany.,Foundation Director of IMSaT (Institute for Medical Science & Technology), IMSaT, University Dundee, UK
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12
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Tonguc T, Strunk H, Gonzalez-Carmona MA, Recker F, Lütjohann D, Thudium M, Conrad R, Becher MU, Savchenko O, Davidova D, Luechters G, Mustea A, Strassburg CP, Attenberger U, Pieper CC, Jenne J, Marinova M. US-guided high-intensity focused ultrasound (HIFU) of abdominal tumors: outcome, early ablation-related laboratory changes and inflammatory reaction. A single-center experience from Germany. Int J Hyperthermia 2021; 38:65-74. [PMID: 34420445 DOI: 10.1080/02656736.2021.1900926] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
INTRODUCTION High-intensity focused ultrasound (HIFU) is an innovative noninvasive procedure for local ablation of different benign and malignant tumors. Preliminary data of animal studies suggest an ablation-associated immune response after HIFU that is induced by cell necrosis and release of intracellular components. The aim of this study is to evaluate if a HIFU-induced early sterile inflammatory reaction is initiated after ablation of uterine fibroids (UF) and pancreatic carcinoma (PaC) which might contribute to the therapeutic effect. MATERIAL AND METHODS A hundred patients with PaC and 30 patients with UF underwent US-guided HIFU treatment. Serum markers of inflammation (leukocytes, CRP, IL-6) and LDH in both collectives as well as tumor markers CA 19-9, CEA and CYFRA in PaC patients were determined in sub-cohorts before and directly after HIFU (0, 2, 5 and 20 h post-ablation) as well as at 3, 6, 9 and 12 months follow-up. Peri-/post interventional imaging included contrast-enhanced MRI of both cohorts and an additional CT scan of PaC patients. RESULTS An early post-ablation inflammatory response was observed in both groups with a significant increase of leukocytes, CRP and LDH within the first 20 h after HIFU. Interestingly, IL-6 was increased at 20 h after HIFU in PaC patients. A significant reduction of tumor volumes was observed during one year follow-up (p < .001) for both tumor entities demonstrating effective treatment outcome. CONCLUSION Tumor ablation with HIFU induces an early sterile inflammation that might serve as a precondition for long-term tumor immunity and a sustainable therapeutic effect.
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Affiliation(s)
- Tolga Tonguc
- Department of Diagnostic and Interventional Radiology, University Hospital Bonn, University Bonn, Bonn, Germany
| | - Holger Strunk
- Department of Radiology, Städtisches Klinikum Solingen, Solingen, Germany
| | | | - Florian Recker
- Department of Gynaecology and Gynaecological Oncology, University Hospital Bonn, University Bonn, Bonn, Germany
| | - Dieter Lütjohann
- Department of Clinical Pharmacology and Laboratory Medicine, University Hospital Bonn, University Bonn, Bonn, Germany
| | - Marcus Thudium
- Department of Anesthesiology, University Hospital Bonn, University Bonn, Bonn, Germany
| | - Rupert Conrad
- Clinic and Polyclinic for Psychosomatic Medicine and Psychotherapy, University Hospital Bonn, University Bonn, Bonn, Germany
| | - Marc U Becher
- Department of Internal Medicine I, University Hospital Bonn, University Bonn, Bonn, Germany
| | - Oleksandr Savchenko
- Department of Diagnostic and Interventional Radiology, University Hospital Bonn, University Bonn, Bonn, Germany
| | - Darya Davidova
- Department of Diagnostic and Interventional Radiology, University Hospital Bonn, University Bonn, Bonn, Germany
| | - Guido Luechters
- Center for Development Research (ZEF), University Bonn, Bonn, Germany
| | - Alexander Mustea
- Department of Gynaecology and Gynaecological Oncology, University Hospital Bonn, University Bonn, Bonn, Germany
| | - Christian P Strassburg
- Department of Internal Medicine I, University Hospital Bonn, University Bonn, Bonn, Germany
| | - Ulrike Attenberger
- Department of Diagnostic and Interventional Radiology, University Hospital Bonn, University Bonn, Bonn, Germany
| | - Claus C Pieper
- Department of Diagnostic and Interventional Radiology, University Hospital Bonn, University Bonn, Bonn, Germany
| | - Jürgen Jenne
- Fraunhofer Institute for Digital Medicine, MEVIS, Bremen, Germany
| | - Milka Marinova
- Department of Diagnostic and Interventional Radiology, University Hospital Bonn, University Bonn, Bonn, Germany
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13
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Tranberg KG. Local Destruction of Tumors and Systemic Immune Effects. Front Oncol 2021; 11:708810. [PMID: 34307177 PMCID: PMC8298109 DOI: 10.3389/fonc.2021.708810] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 06/23/2021] [Indexed: 12/22/2022] Open
Abstract
Current immune-based therapies signify a major advancement in cancer therapy; yet, they are not effective in the majority of patients. Physically based local destruction techniques have been shown to induce immunologic effects and are increasingly used in order to improve the outcome of immunotherapies. The various local destruction methods have different modes of action and there is considerable variation between the different techniques with respect to the ability and frequency to create a systemic anti-tumor immunologic effect. Since the abscopal effect is considered to be the best indicator of a relevant immunologic effect, the present review focused on the tissue changes associated with this effect in order to find determinants for a strong immunologic response, both when local destruction is used alone and combined with immunotherapy. In addition to the T cell-inflammation that was induced by all methods, the analysis indicated that it was important for an optimal outcome that the released antigens were not destroyed, tumor cell death was necrotic and tumor tissue perfusion was at least partially preserved allowing for antigen presentation, immune cell trafficking and reduction of hypoxia. Local treatment with controlled low level hyperthermia met these requisites and was especially prone to result in abscopal immune activity on its own.
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14
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Adnan A, Muñoz NM, Prakash P, Habibollahi P, Cressman ENK, Sheth RA. Hyperthermia and Tumor Immunity. Cancers (Basel) 2021; 13:2507. [PMID: 34063752 PMCID: PMC8196672 DOI: 10.3390/cancers13112507] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 05/19/2021] [Accepted: 05/20/2021] [Indexed: 12/12/2022] Open
Abstract
Thermal ablation is a cornerstone in the management of cancer patients. Typically, ablation procedures are performed for patients with a solitary or oligometastatic disease with the intention of eradicating all sites of the disease. Ablation has traditionally played a less prominent role for patients with a widely metastatic disease. For such patients, attempting to treat numerous sites of disease compounds potential risks without a clear clinical benefit and, as such, a compelling justification for performing an intervention that is unlikely to alter a patient's clinical trajectory is uncommon. However, the discovery of immune checkpoints and the development of immune checkpoint inhibitors have brought a new perspective to the relevance of local cancer therapies such as ablation for patients with a metastatic disease. It is becoming increasingly apparent that local cancer therapies can have systemic immune effects. Thus, in the new perspective of cancer care centered upon immunologic principles, there is a strong interest in exploring the utility of ablation for patients with a metastatic disease for its immunologic implications. In this review, we summarize the unmet clinical need for adjuvant interventions such as ablation to broaden the impact of systemic immunotherapies. We additionally highlight the extant preclinical and clinical data for the immunogenicity of common thermal ablation modalities.
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Affiliation(s)
- Ather Adnan
- Texas A&M Health Science Center, Texas A&M College of Medicine, Houston, TX 77030, USA;
| | - Nina M. Muñoz
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (N.M.M.); (P.H.); (E.N.K.C.)
| | - Punit Prakash
- Department of Electrical and Computer Engineering, Kansas State University, Manhattan, KS 66506, USA;
| | - Peiman Habibollahi
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (N.M.M.); (P.H.); (E.N.K.C.)
| | - Erik N. K. Cressman
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (N.M.M.); (P.H.); (E.N.K.C.)
| | - Rahul A. Sheth
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (N.M.M.); (P.H.); (E.N.K.C.)
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15
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Toffoli EC, Sheikhi A, Höppner YD, de Kok P, Yazdanpanah-Samani M, Spanholtz J, Verheul HMW, van der Vliet HJ, de Gruijl TD. Natural Killer Cells and Anti-Cancer Therapies: Reciprocal Effects on Immune Function and Therapeutic Response. Cancers (Basel) 2021; 13:cancers13040711. [PMID: 33572396 PMCID: PMC7916216 DOI: 10.3390/cancers13040711] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/03/2021] [Accepted: 02/06/2021] [Indexed: 12/16/2022] Open
Abstract
Simple Summary Natural Killer (NK) cells are innate lymphocytes that play an important role in the immune response against cancer. Their activity is controlled by a balance of inhibitory and activating receptors, which in cancer can be skewed to favor their suppression in support of immune escape. It is therefore imperative to find ways to optimize their antitumor functionality. In this review, we explore and discuss how their activity influences, or even mediates, the efficacy of various anti-cancer therapies and, vice versa, how their activity can be affected by these therapies. Knowledge of the mechanisms underlying these observations could provide rationales for combining anti-cancer treatments with strategies enhancing NK cell function in order to improve their therapeutic efficacy. Abstract Natural Killer (NK) cells are innate immune cells with the unique ability to recognize and kill virus-infected and cancer cells without prior immune sensitization. Due to their expression of the Fc receptor CD16, effector NK cells can kill tumor cells through antibody-dependent cytotoxicity, making them relevant players in antibody-based cancer therapies. The role of NK cells in other approved and experimental anti-cancer therapies is more elusive. Here, we review the possible role of NK cells in the efficacy of various anti-tumor therapies, including radiotherapy, chemotherapy, and immunotherapy, as well as the impact of these therapies on NK cell function.
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Affiliation(s)
- Elisa C. Toffoli
- Cancer Center Amsterdam, Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands; (E.C.T.); (A.S.); (Y.D.H.); (P.d.K.); (H.J.v.d.V.)
| | - Abdolkarim Sheikhi
- Cancer Center Amsterdam, Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands; (E.C.T.); (A.S.); (Y.D.H.); (P.d.K.); (H.J.v.d.V.)
- Department of Immunology, School of Medicine, Dezful University of Medical Sciences, Dezful 64616-43993, Iran
| | - Yannick D. Höppner
- Cancer Center Amsterdam, Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands; (E.C.T.); (A.S.); (Y.D.H.); (P.d.K.); (H.J.v.d.V.)
| | - Pita de Kok
- Cancer Center Amsterdam, Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands; (E.C.T.); (A.S.); (Y.D.H.); (P.d.K.); (H.J.v.d.V.)
| | - Mahsa Yazdanpanah-Samani
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz 71348-45794, Iran;
| | - Jan Spanholtz
- Glycostem, Kloosterstraat 9, 5349 AB Oss, The Netherlands;
| | - Henk M. W. Verheul
- Department of Medical Oncology, Radboud Institute for Health Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands;
| | - Hans J. van der Vliet
- Cancer Center Amsterdam, Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands; (E.C.T.); (A.S.); (Y.D.H.); (P.d.K.); (H.J.v.d.V.)
- Lava Therapeutics, Yalelaan 60, 3584 CM Utrecht, The Netherlands
| | - Tanja D. de Gruijl
- Cancer Center Amsterdam, Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands; (E.C.T.); (A.S.); (Y.D.H.); (P.d.K.); (H.J.v.d.V.)
- Correspondence: ; Tel.: +31-20-4444063
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16
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Duan X, Wang M, Han X, Ren J, Huang G, Ju S, Zhang Q. Combined use of microwave ablation and cell immunotherapy induces nonspecific immunity of hepatocellular carcinoma model mice. Cell Cycle 2020; 19:3595-3607. [PMID: 33283623 DOI: 10.1080/15384101.2020.1853942] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Microwave ablation (MWA) has been widely used in the treatment of solid tumors. Studies have been less conducted on the efficacy of MWA used with cell immunotherapy in treating hepatocellular carcinoma (HCC). The current study aimed at exploring the efficacy of MWA in combination with cell immunotherapy in treating HCC. Hepa1-6 HCC mice were treated by MWA, blockade, or the combined therapy (MWA used with blockade), or left untreated. Survival rates of the mice were plotted by Kaplan-Meier Curve, followed by log-rank test. 25 days after the operation, surviving mice were monitored for tumor recurrence, and tumor volumes were calculated every 5 days. Immunohistochemistry and flow cytometry were performed to detect the numbers of CD4+ and CD8+ cells in the tumors and spleens of mice. The expressions of related cytokines were detected and measured by ELISPOT and ELISA. The results showed that MWA combined with anti-PD-1/anti-CTLA-4 not only increased the survival time, protected the mice against tumor recurrence, but also enhanced the intratumoral infiltration of cytotoxic T lymphocyte and systemic T-cell immune responses induced by MWA through activation of synergistically specific antitumor immunity. In addition, the combined therapy increased T-helper 1 cell (Th1-type) cytokines, but reduced Th2-type cytokines, resulting in the polarization of Th1 cells. T-cell immune responses of HCC cells were activated by MWA. In addition, the combined therapy of MWA and anti-PD-1/anti-CTLA-4 induced Th1-type immune response, and showed specific antitumor immunity.
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Affiliation(s)
- Xuhua Duan
- Department of Interventional Radiology, the First Affiliated Hospital, Zhengzhou University , Zhengzhou, Henan Province, China
| | - Manzhou Wang
- Department of Interventional Radiology, the First Affiliated Hospital, Zhengzhou University , Zhengzhou, Henan Province, China
| | - Xinwei Han
- Department of Interventional Radiology, the First Affiliated Hospital, Zhengzhou University , Zhengzhou, Henan Province, China
| | - Jianzhuang Ren
- Department of Interventional Radiology, the First Affiliated Hospital, Zhengzhou University , Zhengzhou, Henan Province, China
| | - Guohao Huang
- Department of Interventional Radiology, the First Affiliated Hospital, Zhengzhou University , Zhengzhou, Henan Province, China
| | - Shuguang Ju
- Department of Interventional Radiology, the First Affiliated Hospital, Zhengzhou University , Zhengzhou, Henan Province, China
| | - Qinghui Zhang
- Department of Interventional Radiology, the First Affiliated Hospital, Zhengzhou University , Zhengzhou, Henan Province, China
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17
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Leuchte K, Staib E, Thelen M, Gödel P, Lechner A, Zentis P, Garcia-Marquez M, Waldschmidt D, Datta RR, Wahba R, Wybranski C, Zander T, Quaas A, Drebber U, Stippel DL, Bruns C, von Bergwelt-Baildon M, Wennhold K, Schlößer HA. Microwave ablation enhances tumor-specific immune response in patients with hepatocellular carcinoma. Cancer Immunol Immunother 2020; 70:893-907. [PMID: 33006650 PMCID: PMC7979675 DOI: 10.1007/s00262-020-02734-1] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 09/20/2020] [Indexed: 12/14/2022]
Abstract
Thermal ablative therapies are standard treatments for localized hepatocellular carcinoma (HCC). In addition to local tumor destruction, ablation leads to abscopal effects in distant lesions most likely mediated by an anti-tumor immune response. Although microwave ablation (MWA) is increasingly substituting other ablative techniques, its systemic immunostimulatory effects are poorly studied. We analyzed tumor-specific immune responses in peripheral blood of HCC patients after thermal ablation with regard to T cell responses and disease outcome. While comprehensive flow cytometric analyses in sequential samples of a prospective patient cohort (n = 23) demonstrated only moderate effects of MWA on circulating immune cell subsets, fluorospot analyses of specific T cell responses against seven tumor-associated antigens (TTAs) revealed de-novo or enhanced tumor-specific immune responses in 30% of patients. This anti-tumor immune response was related to tumor control as Interferon-y and Interleukin-5 T cell responses against TAAs were more frequent in patients with a long-time remission (> 1 year) after MWA (7/16) compared to patients suffering from an early relapse (0/13 patients) and presence of tumor-specific T cell response (IFN-y and/or IL-5) was associated to longer progression-free survival (27.5 vs. 10.0 months). Digital image analysis of immunohistochemically stained archival HCC samples (n = 18) of patients receiving combined MWA and resection revealed a superior disease-free survival of patients with high T cell abundance at the time of thermal ablation (37.4 vs. 13.1 months). Our data demonstrates remarkable immune-related effects of MWA in HCC patients and provides additional evidence for a combination of local ablation and immunotherapy in this challenging disease.
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Affiliation(s)
- Katharina Leuchte
- Center for Molecular Medicine Cologne, University of Cologne, Köln, Germany. .,Department I of Internal Medicine and Center for Integrated Oncology (CIO) Aachen Bonn Cologne Duesseldorf, University Hospital Cologne, Kerpener Straße 62, 50937, Köln, Germany.
| | - Elena Staib
- Center for Molecular Medicine Cologne, University of Cologne, Köln, Germany
| | - Martin Thelen
- Center for Molecular Medicine Cologne, University of Cologne, Köln, Germany
| | - Philipp Gödel
- Center for Molecular Medicine Cologne, University of Cologne, Köln, Germany.,Department I of Internal Medicine and Center for Integrated Oncology (CIO) Aachen Bonn Cologne Duesseldorf, University Hospital Cologne, Kerpener Straße 62, 50937, Köln, Germany
| | - Axel Lechner
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital, LMU Munich, München, Germany
| | - Peter Zentis
- Cluster of Excellence in Aging-Associated Disease, Core Facility Imaging, University of Cologne, Köln, Germany
| | | | - Dirk Waldschmidt
- Department of Gastroenterology and Hepatology, University Hospital Cologne, Köln, Germany
| | - Rabi Raj Datta
- Center for Molecular Medicine Cologne, University of Cologne, Köln, Germany.,Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Köln, Germany
| | - Roger Wahba
- Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Köln, Germany
| | - Christian Wybranski
- Department of Diagnostic and Interventional Radiology, University Hospital Cologne, Köln, Germany
| | - Thomas Zander
- Department I of Internal Medicine and Center for Integrated Oncology (CIO) Aachen Bonn Cologne Duesseldorf, University Hospital Cologne, Kerpener Straße 62, 50937, Köln, Germany
| | - Alexander Quaas
- Institute of Pathology, University Hospital Cologne, Köln, Germany
| | - Uta Drebber
- Institute of Pathology, University Hospital Cologne, Köln, Germany
| | - Dirk Ludger Stippel
- Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Köln, Germany
| | - Christiane Bruns
- Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Köln, Germany
| | - Michael von Bergwelt-Baildon
- German Cancer Consortium (DKTK), Heidelberg, Germany.,Department of Internal Medicine III, University Hospital, LMU Munich, München, Germany
| | - Kerstin Wennhold
- Center for Molecular Medicine Cologne, University of Cologne, Köln, Germany
| | - Hans Anton Schlößer
- Center for Molecular Medicine Cologne, University of Cologne, Köln, Germany.,Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Köln, Germany
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18
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Zeng P, Shen D, Zeng CH, Chang XF, Teng GJ. Emerging Opportunities for Combining Locoregional Therapy with Immune Checkpoint Inhibitors in Hepatocellular Carcinoma. Curr Oncol Rep 2020; 22:76. [PMID: 32596779 DOI: 10.1007/s11912-020-00943-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW Immunotherapy shows great promises in solid tumors. Locoregional therapy can promote systemic immune response in hepatocellular carcinoma (HCC). The combination of locoregional therapy and immune checkpoint inhibitors (ICIs) activates a synergistic effect that can enhance the potency of anti-tumor immunity. This review aims to summarize the underlying mechanisms of locoregional therapy combined with ICIs and their applications in clinical settings. RECENT FINDINGS The characteristics of high invasiveness and refractoriness of HCC are what limit the outcomes of treatments. Sorafenib provides an additional treatment option for extrahepatic spread and vascular invasion, making long-term survival possible for patients with advanced HCC to some degree. However, its shortcomings of low response rate and high toxicity result in limited applications in clinical practice. Immunotherapy is a promising emerging therapy with great prospect in HCC, but the self-tolerance of HCC constrains the effectiveness of ICIs. Consequently, the efficacy of single immunotherapy is unsatisfactory. Locoregional therapy can not only destroy primary tumors but also stimulate the release of neoplasm antigens to increase the efficiency of immune response in HCC. Locoregional therapy combined with ICIs may have an amplification effect on immune response. Locoregional therapy plays a vital role in stimulating anti-tumor immune response. The combination of locoregional therapy and ICIs has a synergistic effect on anti-tumor immunity.
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Affiliation(s)
- Peng Zeng
- Department of Radiology, Zhongda Hospital, Center of Interventional Radiology and Vascular Surgery, Medical School, Southeast University, 87 Dingjiaqiao Rd., Nanjing, 210009, China
| | - Duo Shen
- Department of Gastroenterology, Zhongda Hospital, Medical School, Southeast University, 87 Dingjiaqiao Rd., Nanjing, 210009, China
| | - Chu-Hui Zeng
- Department of Radiology, Zhongda Hospital, Center of Interventional Radiology and Vascular Surgery, Medical School, Southeast University, 87 Dingjiaqiao Rd., Nanjing, 210009, China
| | - Xiao-Feng Chang
- Department of Oncology, Nanjing Drum Tower Hospital, Medical School, Nanjing University, 321 Zhongshan Rd, Nanjing, 210008, China
| | - Gao-Jun Teng
- Department of Radiology, Zhongda Hospital, Center of Interventional Radiology and Vascular Surgery, Medical School, Southeast University, 87 Dingjiaqiao Rd., Nanjing, 210009, China.
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Dumolard L, Ghelfi J, Roth G, Decaens T, Macek Jilkova Z. Percutaneous Ablation-Induced Immunomodulation in Hepatocellular Carcinoma. Int J Mol Sci 2020; 21:E4398. [PMID: 32575734 PMCID: PMC7352237 DOI: 10.3390/ijms21124398] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 06/17/2020] [Accepted: 06/19/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related deaths worldwide and its incidence is rising. Percutaneous locoregional therapies, such as radiofrequency ablation and microwave ablation, are widely used as curative treatment options for patients with small HCC, but their effectiveness remains restricted because of the associated high rate of recurrence, occurring in about 70% of patients at five years. These thermal ablation techniques have the particularity to induce immunomodulation by destroying tumours, although this is not sufficient to raise an effective antitumour immune response. Ablative therapies combined with immunotherapies could act synergistically to enhance antitumour immunity. This review aims to understand the different immune changes triggered by radiofrequency ablation and microwave ablation as well as the interest in using immunotherapies in combination with thermal ablation techniques as a tool for complementary immunomodulation.
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Affiliation(s)
- Lucile Dumolard
- Université Grenoble Alpes, 38000 Grenoble, France; (L.D.); (G.R.); (T.D.)
- Institute for Advanced Biosciences, Research Center UGA/Inserm U 1209/CNRS 5309, 38700 La Tronche, France
| | - Julien Ghelfi
- Service de Radiologie, Pôle Digidune, CHU Grenoble Alpes, 38700 La Tronche, France;
| | - Gael Roth
- Université Grenoble Alpes, 38000 Grenoble, France; (L.D.); (G.R.); (T.D.)
- Institute for Advanced Biosciences, Research Center UGA/Inserm U 1209/CNRS 5309, 38700 La Tronche, France
- Service d’Hépato-Gastroentérologie, Pôle Digidune, CHU Grenoble Alpes, 38700 La Tronche, France
| | - Thomas Decaens
- Université Grenoble Alpes, 38000 Grenoble, France; (L.D.); (G.R.); (T.D.)
- Institute for Advanced Biosciences, Research Center UGA/Inserm U 1209/CNRS 5309, 38700 La Tronche, France
- Service d’Hépato-Gastroentérologie, Pôle Digidune, CHU Grenoble Alpes, 38700 La Tronche, France
| | - Zuzana Macek Jilkova
- Université Grenoble Alpes, 38000 Grenoble, France; (L.D.); (G.R.); (T.D.)
- Institute for Advanced Biosciences, Research Center UGA/Inserm U 1209/CNRS 5309, 38700 La Tronche, France
- Service d’Hépato-Gastroentérologie, Pôle Digidune, CHU Grenoble Alpes, 38700 La Tronche, France
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20
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Microwave ablation of primary breast cancer inhibits metastatic progression in model mice via activation of natural killer cells. Cell Mol Immunol 2020; 18:2153-2164. [PMID: 32385362 DOI: 10.1038/s41423-020-0449-0] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 04/14/2020] [Indexed: 11/08/2022] Open
Abstract
Surgery is essential for controlling the symptoms and complications of stage IV breast cancer. However, locoregional treatment of primary tumors often results in distant progression, including lung metastasis, the most common type of visceral metastasis. As a minimally invasive thermal therapy, microwave ablation (MWA) has been attempted in the treatment of breast cancer, but the innate immune response after MWA has not yet been reported. Using two murine models of stage IV breast cancer, we found that MWA of primary breast cancer inhibited the progression of lung metastasis and improved survival. NK cells were activated after MWA of the primary tumor and exhibited enhanced cytotoxic functions, and the cytotoxic pathways of NK cells were activated. Depletion experiments showed that NK cells but not CD4+ or CD8+ T cells played a pivotal role in prolonging survival. Then, we found that compared with surgery or control treatment, MWA of the primary tumor induced completely different NK-cell-related cytokine profiles. Macrophages were activated after MWA of the primary tumor and produced IL-15 that activated NK cells to inhibit the progression of metastasis. In addition, MWA of human breast cancer stimulated an autologous NK-cell response. These results demonstrate that MWA of the primary tumor in metastatic breast cancer inhibits metastatic progression via the macrophage/IL-15/NK-cell axis. MWA of the primary tumor may be a promising treatment strategy for de novo stage IV breast cancer, although further substantiation is essential for clinical testing.
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Hou J, Zhang H, Sun B, Karin M. The immunobiology of hepatocellular carcinoma in humans and mice: Basic concepts and therapeutic implications. J Hepatol 2020; 72:167-182. [PMID: 31449859 DOI: 10.1016/j.jhep.2019.08.014] [Citation(s) in RCA: 123] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 08/02/2019] [Accepted: 08/14/2019] [Indexed: 02/08/2023]
Abstract
Basic and clinical studies have demonstrated the efficacy of immunotherapy, a technical and conceptual breakthrough that has revolutionised cancer treatment. Hepatocellular carcinoma (HCC), a deadly malignancy with aetiologic diversity and a chronic course, is strongly influenced by the immune system, and was recently found to partially benefit from immune-checkpoint inhibitor therapy. Notably, HCC onco-immunology depends on diverse genetic and environmental factors that together shape cancer-promoting inflammation and immune dysfunction - critical processes that control HCC malignant progression and response to therapy. Herein, we summarise the current understanding of liver and HCC onco-immunology obtained through basic studies with mouse models and clinical practice in humans. In particular, we discuss preclinical and clinical findings that implicate immunomodulation as a major factor in HCC development and explain the basis for HCC-targeting immunotherapy.
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Affiliation(s)
- Jiajie Hou
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China; Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Haiyan Zhang
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Beicheng Sun
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China; Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, School of Medicine, La Jolla, CA 92093, USA.
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Yang Y, Hao Y, Zhang J, Han Z, Yu J, Liu F, Ma X, Xu R. Ultrasound-Guided Percutaneous Microwave Ablation for Subserosal Uterine Myomas. J Minim Invasive Gynecol 2018; 26:544-550. [PMID: 29964178 DOI: 10.1016/j.jmig.2018.06.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 06/21/2018] [Accepted: 06/22/2018] [Indexed: 12/12/2022]
Abstract
STUDY OBJECTIVE To prospectively evaluate the clinical effectiveness and safety of ultrasound-guided percutaneous microwave ablation for symptomatic subserosal uterine myomas. DESIGN Prospective observational study (Canadian Task Force classification II-1). SETTING A teaching hospital (Department of Interventional Ultrasound, General Hospital of Chinese PLA, Beijing, China). PATIENTS Sixty-nine patients with symptomatic subserosal uterine myomas treated with ultrasound-guided percutaneous microwave ablation. INTERVENTIONS All 69 patients underwent ultrasound-guided percutaneous microwave ablation. The number of patients lost to follow-up at was 21 at 3 months, 34 at 6 months, and 35 at 12 months. MEASUREMENTS AND MAIN RESULTS The efficacy of treatment was evaluated based the mean myoma volume shrinkage rate and changes in Uterine Fibroid Symptom and Quality of Life Questionnaire scores at 3, 6, and 12 months after therapy. Treatment safety was evaluated based on the Society of Interventional Radiology practice guidelines. The mean patient age was 40.3 ± 4.9 years (range, 26-49 years). The mean myoma volume was 221.74 ± 153.18 cm3 before ablation, decreasing to 87.24 ± 45.93 cm3 at 3 months after ablation (p < .001), 46.68 ± 24.7 cm3 at 6 months after ablation (p < .001), and 38.05 ± 24.93 cm3 at 12 months after ablation (p <.001), respectively. Between pretreatment and 3-month follow-up, the mean symptom severity score decreased from 34.53 ± 3.83 to 12.74 ± 3.07 (p < .001), and the mean health-related quality of life score increased from 45.25 ± 10.97 to 78.48 ± 11.39 (p < .001). Both scores remained stable at the 6- and 12-month follow-up time points. No permanent injury or fatal complications were seen in this series. CONCLUSION Ultrasound-guided percutaneous microwave ablation of subserosal uterine myomas is a promising treatment method. Further studies with larger sample sizes and a control group are needed.
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Affiliation(s)
- Yu Yang
- Department of Ultrasound, Beijing Friendship Hospital, Capital Medical University, Beijing, China and the Department of Interventional Ultrasound, General Hospital of Chinese PLA, Beijing, China (Drs Yang, Ma, and Xu)
| | - Yanli Hao
- Department of Ultrasound, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China (Dr Hao); Department of Interventional Ultrasound, General Hospital of Chinese PLA, Beijing, China (Dr Hao)
| | - Jing Zhang
- Department of Interventional Ultrasound, General Hospital of Chinese PLA, Beijing, China (Drs Zhang, Han, Yu and Liu)..
| | - Zhiyu Han
- Department of Interventional Ultrasound, General Hospital of Chinese PLA, Beijing, China (Drs Zhang, Han, Yu and Liu)
| | - Jie Yu
- Department of Ultrasound, Beijing Friendship Hospital, Capital Medical University, Beijing, China and the Department of Interventional Ultrasound, General Hospital of Chinese PLA, Beijing, China (Drs Yang, Ma, and Xu)
| | - Fangyi Liu
- Department of Ultrasound, Beijing Friendship Hospital, Capital Medical University, Beijing, China and the Department of Interventional Ultrasound, General Hospital of Chinese PLA, Beijing, China (Drs Yang, Ma, and Xu)
| | - Xia Ma
- Department of Ultrasound, Beijing Friendship Hospital, Capital Medical University, Beijing, China and the Department of Interventional Ultrasound, General Hospital of Chinese PLA, Beijing, China (Drs Yang, Ma, and Xu)
| | - Ruifang Xu
- Department of Ultrasound, Beijing Friendship Hospital, Capital Medical University, Beijing, China and the Department of Interventional Ultrasound, General Hospital of Chinese PLA, Beijing, China (Drs Yang, Ma, and Xu)
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Shen S, Peng H, Wang Y, Xu M, Lin M, Xie X, Peng B, Kuang M. Screening for immune-potentiating antigens from hepatocellular carcinoma patients after radiofrequency ablation by serum proteomic analysis. BMC Cancer 2018; 18:117. [PMID: 29386009 PMCID: PMC5793368 DOI: 10.1186/s12885-018-4011-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2016] [Accepted: 01/21/2018] [Indexed: 12/20/2022] Open
Abstract
Background Radiofrequency ablation (RFA) can not only effectively kill hepatocellular carcinoma (HCC) tumour cells but also release tumour antigens that can provoke an immune response. However, there is no consensus regarding which antigens could constitutively be generated after RFA and could potentiate the immune response. The aim of this study was to identify these immune-potentiating antigens. Methods We performed two-dimensional electrophoresis (2-DE) and MALDI-TOF-MS/MS analyses on serum obtained before and after RFA from 5 HCC patients. Further validation for selected proteins was performed utilizing ELISA analysis on another 52 HCC patients. Disease-free survival (DFS) analysis according to the differential expression of the interested protein before and after RFA was performed. Results Twelve decreased and 6 increased proteins after RFA were identified by MS. Three proteins, including clusterin, Ficolin-3, and serum retinol binding protein-4, were further verified by ELISA on the 52 HCC patients. Only Ficolin-3 proved to be significantly changed after RFA. The 52 patients were divided into two groups according to the expression of Ficolin-3 before and after RFA. The 1-, 2- and 3-year DFS rates were 59.1%, 31.8%, and 22.7%, respectively, for patients in the low Ficolin-3 group (22 patients) and 73.3%, 60.0%, and 50.0%, respectively, for patients in the high Ficolin-3 group (30 patients) (P = 0.038). Conclusions In conclusion, Ficolin-3 was overexpressed in the serum of most HCC patients after RFA. Ficolin-3 might be a biomarker for RFA treatment efficacy and a potential target for HCC immunotherapy.
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Affiliation(s)
- Shunli Shen
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou, 510080, People's Republic of China
| | - Hong Peng
- Department of Bilio-pancreatic Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou, 510080, People's Republic of China
| | - Ye Wang
- Division of Interventional Ultrasound, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou, 510080, People's Republic of China
| | - Ming Xu
- Division of Interventional Ultrasound, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou, 510080, People's Republic of China.,Department of Medical Ultrasonics, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou, 510080, People's Republic of China
| | - Manxia Lin
- Division of Interventional Ultrasound, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou, 510080, People's Republic of China.,Department of Medical Ultrasonics, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou, 510080, People's Republic of China
| | - Xiaoyan Xie
- Division of Interventional Ultrasound, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou, 510080, People's Republic of China.,Department of Medical Ultrasonics, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou, 510080, People's Republic of China
| | - Baogang Peng
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou, 510080, People's Republic of China
| | - Ming Kuang
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou, 510080, People's Republic of China. .,Division of Interventional Ultrasound, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou, 510080, People's Republic of China.
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Impact of Interventional Oncology Therapies on Tumor Microenvironment and Strategies to Enhance Their Efficacy. AJR Am J Roentgenol 2018; 210:648-656. [PMID: 29364726 DOI: 10.2214/ajr.16.17677] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE We provide a brief review of the tumor microenvironment, the impact of six interventional radiology treatments on the tumor microenvironment, and potential methods to improve treatment efficacy. CONCLUSION Interventional oncology plays a unique role in cancer therapy, contributing to both antitumorigenic and protumorigenic effects.
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25
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Zhou Q, Wu S, Gong N, Li X, Dou J, Mu M, Yu X, Yu J, Liang P. Liposomes loading sodium chloride as effective thermo-seeds for microwave ablation of hepatocellular carcinoma. NANOSCALE 2017; 9:11068-11076. [PMID: 28741635 DOI: 10.1039/c7nr02955a] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
UNLABELLED Microwave ablation (MWA) is a promising minimally invasive therapy that has been widely used to treat hepatocellular carcinoma (HCC). However, the efficiency of MWA in treating HCC is evidently limited by the incomplete ablation of large tumors and tumors in high-risk locations. Here, we report the value of using liposomes packed with sodium chloride (NaCl-LPs) as effective thermo-seeds for MWA of HCC. The prepared liposomes exhibited excellent heat conversion ability by showing a more rapid temperature increase than free NaCl medium, blank liposomes or water under microwave irradiation. The high efficiency of this new microwave sensitization strategy was fully demonstrated in vitro in subcutaneous and orthotopic tumors. The results showed that MWA combined with NaCl-LPs clearly enhanced the ablation efficiency, leading to apparent tumor inhibition and low recurrence. What's more, we verified the susceptibility of NaCl-LPs on orthotopic tumors. Based on the unique properties of NaCl-LPs, sublethal MWA was used to mimic the transitional zone, and large-scale necrosis was observed in tumors combined with NaCl-LPs. In addition, HE staining and blood hematology analysis revealed no noticeable toxicity of NaCl-LPs in vivo, which confirmed that NaCl-LPs possessed good biocompatibility. CONCLUSION The effective nanoparticles could play a valuable role in enhancing the thermo-sensitizing effect of MWA for achieving better therapeutic efficacy.
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Affiliation(s)
- Qunfang Zhou
- Department of Interventional Ultrasound, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853, China.
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Cornelis FH, Durack JC, Kimm SY, Wimmer T, Coleman JA, Solomon SB, Srimathveeravalli G. A Comparative Study of Ablation Boundary Sharpness After Percutaneous Radiofrequency, Cryo-, Microwave, and Irreversible Electroporation Ablation in Normal Swine Liver and Kidneys. Cardiovasc Intervent Radiol 2017; 40:1600-1608. [PMID: 28516273 DOI: 10.1007/s00270-017-1692-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 05/03/2017] [Indexed: 02/08/2023]
Abstract
PURPOSE To compare ablation boundary sharpness after percutaneous radiofrequency ablation (RFA), cryoablation (CA), microwave ablation (MWA) and irreversible electroporation (IRE) ablation in normal swine liver and kidney. MATERIALS AND METHODS Percutaneous CT-guided RFA (n = 5), CA (n = 5), MWA (n = 5) and IRE (n = 5) were performed in the liver and kidney of four Yorkshire pigs. Parameters were chosen to produce ablations 2-3 cm in diameter with a single ablation probe. Contrast-enhanced CT imaging was performed 24 h after ablation, and animals were killed. Treated organs were removed and processed for histologic analysis with hematoxylin and eosin, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Three readers independently analyzed CT, H&E and TUNEL stained images of the ablation boundary to delineate regions of (1) viable cells, (2) complete necrosis or (3) mixture of viable and necrotic cells which was defined as the transition zone (TZ). The width of TZ was compared across the techniques and organs. RESULTS Ablations appeared as non-contrast-enhancing regions on CT with sharp transition to enhancing normal tissue. On TUNEL stained slides, the mean width (μm) of the TZ after MWA was 319 ± 157 in liver and 267 ± 95 in kidney, which was significantly lower than RFA (811 ± 477 and 938 ± 429); CA (452 ± 222 and 700 ± 563); and IRE (1319 ± 682 and 1570 ± 962) (all p < 0.01). No significant differences were observed between the organs. CONCLUSION Under similar conditions, the width of the TZ at the ablation boundary varies significantly between different ablation techniques.
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Affiliation(s)
- Francois H Cornelis
- Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Jeremy C Durack
- Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Simon Y Kimm
- Department of Urology, Palo Alto Medical Foundation, Palo Alto, CA, USA
| | | | - Jonathan A Coleman
- Division of Urology, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Stephen B Solomon
- Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Govindarajan Srimathveeravalli
- Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. .,Weill Cornell Medical College, New York, NY, USA.
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27
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Li L, Wang W, Pan H, Ma G, Shi X, Xie H, Liu X, Ding Q, Zhou W, Wang S. Microwave ablation combined with OK-432 induces Th1-type response and specific antitumor immunity in a murine model of breast cancer. J Transl Med 2017; 15:23. [PMID: 28137271 PMCID: PMC5282633 DOI: 10.1186/s12967-017-1124-9] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 01/19/2017] [Indexed: 12/11/2022] Open
Abstract
Background Minimally invasive therapies, such as microwave ablation (MWA), are widely used for the treatment of solid tumors. Previous studies suggest that MWA is feasible for the treatment of small breast cancer, and thermal ablation may induce adaptive antitumor immunity. However, the induced immune responses are mostly weak, and the immunomodulation effects of MWA in breast cancer are unclear. Immunostimulant OK-432 can induce tumor-specific T-cell responses and may augment the immunity induced by MWA. Methods We treated 4T1 breast cancer bearing BALB/c mice with MWA, OK-432, MWA plus OK-432, or left without treatment. Survival time was evaluated with the Kaplan–Meyer method comparing survival curves by log-rank test. On day 25 after ablation, surviving mice received tumor rechallenge, and the rechallenged tumor volumes were calculated every 5 days. Immunohistochemistry and flow cytometry were used to evaluate the T-cell immune responses in ablated tissues and spleens. The tumor-specific immunity was assessed by enzyme-linked immunospot assays. Besides, the cytokine patterns were identified from enzyme-linked immunosorbent assay. Results Microwave ablation plus OK-432 resulted in longer survival than single treatment and protect most surviving mice from tumor rechallenge. Both local and systemic T-cell responses were induced by MWA and were further enhanced by subsequent administration of OK-432. Moreover, the combination of MWA and OK-432 induced stronger tumor-specific immune responses than MWA alone. In addition, OK-432 and MWA synergistically promoted the production of Th1-type but not Th2-type cytokines, and polarized T-cell responses to Th1-dominant state. Conclusions The T-cell immune responses were activated by MWA in breast cancer. Furthermore, the combination of MWA and OK-432 induced Th1-type response and elicited specific antitumor immunity.
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Affiliation(s)
- Li Li
- Department of Breast Surgery, the First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Wei Wang
- Department of Breast Surgery, the First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Hong Pan
- Department of Breast Surgery, the First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Ge Ma
- Department of Breast Surgery, the First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Xinyi Shi
- Department of Breast Surgery, the First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Hui Xie
- Department of Breast Surgery, the First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Xiaoan Liu
- Department of Breast Surgery, the First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Qiang Ding
- Department of Breast Surgery, the First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Wenbin Zhou
- Department of Breast Surgery, the First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.
| | - Shui Wang
- Department of Breast Surgery, the First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.
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Wu F. Heat-Based Tumor Ablation: Role of the Immune Response. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 880:131-53. [DOI: 10.1007/978-3-319-22536-4_8] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Bastianpillai C, Petrides N, Shah T, Guillaumier S, Ahmed HU, Arya M. Harnessing the immunomodulatory effect of thermal and non-thermal ablative therapies for cancer treatment. Tumour Biol 2015; 36:9137-46. [PMID: 26423402 DOI: 10.1007/s13277-015-4126-3] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Accepted: 09/20/2015] [Indexed: 01/10/2023] Open
Abstract
Minimally invasive interventional therapies are evolving rapidly and their use for the treatment of solid tumours is becoming more extensive. The in situ destruction of solid tumours by such therapies is thought to release antigens that can prime an antitumour immune response. In this review, we offer an overview of the current evidence for immune response activation associated with the utilisation of the main thermal and non-thermal ablation therapies currently in use today. This is followed by an assessment of the hypothesised mechanisms behind this immune response priming and by a discussion of potential methods of harnessing this specific response, which may subsequently be applicable in the treatment of cancer patients. References were identified through searches of PubMed/MEDLINE and Cochrane databases to identify peer-reviewed original articles, meta-analyses and reviews. Papers were searched from 1850 until October 2014. Articles were also identified through searches of the authors' files. Only papers published in English were reviewed. Thermal and non-thermal therapies have the potential to stimulate antitumour immunity although the current body of evidence is based mostly on murine trials or small-scale phase 1 human trials. The evidence for this immune-modulatory response is currently the strongest in relation to cryotherapy and radiotherapy, although data is accumulating for related ablative treatments such as high-intensity focused ultrasound, radiofrequency ablation and irreversible electroporation. This effect may be greatly enhanced by combining these therapies with other immunostimulatory interventions. Evidence is emerging into the immunomodulatory effect associated with thermal and non-thermal ablative therapies used in cancer treatment in addition to the mechanism behind this effect and how it may be harnessed for therapeutic use. A potential exists for treatment approaches that combine ablation of the primary tumour with control and possible eradication of persistent, locally recurrent and metastatic disease. However, more work is needed into each of these modalities, initially in further animal studies and then subsequently in large-scale prospective human studies.
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Affiliation(s)
| | - Neophytos Petrides
- Division of Surgery and Interventional Science, University College London, London, UK. .,Princess Alexandra Hospital, Hamstel Road, Harlow, CM20 1QX, UK.
| | - Taimur Shah
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Stephanie Guillaumier
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Hashim U Ahmed
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Manit Arya
- Division of Surgery and Interventional Science, University College London, London, UK.,Princess Alexandra Hospital, Hamstel Road, Harlow, CM20 1QX, UK
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Abstract
Image-guided tumor ablation for early stage hepatocellular carcinoma (HCC) is an accepted non-surgical treatment that provides excellent local tumor control and favorable survival benefit. This review summarizes the recent advances in tumor ablation for HCC. Diagnostic imaging and molecular biology of HCC has recently undergone marked improvements. Second-generation ultrasonography (US) contrast agents, new computed tomography (CT) techniques, and liver-specific contrast agents for magnetic resonance imaging (MRI) have enabled the early detection of smaller and inconspicuous HCC lesions. Various imaging-guidance tools that incorporate imaging-fusion between real-time US and CT/MRI, that are now common for percutaneous tumor ablation, have increased operator confidence in the accurate targeting of technically difficult tumors. In addition to radiofrequency ablation (RFA), various therapeutic modalities including microwave ablation, irreversible electroporation, and high-intensity focused ultrasound ablation have attracted attention as alternative energy sources for effective locoregional treatment of HCC. In addition, combined treatment with RFA and chemoembolization or molecular agents may be able to overcome the limitation of advanced or large tumors. Finally, understanding of the biological mechanisms and advances in therapy associated with tumor ablation will be important for successful tumor control. All these advances in tumor ablation for HCC will result in significant improvement in the prognosis of HCC patients. In this review, we primarily focus on recent advances in molecular tumor biology, diagnosis, imaging-guidance tools, and therapeutic modalities, and refer to the current status and future perspectives for tumor ablation for HCC.
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Affiliation(s)
| | - Hyunchul Rhim
- *Hyunchul Rhim, MD, Department of Radiology and Center for Imaging Science, Samsung, Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-Dong, Gangnam-gu, Seoul 135-710 (Republic of Korea), Tel. +82 2 3410 2507, E-mail
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Du Q, Fu C, Tie J, Liu T, Li L, Ren X, Huang Z, Liu H, Tang F, Li L, Meng X. Gelatin microcapsules for enhanced microwave tumor hyperthermia. NANOSCALE 2015; 7:3147-3154. [PMID: 25613756 DOI: 10.1039/c4nr07104b] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Local and rapid heating by microwave (MW) irradiation is important in the clinical treatment of tumors using hyperthermia. We report here a new thermo-seed technique for the highly efficient MW irradiation ablation of tumors in vivo based on gelatin microcapsules. We achieved 100% tumor elimination in a mouse model at an ultralow power of 1.8 W without any side-effects. The results of MTT assays, a hemolysis test and the histological staining of organs indicated that the gelatin microcapsules showed excellent compatibility with the physiological environment. A possible mechanism is proposed for MW hyperthermia using gelatin microcapsules. We also used gelatin microcapsules capped with CdTe quantum dots for in vivo optical imaging. Our study suggests that these microcapsules may have potential applications in imaging-guided cancer treatment.
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Affiliation(s)
- Qijun Du
- Laboratory of Controllable Preparation and Application of Nanomaterials, Center for Micro/nanomaterials and Technology, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
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Chen Y, Youn P, Pysher TJ, Scaife CL, Furgeson DY. Tumour eradication using synchronous thermal ablation and Hsp90 chemotherapy with protein engineered triblock biopolymer-geldanamycin conjugates. Int J Hyperthermia 2014; 30:550-64. [PMID: 25403416 DOI: 10.3109/02656736.2014.974694] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
PURPOSE Hepatocellular carcinoma (HCC) suffers high tumour recurrence rate after thermal ablation. Heat shock protein 90 (Hsp90) induced post-ablation is critical for tumour survival and progression. A combination therapy of thermal ablation and polymer conjugated Hsp90 chemotherapy was designed and evaluated for complete tumour eradication of HCC. MATERIALS AND METHODS A thermo-responsive, elastin-like polypeptide (ELP)-based tri-block biopolymer was developed and conjugated with a potent Hsp90 inhibitor, geldanamycin (GA). The anti-cancer efficacy of conjugates was evaluated in HCC cell cultures with and without hyperthermia (43 °C). The conjugates were also administered twice weekly in a murine HCC model as a single treatment or in combination with single electrocautery as the ablation method. RESULTS ELP-GA conjugates displayed enhanced cytotoxicity in vitro and effective heat shock inhibition under hyperthermia. The conjugates alone significantly slowed the tumour growth without systemic toxicity. Four doses of thermo-responsive ELP-GA conjugates with concomitant simple electrocautery accomplished significant Hsp90 inhibition and sustained tumour suppression. CONCLUSION Hsp90 inhibition plays a key role in preventing the recurrence of HCC, and the combination of ablation with targeted therapy holds great potential to improve prognosis and survival of HCC patients.
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Affiliation(s)
- Yizhe Chen
- Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, University of Utah , Salt Lake City
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Hansen PD, Cassera MA, Wolf RF. Ablative technologies for hepatocellular, cholangiocarcinoma, and metastatic colorectal cancer of the liver. Surg Oncol Clin N Am 2014; 24:97-119. [PMID: 25444471 DOI: 10.1016/j.soc.2014.09.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
A wide array of ablation technologies, in addition to the progressive sophistication of imaging technologies and percutaneous, laparoscopic, and open surgical techniques, have allowed us to expand treatment options for patients with liver tumors. In this article, technical considerations of chemical and thermal ablations and their application in hepatic oncology are reviewed.
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Affiliation(s)
- Paul D Hansen
- Hepatobiliary and Pancreatic Surgery Program, Providence Cancer Center, Providence Portland Medical Center, 4805 NE Glisan St, Suite 6N60, Portland, OR 97213, USA.
| | - Maria A Cassera
- Hepatobiliary and Pancreatic Surgery Program, Providence Cancer Center, Providence Portland Medical Center, 4805 NE Glisan St, Suite 6N60, Portland, OR 97213, USA
| | - Ronald F Wolf
- Hepatobiliary and Pancreatic Surgery Program, Providence Cancer Center, Providence Portland Medical Center, 4805 NE Glisan St, Suite 6N60, Portland, OR 97213, USA
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Abstract
Minimally invasive thermal ablation of tumours has become common since the advent of modern imaging. From the ablation of small, unresectable tumours to experimental therapies, percutaneous radiofrequency ablation, microwave ablation, cryoablation and irreversible electroporation have an increasing role in the treatment of solid neoplasms. This Opinion article examines the mechanisms of tumour cell death that are induced by the most common thermoablative techniques and discusses the rapidly developing areas of research in the field, including combinatorial ablation and immunotherapy, synergy with conventional chemotherapy and radiation, and the development of a new ablation modality in irreversible electroporation.
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Affiliation(s)
- Katrina F Chu
- The Department of Diagnostic Imaging, The Warren Alpert Medical School of Brown University and Rhode Island Hospital, 593 Eddy Street, Providence, Rhode Island 02903, USA
| | - Damian E Dupuy
- The Department of Diagnostic Imaging, The Warren Alpert Medical School of Brown University and Rhode Island Hospital, 593 Eddy Street, Providence, Rhode Island 02903, USA
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Deng ZS, Liu J. Chemothermal therapy for localized heating and ablation of tumor. JOURNAL OF HEALTHCARE ENGINEERING 2013; 4:409-26. [PMID: 23965596 DOI: 10.1260/2040-2295.4.3.409] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Chemothermal therapy is a new hyperthermia treatment on tumor using heat released from exothermic chemical reaction between the injected reactants and the diseased tissues. With the highly minimally invasive feature and localized heating performance, this method is expected to overcome the ubiquitous shortcomings encountered by many existing hyperthermia approaches in ablating irregular tumor. This review provides a relatively comprehensive review on the latest advancements and state of the art in chemothermal therapy. The basic principles and features of two typical chemothermal ablation strategies (acid-base neutralization-reaction-enabled thermal ablation and alkali-metal-enabled thermal/chemical ablation) are illustrated. The prospects and possible challenges facing chemothermal ablation are analyzed. The chemothermal therapy is expected to open many clinical possibilities for precise tumor treatment in a minimally invasive way.
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Affiliation(s)
- Zhong-Shan Deng
- Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing, China.
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Cui J, Wang N, Zhao H, Jin H, Wang G, Niu C, Terunuma H, He H, Li W. Combination of radiofrequency ablation and sequential cellular immunotherapy improves progression-free survival for patients with hepatocellular carcinoma. Int J Cancer 2013; 134:342-51. [PMID: 23825037 DOI: 10.1002/ijc.28372] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2013] [Revised: 05/16/2013] [Accepted: 06/18/2013] [Indexed: 01/27/2023]
Abstract
Hepatocellular carcinoma (HCC) recurs frequently after minimally invasive therapy. The aim of our study was to observe the efficiency and safety of the combined treatment of radiofrequency ablation (RFA) with cellular immunotherapy (CIT) for HCC patients. In our study, 62 patients with HCC who were treated with radical RFA were divided into two groups: RFA alone (32 patients) and RFA/CIT (30 patients). Autologous mononuclear cells were collected from the peripheral blood and separated by apheresis, and then induced into natural killer (NK) cells, γδT cells and cytokine-induced killer (CIK) cells. These cells were identified by flow cytometry with their specific antibodies and then were infused intravenously to RFA/CIT patients for three or six courses. The tumor recurrent status of these patients was evaluated with computed tomography or magnetic resonance imaging every 3 months after RFA. Progression-free survival (PFS), liver function, viral load and adverse effects were examined. The results implied that PFS was higher in RFA/CIT group than that in RFA group. In RFA/CIT group, six courses had better survival prognosis than three courses. Viral load of hepatitis C was decreased in two of three patients without antiviral therapy in RFA/CIT group, but was increased in RFA group. No significant adverse reaction was found in the patients with CIT. In summary, these preliminary results suggest that combination of sequential CIT with RFA for HCC patients was efficient and safe, and may be helpful in the prevention of the recurrence for the patients with HCC after RFA.
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Affiliation(s)
- Jiuwei Cui
- Cancer Center of the First Hospital of Jilin University, Changchun, China
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More than just tumor destruction: immunomodulation by thermal ablation of cancer. Clin Dev Immunol 2011; 2011:160250. [PMID: 22242035 PMCID: PMC3254009 DOI: 10.1155/2011/160250] [Citation(s) in RCA: 156] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2011] [Accepted: 08/25/2011] [Indexed: 02/07/2023]
Abstract
Over the past decades, thermoablative techniques for the therapy of localized tumors have gained importance in the treatment of patients not eligible for surgical resection. Anecdotal reports have described spontaneous distant tumor regression after thermal ablation, indicating a possible involvement of the immune system, hence an induction of antitumor immunity after thermoinduced therapy. In recent years, a growing body of evidence for modulation of both adaptive and innate immunity, as well as for the induction of danger signals through thermoablation, has emerged. Induced immune responses, however, are mostly weak and not sufficient for the complete eradication of established tumors or durable prevention of disease progression, and combination therapies with immunomodulating drugs are being evaluated with promising results. This article aims to summarize published findings on immune modulation through radiofrequency ablation, cryoablation, microwave ablation therapy, high-intensity focused ultrasound, and laser-induced thermotherapy.
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Zhou P, Liang P, Dong B, Yu X, Han X, Wang Y, Han Z. Long-term results of a phase II clinical trial of superantigen therapy with staphylococcal enterotoxin C after microwave ablation in hepatocellular carcinoma. Int J Hyperthermia 2011; 27:132-9. [DOI: 10.3109/02656736.2010.506670] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
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Yang C, Zhu H, Wu S, Bai Y, Gao H. Correlations between B-mode ultrasonic image texture features and tissue temperature in microwave ablation. JOURNAL OF ULTRASOUND IN MEDICINE : OFFICIAL JOURNAL OF THE AMERICAN INSTITUTE OF ULTRASOUND IN MEDICINE 2010; 29:1787-1799. [PMID: 21098851 DOI: 10.7863/jum.2010.29.12.1787] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
OBJECTIVE The purpose of this study was to find the correlations between B-mode ultrasonic tissue texture features and tissue temperature in microwave ablation. METHODS A total of 20 in vitro porcine liver samples were used for microwave ablation experiments. B-mode ultrasonic images under various temperatures were acquired. The texture features of the differential images based on the gray level histogram, including the mean of the gray scale (MGS), standard deviation of the gray scale, and entropy of the gray scale (ENT), and those based on the gray level co-occurrence matrix, including the contrast (CON), angular second moment (ASM), inverse difference moment (IDM), and correlation, were extracted. Correlations between the features and liver sample temperature were analyzed. In addition, water bath heating experiments were also performed on 15 in vitro porcine liver samples for analysis validation. RESULTS The correlation coefficients across the MGS, ENT, and ASM in 4 directions (0°, 45°, 90°, and 135°), the CON and IDM in 3 directions (45°, 90°, and 135°), and a temperature range of 15°C to 90°C were high and greater than 0.9 during microwave ablation. All texture features of the differential B-mode ultrasonic images changed with rising temperature from 25°C to 60°C during water bath heating. CONCLUSIONS Changes in image features reflect changes in tissue temperature during microwave ablation.
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Affiliation(s)
- Chunlan Yang
- College of Life Science and Bioengineering, Beijing University of Technology, Beijing, China.
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Rao P, Escudier B, de Baere T. Spontaneous Regression of Multiple Pulmonary Metastases After Radiofrequency Ablation of a Single Metastasis. Cardiovasc Intervent Radiol 2010; 34:424-30. [DOI: 10.1007/s00270-010-9896-9] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2010] [Accepted: 05/06/2010] [Indexed: 11/30/2022]
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Yu Z, Liu W, Fan L, Shao J, Huang Y, Si X. The efficacy and safety of percutaneous microwave coagulation by a new microwave delivery system in large hepatocellular carcinomas: four case studies. Int J Hyperthermia 2009; 25:392-8. [PMID: 19551547 DOI: 10.1080/02656730902976815] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
PURPOSE To demonstrate the efficacy and safety of percutaneous microwave coagulation treatment (PMCT) by a new microwave delivery system (Forsea Microwave) in large hepatocellular carcinomas (HCC) (> or =5 cm). MATERIALS AND METHODS Four patients with 4 HCC lesions measuring > or =6 cm in the greatest dimension underwent PMCT by means of the Forsea Microwave microwave delivery system. Final therapeutic efficacy was evaluated with dynamic computer tomography (CT) scans performed within one month after PMCT. During and after PMCT, patients' complaints and any abnormal physical signs were recorded for safety assay. CT or ultrasound scan (US) performed immediately after the treatment was used to detect acute complications related to the treatment. Repeated dynamic CT scans were performed every three to four months thereafter to detect local disease recurrence and/or other recurrences. RESULTS Three of these patients achieved a complete ablation of the cancer nodules (two patients with two treatment sessions and one patient with three treatment sessions). One of these patients obtained a complete ablation of the cancer nodule with two treatment sessions except the lesion of portal vein tumour thrombus (PVTT). No obvious symptomatic complication was observed except abdominal pain during and after the treatment in two of these patients. All the patients remained asymptomatic and no recurrent tumour was observed during their follow-up (1-19 months). CONCLUSIONS PMCT by the Forsea Microwave microwave delivery system could offer a satisfactory therapeutic effect and is applicable to the treatment of large HCC.
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Affiliation(s)
- Zhaocai Yu
- Department of Clinical Oncology, Xijing Hospital, The Fourth Military Medical University, PR China
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Rao W, Liu J. Tumor thermal ablation therapy using alkali metals as powerful self‐heating seeds. MINIM INVASIV THER 2009; 17:43-9. [DOI: 10.1080/13645700701803826] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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43
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Rhim H. Review of Asian experience of thermal ablation techniques and clinical practice. Int J Hyperthermia 2009; 20:699-712. [PMID: 15675666 DOI: 10.1080/0265673042000196487] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
The field of image-guided tumour ablation has gained great attention from Asian physicians because it represents a safe and effective technique for many commonly seen tumours in this population, showing minimal morbidity and excellent local control rates. Based on the current survey data from Asian physicians who are currently performing image-guided tumour ablation, thermal ablation has been mainly performed for patients with unresectable liver tumours. Radiofrequency ablation has replaced many other local ablation techniques such as microwave or ethanol ablation in treating small focal hepatic tumours for the last 5 years. Surgery and transcatheter arterial chemoembolization also have a unique role as curative and palliative treatment options for patients with more extensive tumour burden. Although radiofrequency ablation represents a paradigm shift in local therapy, more sophisticated strategies to enhance the therapeutic efficacy are necessary and more randomized and controlled investigations to estimate its clinical benefit are warranted.
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Affiliation(s)
- H Rhim
- Department of Diagnostic Radiology, Hanyang University Hospital, 17 Haengdang-Dong, Sungdong-Gu, Seoul 133-792, Korea.
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Efficacy and safety of microwave ablation for primary and secondary liver malignancies: a systematic review. Eur J Gastroenterol Hepatol 2009; 21:599-605. [PMID: 19282763 DOI: 10.1097/meg.0b013e328318ed04] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
This article reviews the therapeutic efficacy and complications of microwave ablation (MWA) in the treatment of primary and secondary liver malignancies. A PubMed search using keywords 'microwave', 'liver', 'malignancy', 'cancer' and 'tumour' was performed to identify articles related to MWA of liver malignancies published in English from 1975 to February 2008. MWA is an effective treatment options for both primary and secondary liver malignancies with survivals comparable with those of liver resections. Local recurrences can be managed with further ablation. Small tumour size, well-differentiated tumour and a reduced number of lesions are factors associated with good prognosis. Temporary occlusion of the portal venous and hepatic arterial flow may increase the size of ablation but the safety aspect requires further validation. MWA is a minimally invasive technique that has broadened the therapeutic option for patients with conventionally unresectable liver tumours with promising survival data. Future advances in the applicator design and treatment monitoring may further improve its efficacy and widen the indications.
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Gravante G, Sconocchia G, Ong SL, Dennison AR, Lloyd DM. Immunoregulatory effects of liver ablation therapies for the treatment of primary and metastatic liver malignancies. Liver Int 2009; 29:18-24. [PMID: 19018971 DOI: 10.1111/j.1478-3231.2008.01915.x] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Ablation of liver tissue produces in situ tumoural antigens and elicits specific immune responses. The aim of this review is to examine the available data about the local and systemic responses produced and to compare differences between the methods available. A literature search was undertaken for all papers focusing on immune responses following ablative therapy of the liver, including experimental and clinical studies. Following ablative procedures, the cellular response is elicited by the presentation of antigens by dendritic cells to specific CD4(+) T cells, which in turn stimulate natural killer or CD8(+) cytotoxic cells. The local release of intracellular debris activates Kupffer cells to produce cytokines, which, in the immediate vicinity, activate monocytes/macrophages or specific T cells that respond and produce systemic reactions such as fever, thrombocytopaenia or shock. The immune responses elicited by cryotherapy, both cellular and cytokine, seem far greater than those produced by radiofrequency or microwave ablation, probably as a consequence of the peculiar mechanism of cell death of the former (disruptive necrosis). This mechanism is considered central to the pathogenesis of cryoshock. Ablative techniques stimulate the immune system and provide an easy way to achieve in vivo vaccination against tumoural antigens. Immunomodulatory approaches have the potential to augment the initial immune stimulation and this combined approach could pave the way to a more selective and specific method of treating liver tumours.
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Affiliation(s)
- Gianpiero Gravante
- Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, University Hospitals of Leicester, Leicester, UK.
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Abstract
OBJECTIVE This article reviews the basic principles, equipment, current therapeutic status and future trends of microwave ablation (MWA) in the treatment of hepatocellular carcinoma (HCC). METHODS All articles published in English on MWA or MWA as a treatment for HCC were identified with a PubMed search from the 1990s through June 2007. Papers were reviewed on the technical advances of MWA equipment and the clinical applications of MWA including indications, techniques, therapeutic outcomes, complications and combination therapies. RESULTS MWA has several advantages, including high thermal efficiency, higher capability of coagulating blood vessels, faster ablation time, and an improved convention profile. MWA can induce large ablation volumes and yield good local tumor control, especially for small HCC. Larger HCC can also be completely ablated by using more effective antenna or simultaneous application of multiple antennae. Long-term survival comparable to that of surgery was obtained for tumors measuring 4 cm or less. Associated complications appear to be low. CONCLUSIONS MWA is a promising minimally invasive technique for the treatment of HCC. Future advances are warranted to improve the therapeutic efficacy.
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Affiliation(s)
- Ping Liang
- Department of Ultrasound, Chinese PLA General Hospital, Beijing, PR China.
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Duan YQ, Gao YY, Ni XX, Wang Y, Feng L, Liang P. Changes in peripheral lymphocyte subsets in patients after partial microwave ablation of the spleen for secondary splenomegaly and hypersplenism: a preliminary study. Int J Hyperthermia 2007; 23:467-72. [PMID: 17701538 DOI: 10.1080/02656730701474533] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
PURPOSE Microwave ablation therapy for secondary splenomegaly and hypersplenism has been shown to be effective from pre-clinical animal models and clinical investigations. This study was performed to determine its effects on the status of peripheral lymphocyte subsets in patients receiving microwave ablation of the spleen. MATERIALS AND METHODS Ten patients with secondary splenomegaly and hypersplenism received microwave ablation of the spleen during laparoscopy or percutaneously under ultrasound guidance. The percentage peripheral blood T cells, B lymphocytes and NK cells were measured using flow cytometry before and on days 1, 3 and 7 after therapy, as well as 1 and 3 months afterwards. RESULTS Percentages of CD3(+) and CD4(+) cells increased rapidly 1 month after therapy. There was no significant change in CD8(+), CD4(+)/CD8(+) or NK cells of the pre- and post-therapy levels and B lymphocytes increased significantly after therapy. In patients with an ablation volume (AV) less than 20% (group A), T cells increased 1 month after ablation but decreased 3 months after ablation. B lymphocytes increased significantly after surgery. Levels of NK cells were lower than that before therapy on each testing. In patients with 20-40% AV (group B), levels of T cells, B lymphocytes and NK cells showed an increase. Levels of CD4(+) cells were significantly higher in group B than in group A, 3 months after therapy. CONCLUSIONS Microwave ablation therapy for splenomegaly and hypersplenism appears to have a favourable effect on peripheral lymphocyte subsets. A relationship may exist between the ablation volume and the level of peripheral lymphocyte subsets.
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Affiliation(s)
- Y Q Duan
- Department of Ultrasound, Chinese PLA General Hospital, China
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Mizukoshi E, Nakamoto Y, Tsuji H, Yamashita T, Kaneko S. Identification of alpha-fetoprotein-derived peptides recognized by cytotoxic T lymphocytes in HLA-A24+ patients with hepatocellular carcinoma. Int J Cancer 2006; 118:1194-204. [PMID: 16152611 DOI: 10.1002/ijc.21468] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Alpha-fetoprotein (AFP) has been proposed as a potential target forT-cell-based immunotherapy for hepatocellular carcinoma (HCC), but the number of its epitopes that have been identified is limited and the status of AFP-specific immunological responses in HCC patients has not been well-characterized. To address the issue, we examined the possibility of inducing AFP-specific cytotoxic T cells (CTLs) using novel HLA-A*2402-restricted T-cell epitopes (HLA, human leukocyte antigen) derived from AFP and then analyzed the relationship between its frequency of occurrence and clinical features associated with patients having HCC. Five AFP-derived peptides containing HLA-A*2402 binding motifs and showing high binding affinity to HLA-A*2402 induced CTLs to produce IFN-gamma and kill an AFP-producing hepatoma cell line. The frequency of AFP-specific CTLs was 30-190 per 1 x 10(6) peripheral blood mononuclear cells, which was the same as that of other immunogenic cancer associated antigen-derived epitopes. Analyses of the relationships between AFP-specific CTL responses and clinical features of patients with HCC revealed that AFP epitopes were more frequently recognized by CTLs in patients with advanced HCC correlating to tumor factors or the stage of TNM classification. The analyses of CTL responses before and after HCC treatments showed that the treatments changed the frequency of AFP-specific CTLs. In conclusion, we identified five HLA-A*2402-restricted T-cell epitopes derived from AFP. The newly identified AFP epitopes could be a valuable component of HCC immunotherapy and for analyzing host immune responses to HCC.
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Affiliation(s)
- Eishiro Mizukoshi
- Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
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Kuang M, Liu SQ, Saijo K, Uchimura E, Huang L, Leong KW, Lu MD, Huang JF, Ohno T. Microwave tumour coagulation plus in situ treatment with cytokine-microparticles: induction of potent anti-residual tumour immunity. Int J Hyperthermia 2005; 21:247-57. [PMID: 16019851 DOI: 10.1080/02656730500052027] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Abstract
After local microwave coagulation and subsequent intra-tumoural injection of microparticles encapsulating interleukin-2 and granulocyte-macrophage colony-stimulating factor, the anti-tumour efficacy against subcutaneous Lewis lung carcinoma in syngeneic mice was evaluated. This treatment elicited a potent systemic anti-tumour immunity that protected treated mice from re-challenge with the same tumour cells and caused the distal tumours in a bilateral tumour model to be rejected. Cytotoxicity assay indicated that both T- and natural killer cells acted as the effector cells in the anti-tumour immunity. These data highlight the feasibility of microwave-pre-treated in situ cancer vaccination for clinical use.
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Affiliation(s)
- M Kuang
- The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
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Cui J, Dong BW, Liang P, Yu XL, Yu DJ. Construction and clinical significance of a predictive system for prognosis of hepatocellular carcinoma. World J Gastroenterol 2005; 11:3027-33. [PMID: 15918184 PMCID: PMC4305834 DOI: 10.3748/wjg.v11.i20.3027] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: The aims of this study were to explore individualized treatment method for hepatocellular carcinoma (HCC) patients whose maximum tumor size was less than 5 cm to improve prognosis and survival quality.
METHODS: Thirty cases of primary HCC patients undergoing tumor resection were retrospectively analyzed (resection group). All the tumors were proved as primary HCC with pathologic examination. The patients were divided into two groups according to follow-up results: group A, with tumor recurrence within 1 year after resection; group B, without tumor recurrence within 1 year. Immunohist-ochemical stainings were performed using 11 kinds of monoclonal antibodies (AFP, c-erbB2, c-met, c-myc, HBsAg, HCV, Ki-67, MMP-2, nm23-H1, P53, and VEGF), and expressing intensities were quantitatively analyzed. Regression equation using factors affecting prognosis of HCC was constructed with binary logistic method. HCC patients undergoing percutaneous microwave coagulation therapy (PMCT) were also retrospectively analyzed (PMCT group). Immunohistochemical stainings of tumor biopsy samples were performed with molecules related to HCC prognosis, staining intensities were quantitatively analyzed, coincidence rate of prediction was calculated.
RESULTS: In resection group, the expressing intensities of c-myc, Ki-67, MMP-2 and VEGF in cancer tissue in group A were significantly higher than those in group B (t = 2.97, P = 0.01; t = 2.42, P = 0.03<0.05; t = 2.57, P = 0.02<0.05; t = 3.43, P = 0.004<0.01, respectively); the expressing intensities of 11 kinds of detected molecules in para-cancer tissue in groups A and B were not significantly different (P>0.05). The regression equation predicting prognosis of HCC is as follows: P(1) = 1/[1+e-(3.663-0.412mycc-2.187Ki-67c-0.397vegfc)]. It demonstrates that prognosis of HCC in resection group was related with c-myc, Ki-67 and VEGF expressing intensity in cancer tissue. In PMCT group, the expressing intensities of c-myc, Ki-67 and VEGF in cancer tissue in group A were significantly higher than those in group B (t = 4.57, P = 0.000<0.01; t = 2.08, P = 0.04<0.05; t = 2.38, P = 0.02<0.05, respectively); the expressing intensities of c-myc, Ki-67 and VEGF in para-cancer tissue in groups A and B were not significantly different (P>0.05). The coincidence rate of patients undergoing PMCT in group A was 88.00% (22/25), in group B 68.75% (11/16), the total coincidence rate was 80.49% (33/41).
CONCLUSION: The regression equation is accurate and feasible and could be used for predicting prognosis of HCC, it helps to select treatment method (resection or PMCT) for HCC patients to realize individualized treatment to improve prognosis.
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Affiliation(s)
- Jun Cui
- Department of Ultrasound, Chinese PLA General Hospital, Beijing, China.
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