|
1
|
Furukawa J, Kakei Y, Murakami S, Kita H, Ueki H, Hara T, Teishima J, Hinata N, Miyake H, Fujisawa M, Shirakawa T. Safety and efficacy of oral cancer vaccine B440 in patients with PD-1/PD-L1 inhibitor-resistant advanced urothelial cancer: a study protocol for a phase 1 multicenter, open-label, single-arm clinical trial. BMC Cancer 2025; 25:195. [PMID: 39905323 PMCID: PMC11792616 DOI: 10.1186/s12885-025-13514-4] [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: 07/13/2024] [Accepted: 01/14/2025] [Indexed: 02/06/2025] Open
Abstract
BACKGROUND This is a multicenter, open-label, single-arm clinical trial to evaluate the safety and efficacy of oral cancer vaccine B440 in patients with PD-1/PD-L1 inhibitor-resistant advanced urothelial cancer. METHODS The trial will be performed at three university hospitals in Japan. The target number of patients will be 12. The patients will be treated orally with B440 once daily for 5 days followed by 2 days for four consecutive courses (4 weeks, 20 treatments). The low-dose group will receive 800 mg (4 capsules) per dose and the high-dose group will receive 1,600 mg (8 capsules) per dose. The primary outcome will be the number and incidence of DLT cases the start of treatment and Day 28. Secondary outcomes are the presence or absence of a response, the best overall response and PFS. DISCUSSION If this trial shows B440 to be safe and effective, it may lead to a late phase randomized controlled trial in advanced urothelial cancer. Ultimately, we hope to provide a new treatment option for such patients. TRIAL REGISTRATION Japan Registry of Clinical Trials (jRCT) identifier: jRCT2051220143. Registered on December 27, 2022.
Collapse
Affiliation(s)
- Junya Furukawa
- Department of Urology, Kobe University Graduate School of Medicine, Kobe, Japan
- Department of Urology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Yasumasa Kakei
- Department of Clinical and Translational Research Center, Kobe University Hospital, Kobe, Japan.
| | - Sae Murakami
- Department of Clinical and Translational Research Center, Kobe University Hospital, Kobe, Japan
| | - Hiroshi Kita
- Department of Clinical and Translational Research Center, Kobe University Hospital, Kobe, Japan
| | - Hideto Ueki
- Department of Urology, Kobe University Graduate School of Medicine, Kobe, Japan
- Division of Advanced Medical Science, Kobe University Graduate School of Science, Technology and Innovation, Kobe, Japan
| | - Takuto Hara
- Department of Urology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Jun Teishima
- Department of Urology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Nobuyuki Hinata
- Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hideaki Miyake
- Department of Urology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Masato Fujisawa
- Department of Urology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Toshiro Shirakawa
- Department of Urology, Kobe University Graduate School of Medicine, Kobe, Japan
- Division of Advanced Medical Science, Kobe University Graduate School of Science, Technology and Innovation, Kobe, Japan
- Immunorock Co., Lt, Kobe, Japan
| |
Collapse
|
|
2
|
Couzinet A, Suzuki T, Nakatsura T. Progress and challenges in glypican-3 targeting for hepatocellular carcinoma therapy. Expert Opin Ther Targets 2024; 28:895-909. [PMID: 39428649 DOI: 10.1080/14728222.2024.2416975] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 10/11/2024] [Indexed: 10/22/2024]
Abstract
INTRODUCTION Glypican-3 (GPC3) is a cell membrane-anchored heparan sulfate proteoglycan that has recently garnered attention as a cancer antigen owing to its high expression in numerous cancers, particularly hepatocellular carcinoma (HCC), and to limited expression in adult normal tissue. AREAS COVERED Here, we propose the potential of GPC3 as a cancer antigen based on our experience with the GPC3 peptide vaccine against HCC, having developed a vaccine that progressed from preclinical studies to first-in-human clinical trials. In this review, we present a summary of the current status and future prospects of immunotherapies targeting GPC3 by focusing on clinical trials; peptide vaccines, mRNA vaccines, antibody therapy, and chimeric antigen receptor/T-cell receptor - T-cell therapy and discuss additional strategies for effectively eliminating HCC through immunotherapy. EXPERT OPINION GPC3 is an ideal cancer antigen for HCC immunotherapy. In resectable HCC, immunotherapies that leverage physiological immune surveillance, immune checkpoint inhibitors, and GPC3-target cancer vaccines appear promising in preventing recurrence and could be considered as a prophylactic adjuvant therapy. However, in advanced HCC, clinical trials have not demonstrated sufficient anti-tumor efficacy, in contrast with preclinical studies. Reverse translation, bedside-to-bench research, is crucial to identify the factors that have hindered GPC3 target immunotherapies.
Collapse
Affiliation(s)
- Arnaud Couzinet
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Toshihiro Suzuki
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Tetsuya Nakatsura
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| |
Collapse
|
|
3
|
Sabaghian A, Shamsabadi S, Momeni S, Mohammadikia M, Mohebbipour K, Sanami S, Ahmad S, Akhtar N, Sharma NR, Kushwah RBS, Gupta Y, Prakash A, Pazoki-Toroudi H. The role of PD-1/PD-L1 signaling pathway in cancer pathogenesis and treatment: a systematic review. JOURNAL OF CANCER METASTASIS AND TREATMENT 2024. [DOI: 10.20517/2394-4722.2024.15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
Abstract
Aim: Cancer as a complex disease poses significant challenges for both diagnosis and treatment. Researchers have been exploring various avenues to find effective therapeutic strategies, with a particular emphasis on cellular signaling pathways and immunotherapy. One such pathway that has recently been suggested is the PD-1/PD-L1 pathway, which is an immune checkpoint signaling system that plays an important role in regulating the immune system and maintaining tissue homeostasis. Cancer cells exploit this pathway by producing PD-L1, which attaches to PD-1 on T cells, thus inhibiting immune responses and enabling the cancer cells to escape detection by the immune system. This study aimed to evaluate the role of the PD-1/PD-L1 pathway in cancer pathogenesis and treatment. Method: This study was performed based on the principles of Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). All in vitro , in vivo , and clinical studies that were published in English have been considered during a thorough search of the Scopus, Web of Science, and PubMed databases without date restriction until March 2024. Results: According to the studies reviewed, the PD-1/PD-L1 signaling axis suggests promising therapeutic effects on various types of cancers such as non-small cell lung cancer, melanoma, breast cancer, hepatocellular carcinoma, squamous cell carcinoma, and colorectal cancer, among others. Additionally, research suggests that immune checkpoint inhibitors that block PD1/PD-L1, such as pembrolizumab, atezolizumab, nivolumab, durvalumab, cemiplimab, avelumab, etc. , can effectively prevent tumor cells from escaping the immune system. Moreover, there might be a possible interaction between microbiome, obesity, etc. on immune mechanisms and on the immune checkpoint inhibitors (ICIs). Conclusion: Although we have gained considerable knowledge about ICIs, we are still facing challenges in effectively prescribing the appropriate ICIs for individual patients. This is largely due to the complex interactions between different intracellular pathways, which need to be thoroughly studied. To resolve this issue, it is necessary to conduct more reliable clinical trials that can produce a scientific consensus.
Collapse
|
|
4
|
Qin L, Zhang G, Wu Y, Yang Y, Zou Z. Intratumor injection of BCG Ag85A high-affinity peptides enhanced anti-tumor efficacy in PPD-positive melanoma. Cancer Immunol Immunother 2024; 73:103. [PMID: 38630135 PMCID: PMC11024071 DOI: 10.1007/s00262-024-03693-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Accepted: 03/25/2024] [Indexed: 04/19/2024]
Abstract
As one of the scheduled immunization vaccines worldwide, virtually all individuals have been vaccinated with BCG vaccine. In order to verify the hypothesis that delivering BCG high-affinity peptides to tumor areas could activate the existing BCG memory T cells to attack tumor, we firstly predicted the HLA-A*0201 high-affinity peptides of BCG Ag85A protein (KLIANNTRV, GLPVEYLQV), and then, A375 melanoma cells and HLA-A*0201 PBMCs (from PPD-positive adults) were added to co-incubated with the predicted peptides in vitro. We found that the predicted BCG high-affinity peptides could be directly loaded onto the surface of tumor cells, enhancing the tumor-killing efficacy of PBMCs from PPD-positive volunteer. Then, we constructed PPD-positive mice model bearing B16F10 subcutaneous tumors and found that intratumor injection of BCG Ag85A high-affinity peptides (SGGANSPAL, YHPQQFVYAGAMSGLLD) enhanced the anti-tumor efficacy in PPD-positive melanoma mice. Along with the better anti-tumor efficacy, the expression of PDL1 on tumor cell surface was also increased, and stronger antitumor effects occurred when further combined with anti-PD1 antibody. For microenvironment analysis, the proportion of effector memory T cells was increased and the better treatment efficacy may be attributed to the elevated effector memory CD4 + T cells within the tumor. In conclusion, using the existing immune response of BCG vaccine by delivering high-affinity peptides of BCG to tumor area is a safe and promising therapy for cancer.
Collapse
Affiliation(s)
- Lanqun Qin
- Department of the Comprehensive Cancer Center, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, 321 Zhongshan Road, Nanjing, 210008, China
| | - Guiying Zhang
- Department of the Comprehensive Cancer Center, Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yirong Wu
- Department of the Comprehensive Cancer Center, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Yueling Yang
- Department of the Comprehensive Cancer Center, Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhengyun Zou
- Department of the Comprehensive Cancer Center, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, 321 Zhongshan Road, Nanjing, 210008, China.
- Department of the Comprehensive Cancer Center, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
- Department of the Comprehensive Cancer Center, Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
| |
Collapse
|
|
5
|
Hao L, Li S, Deng J, Li N, Yu F, Jiang Z, Zhang J, Shi X, Hu X. The current status and future of PD-L1 in liver cancer. Front Immunol 2023; 14:1323581. [PMID: 38155974 PMCID: PMC10754529 DOI: 10.3389/fimmu.2023.1323581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 11/27/2023] [Indexed: 12/30/2023] Open
Abstract
The application of immunotherapy in tumor, especially immune checkpoint inhibitors (ICIs), has played an important role in the treatment of advanced unresectable liver cancer. However, the efficacy of ICIs varies greatly among different patients, which has aroused people's attention to the regulatory mechanism of programmed death ligand-1 (PD-L1) in the immune escape of liver cancer. PD-L1 is regulated by multiple levels and signaling pathways in hepatocellular carcinoma (HCC), including gene variation, epigenetic inheritance, transcriptional regulation, post-transcriptional regulation, and post-translational modification. More studies have also found that the high expression of PD-L1 may be the main factor affecting the immunotherapy of liver cancer. However, what is the difference of PD-L1 expressed by different types of cells in the microenvironment of HCC, and which type of cells expressed PD-L1 determines the effect of tumor immunotherapy remains unclear. Therefore, clarifying the regulatory mechanism of PD-L1 in liver cancer can provide more basis for liver cancer immunotherapy and combined immune treatment strategy. In addition to its well-known role in immune regulation, PD-L1 also plays a role in regulating cancer cell proliferation and promoting drug resistance of tumor cells, which will be reviewed in this paper. In addition, we also summarized the natural products and drugs that regulated the expression of PD-L1 in HCC.
Collapse
Affiliation(s)
- Liyuan Hao
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Shenghao Li
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Clinical Research Center, Shijiazhuang Fifth Hospital, Shijiazhuang, Hebei, China
| | - Jiali Deng
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Na Li
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Fei Yu
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Zhi Jiang
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Junli Zhang
- Department of Infectious Diseases, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, China
| | - Xinli Shi
- Center of Experimental Management, Shanxi University of Chinese Medicine, Jinzhong, China
| | - Xiaoyu Hu
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| |
Collapse
|
|
6
|
Nanobody-based CAR T cells targeting intracellular tumor antigens. Biomed Pharmacother 2022; 156:113919. [DOI: 10.1016/j.biopha.2022.113919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 10/18/2022] [Accepted: 10/24/2022] [Indexed: 11/30/2022] Open
|
|
7
|
Rallis KS, Makrakis D, Ziogas IA, Tsoulfas G. Immunotherapy for advanced hepatocellular carcinoma: From clinical trials to real-world data and future advances. World J Clin Oncol 2022; 13:448-472. [PMID: 35949435 PMCID: PMC9244967 DOI: 10.5306/wjco.v13.i6.448] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 04/27/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-associated mortality worldwide. HCC is an inflammation-associated immunogenic cancer that frequently arises in chronically inflamed livers. Advanced HCC is managed with systemic therapies; the tyrosine kinase inhibitor (TKI) sorafenib has been used in 1st-line setting since 2007. Immunotherapies have emerged as promising treatments across solid tumors including HCC for which immune checkpoint inhibitors (ICIs) are licensed in 1st- and 2nd-line treatment setting. The treatment field of advanced HCC is continuously evolving. Several clinical trials are investigating novel ICI candidates as well as new ICI regimens in combination with other therapeutic modalities including systemic agents, such as other ICIs, TKIs, and anti-angiogenics. Novel immunotherapies including adoptive cell transfer, vaccine-based approaches, and virotherapy are also being brought to the fore. Yet, despite advances, several challenges persist. Lack of real-world data on the use of immunotherapy for advanced HCC in patients outside of clinical trials constitutes a main limitation hindering the breadth of application and generalizability of data to this larger and more diverse patient cohort. Consequently, issues encountered in real-world practice include patient ineligibly for immunotherapy because of contraindications, comorbidities, or poor performance status; lack of response, efficacy, and safety data; and cost-effectiveness. Further real-world data from high-quality large prospective cohort studies of immunotherapy in patients with advanced HCC is mandated to aid evidence-based clinical decision-making. This review provides a critical and comprehensive overview of clinical trials and real-world data of immunotherapy for HCC, with a focus on ICIs, as well as novel immunotherapy strategies underway.
Collapse
Affiliation(s)
- Kathrine S Rallis
- Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AD, United Kingdom
- Surgery Working Group, Society of Junior Doctors, Athens 15123, Greece
| | - Dimitrios Makrakis
- Surgery Working Group, Society of Junior Doctors, Athens 15123, Greece
- Division of Oncology, University of Washington School of Medicine, Seattle, WA 98195, United States
| | - Ioannis A Ziogas
- Surgery Working Group, Society of Junior Doctors, Athens 15123, Greece
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States
| | - Georgios Tsoulfas
- Department of Transplantation Surgery, Aristotle University School of Medicine, Thessaloniki 54622, Greece
| |
Collapse
|
|
8
|
Wang K, Wang C, Jiang H, Zhang Y, Lin W, Mo J, Jin C. Combination of Ablation and Immunotherapy for Hepatocellular Carcinoma: Where We Are and Where to Go. Front Immunol 2022; 12:792781. [PMID: 34975896 PMCID: PMC8714655 DOI: 10.3389/fimmu.2021.792781] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 11/25/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide and is increasing in incidence. Local ablative therapy plays a leading role in HCC treatment. Radiofrequency (RFA) is one of the first-line therapies for early local ablation. Other local ablation techniques (e.g., microwave ablation, cryoablation, irreversible electroporation, phototherapy.) have been extensively explored in clinical trials or cell/animal studies but have not yet been established as a standard treatment or applied clinically. On the one hand, single treatment may not meet the needs. On the other hand, ablative therapy can stimulate local and systemic immune effects. The combination strategy of immunotherapy and ablation is reasonable. In this review, we briefly summarized the current status and progress of ablation and immunotherapy for HCC. The immune effects of local ablation and the strategies of combination therapy, especially synergistic strategies based on biomedical materials, were discussed. This review is hoped to provide references for future researches on ablative immunotherapy to arrive to a promising new era of HCC treatment.
Collapse
Affiliation(s)
- Kunpeng Wang
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Cong Wang
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, China
| | - Hao Jiang
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Yaqiong Zhang
- Department of Clinical Laboratory, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Weidong Lin
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Jinggang Mo
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Chong Jin
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| |
Collapse
|
|
9
|
Pei M, Li H, Zhu Y, Lu J, Zhang C. In vitro evidence of oncofetal antigen and TLR-9 agonist co-delivery by alginate nanovaccine for liver cancer immunotherapy. Biomater Sci 2022; 10:2865-2876. [DOI: 10.1039/d1bm02021h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Liver cancer is the most common malignant tumor and liver cancer immunotherapy has been one of the research hotspots. To induce antigen-specific antitumor immune responses against liver cancer, we developed...
Collapse
|
|
10
|
Ni H, Xue J, Wang F, Sun X, Niu M. Nanomedicine Approach to Immunotherapy of Hepatocellular Carcinoma. J Biomed Nanotechnol 2021; 17:771-792. [PMID: 34082866 DOI: 10.1166/jbn.2021.3055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
In recent years, the growing studies focused on the immunotherapy of hepatocellular carcinoma and proved the preclinical and clinical promises of host antitumor immune response. However, there were still various obstacles in meeting satisfactory clinic need, such as low response rate, primary resistance and secondary resistance to immunotherapy. Tackling these barriers required a deeper understanding of immune underpinnings and a broader understanding of advanced technology. This review described immune microenvironment of liver and HCC which naturally decided the complexity of immunotherapy, and summarized recent immunotherapy focusing on different points. The ever-growing clues indicated that the instant killing of tumor cell and the subsequent relive of immunosuppressive microenvironment were both indis- pensables. The nanotechnology applied in immunotherapy and the combination with intervention technology was also discussed.
Collapse
Affiliation(s)
- Hongbo Ni
- Department of Interventional Radiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110000, China
| | - Jian Xue
- Department of Interventional Radiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110000, China
| | - Fan Wang
- Department of Interventional Radiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110000, China
| | - Xiaohan Sun
- Department of Interventional Radiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110000, China
| | - Meng Niu
- Department of Interventional Radiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110000, China
| |
Collapse
|
|
11
|
Anti-PD-1/PD-L1 Based Combination Immunotherapy to Boost Antigen-Specific CD8 + T Cell Response in Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:cancers13081922. [PMID: 33923463 PMCID: PMC8073815 DOI: 10.3390/cancers13081922] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/22/2021] [Accepted: 04/14/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary The cytotoxic T cell response against hepatocellular carcinoma antigens is exhausted and fails in its task of deleting tumoral cells. These cells are featured by the expression of negative immune checkpoints that can be modulated to restore T cell function. The blockade of the PD-1/PD-L1 pathway has shown promising results in rescuing hepatocellular carcinoma-specific CD8 T cells but only a reduced group of cases is sensitive to this treatment and the effect is usually temporary. Therefore, new anti-PD-1 based combinatory strategies are underway to increase the response by adding the effect of blocking neo-angiogenesis and other negative immune checkpoints, boosting positive immune checkpoints, blocking suppressive cytokines, or inducing the expression of tumoral neoantigens. The restoration of T cell responses with these anti-PD-1 based combinatory therapies will change the outcome of advanced hepatocellular carcinoma. Abstract Thirty to fifty percent of hepatocellular carcinomas (HCC) display an immune class genetic signature. In this type of tumor, HCC-specific CD8 T cells carry out a key role in HCC control. Those potential reactive HCC-specific CD8 T cells recognize either HCC immunogenic neoantigens or aberrantly expressed host’s antigens, but they become progressively exhausted or deleted. These cells express the negative immunoregulatory checkpoint programmed cell death protein 1 (PD-1) which impairs T cell receptor signaling by blocking the CD28 positive co-stimulatory signal. The pool of CD8 cells sensitive to anti-PD-1/PD-L1 treatment is the PD-1dim memory-like precursor pool that gives rise to the effector subset involved in HCC control. Due to the epigenetic imprints that are transmitted to the next generation, the effect of PD-1 blockade is transient, and repeated treatments lead to tumor resistance. During long-lasting disease, besides the TCR signaling impairment, T cells develop other failures that should be also set-up to increase T cell reactivity. Therefore, several PD-1 blockade-based combinatory therapies are currently under investigation such as adding antiangiogenics, anti-TGFβ1, blockade of other negative immune checkpoints, or increasing HCC antigen presentation. The effect of these combinations on CD8+ T cells is discussed in this review.
Collapse
|
|
12
|
Ruf B, Heinrich B, Greten TF. Immunobiology and immunotherapy of HCC: spotlight on innate and innate-like immune cells. Cell Mol Immunol 2021; 18:112-127. [PMID: 33235387 PMCID: PMC7852696 DOI: 10.1038/s41423-020-00572-w] [Citation(s) in RCA: 206] [Impact Index Per Article: 51.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 09/29/2020] [Indexed: 12/24/2022] Open
Abstract
Immune-based therapies such as immune checkpoint inhibitors have revolutionized the systemic treatment of various cancer types. The therapeutic application of monoclonal antibodies targeting inhibitory pathways such as programmed cell death-1(PD-1)/programmed cell death ligand 1 (PD-L1) and CTLA-4 to cells of the adaptive immune system has recently been shown to generate meaningful improvement in the clinical outcome of hepatocellular carcinoma (HCC). Nevertheless, current immunotherapeutic approaches induce durable responses in only a subset of HCC patients. Since immunologic mechanisms such as chronic inflammation due to chronic viral hepatitis or alcoholic and nonalcoholic fatty liver disease play a crucial role in the initiation, development, and progression of HCC, it is important to understand the underlying mechanisms shaping the unique tumor microenvironment of liver cancer. The liver is an immunologic organ with large populations of innate and innate-like immune cells and is exposed to bacterial, viral, and fungal antigens through the gut-liver axis. Here, we summarize and highlight the role of these cells in liver cancer and propose strategies to therapeutically target them. We also discuss current immunotherapeutic strategies in HCC and outline recent advances in our understanding of how the therapeutic potential of these agents might be enhanced.
Collapse
Affiliation(s)
- Benjamin Ruf
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Centre for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Bernd Heinrich
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Centre for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Tim F Greten
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Centre for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
- NCI CCR Liver Cancer Program, National Institutes of Health, Bethesda, MD, 20892, USA.
| |
Collapse
|
|
13
|
Hong GQ, Cai D, Gong JP, Lai X. Innate immune cells and their interaction with T cells in hepatocellular carcinoma. Oncol Lett 2021; 21:57. [PMID: 33281968 PMCID: PMC7709558 DOI: 10.3892/ol.2020.12319] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 10/08/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignant tumor and is associated with necroinflammation driven by various immune cells, such as dendritic cells, macrophages and natural killer cells. Innate immune cells can directly affect HCC or regulate the T-cell responses that mediate HCC. In addition, innate immune cells and T cells are not isolated, which means the interaction between them is important in the HCC microenvironment. Considering the current unsatisfactory efficacy of immunotherapy in patients with HCC, understanding the relationship between innate immune cells and T cells is necessary. In the present review the roles and clinical value of innate immune cells that have been widely reported to be involved in HCC, including dendritic cells, macrophages (including kupffer cells), neutrophils, eosinophils, basophils and innate lymphoid cells and the crosstalk between the innate and adaptive immune responses in the antitumor process have been discussed. The present review will facilitate researchers in understanding the importance of innate immune cells in HCC and lead to innovative immunotherapy approaches for the treatment of HCC.
Collapse
Affiliation(s)
- Guo-Qing Hong
- Department of Hepatobiliary and Thyroid Breast Surgery, Tongnan District People's Hospital, Chongqing 402660, P.R. China
| | - Dong Cai
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Jian-Ping Gong
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Xing Lai
- Department of Hepatobiliary and Thyroid Breast Surgery, Tongnan District People's Hospital, Chongqing 402660, P.R. China
- Correspondence to: Dr Xing Lai, Department of Hepatobiliary and Thyroid Breast Surgery, Tongnan District People's Hospital, 271 Datong, Tongnan, Chongqing 402660, P.R. China, E-mail:
| |
Collapse
|
|
14
|
TAS0314, a novel multi-epitope long peptide vaccine, showed synergistic antitumor immunity with PD-1/PD-L1 blockade in HLA-A*2402 mice. Sci Rep 2020; 10:17284. [PMID: 33057061 PMCID: PMC7560884 DOI: 10.1038/s41598-020-74187-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 09/28/2020] [Indexed: 01/05/2023] Open
Abstract
Cancer peptide vaccines are a promising cancer immunotherapy that can induce cancer-specific cytotoxic T lymphocytes (CTLs) in tumors. However, recent clinical trials of cancer vaccines have revealed that the efficacy of the vaccines is limited. Targeting single antigens and vaccination with short peptides are partly the cause of the poor clinical outcomes. We synthesized a novel multi-epitope long peptide, TAS0314, which induced multiple epitope-specific CTLs in HLA knock-in mice. It also showed superior epitope-specific CTL induction and antitumor activity. We also established a combination treatment model of vaccination with PD-1/PD-L1 blockade in HLA-A*2402 knock-in mice, and it showed a synergistic antitumor effect with TAS0314. Thus, our data indicated that TAS0314 treatment, especially in combination with PD-1/PD-L1 blockade, is a promising therapeutic candidate for cancer immunotherapy.
Collapse
|
|
15
|
Bonilla CM, McGrath NA, Fu J, Xie C. Immunotherapy of hepatocellular carcinoma with infection of hepatitis B or C virus. HEPATOMA RESEARCH 2020; 6:68. [PMID: 33134550 PMCID: PMC7597818 DOI: 10.20517/2394-5079.2020.58] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) has one of highest mortalities globally amongst cancers, but has limited therapeutic options once in the advanced stage. Hepatitis B or C virus infection are the most common drivers for HCC carcinogenesis, triggering chronic liver inflammation and adding to the complexity of the immune microecosystem of HCC. The emergence of immunotherapy has afforded a new avenue of therapeutic options for patients with advanced HCC with a history of hepatitis B or C virus infection. This article reviews the change of immunity elicited by hepatitis B or C virus infection, the immune feature of HCC, and the clinical evidence for immunotherapy in advanced HCC and discusses future directions in this field.
Collapse
Affiliation(s)
- Cecilia Monge Bonilla
- Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Nicole A McGrath
- Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jianyang Fu
- Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Changqing Xie
- Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| |
Collapse
|
|
16
|
Dehbarez FM, Nezafat N, Mahmoodi S. In Silico Design of a Novel Multi-Epitope Peptide Vaccine Against Hepatocellular Carcinoma. LETT DRUG DES DISCOV 2020. [DOI: 10.2174/1570180817999200502030038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background:
Hepatocellular Carcinoma (HCC) is a prevalent cancer in the world. As
yet, there is no medication for complete treatment of HCC.
Objective:
There is a critical need to search for an innovative therapy for HCC. Recently, multiepitope
vaccines have been introduced as effective immunotherapy approach against HCC.
Methods:
In this research, several immunoinformatics methods were applied to create an original
multi-epitope vaccine against HCC consisting of CD8+ cytolytic T lymphocytes (CTLs) epitopes
selected from α- fetoprotein (AFP), glypican-3 (GPC3), aspartyl-β-hydroxylase (ASPH); CD4+
helper T lymphocytes (HTLs) epitopes from tetanus toxin fragment C (TTFC), and finally, two tandem
repeats of HSP70407-426 were used which stimulated strong innate and adaptive immune responses.
All the mentioned parts were connected together by relevant linkers.
Results:
According to physicochemical, structural, and immunological results, the designed
vaccine is stable, non-allergen, antigen; it also has a high-quality 3D structure, and numerous linear
and conformational B cell epitopes, whereby this vaccine may stimulate efficient humoral immunity.
Conclusion:
Center on the collected results, the designed vaccine potentially can induce cellular and
humoral immune responses in HCC cases; nonetheless, the efficiency of vaccine must be approved
within in vitro and in vivo immunological analyzes.
Collapse
Affiliation(s)
- Fatemeh Motamedi Dehbarez
- Department of Medical Biotechnology, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Navid Nezafat
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shirin Mahmoodi
- Department of Medical Biotechnology, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| |
Collapse
|
|
17
|
Li X, Wang X, Ito A. An MRI-visible immunoadjuvant based on hollow Gd 2O 3 nanospheres for cancer immunotherapy. Chem Commun (Camb) 2020; 56:8186-8189. [PMID: 32618297 DOI: 10.1039/d0cc03568h] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Hollow Gd2O3 nanospheres significantly promote the cellular uptake of a tumor antigen by antigen presenting cells, exhibit pH-dependent alteration of the MR signal intensity and markedly enhance the antitumor immunity. Hollow Gd2O3 nanospheres are promising as magnetic resonance imaging (MRI)-visible cancer immunoadjuvants for cancer immunotherapy.
Collapse
Affiliation(s)
- Xia Li
- Health and Medical Research Institute, Department of Life Science and Biotechnology, National Institute of Advanced Industrial Science and Technology (AIST), Central 6, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan.
| | | | | |
Collapse
|
|
18
|
Cervantes-Villagrana RD, Albores-García D, Cervantes-Villagrana AR, García-Acevez SJ. Tumor-induced neurogenesis and immune evasion as targets of innovative anti-cancer therapies. Signal Transduct Target Ther 2020; 5:99. [PMID: 32555170 PMCID: PMC7303203 DOI: 10.1038/s41392-020-0205-z] [Citation(s) in RCA: 159] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Revised: 05/15/2020] [Accepted: 05/24/2020] [Indexed: 12/11/2022] Open
Abstract
Normal cells are hijacked by cancer cells forming together heterogeneous tumor masses immersed in aberrant communication circuits that facilitate tumor growth and dissemination. Besides the well characterized angiogenic effect of some tumor-derived factors; others, such as BDNF, recruit peripheral nerves and leukocytes. The neurogenic switch, activated by tumor-derived neurotrophins and extracellular vesicles, attracts adjacent peripheral fibers (autonomic/sensorial) and neural progenitor cells. Strikingly, tumor-associated nerve fibers can guide cancer cell dissemination. Moreover, IL-1β, CCL2, PGE2, among other chemotactic factors, attract natural immunosuppressive cells, including T regulatory (Tregs), myeloid-derived suppressor cells (MDSCs), and M2 macrophages, to the tumor microenvironment. These leukocytes further exacerbate the aberrant communication circuit releasing factors with neurogenic effect. Furthermore, cancer cells directly evade immune surveillance and the antitumoral actions of natural killer cells by activating immunosuppressive mechanisms elicited by heterophilic complexes, joining cancer and immune cells, formed by PD-L1/PD1 and CD80/CTLA-4 plasma membrane proteins. Altogether, nervous and immune cells, together with fibroblasts, endothelial, and bone-marrow-derived cells, promote tumor growth and enhance the metastatic properties of cancer cells. Inspired by the demonstrated, but restricted, power of anti-angiogenic and immune cell-based therapies, preclinical studies are focusing on strategies aimed to inhibit tumor-induced neurogenesis. Here we discuss the potential of anti-neurogenesis and, considering the interplay between nervous and immune systems, we also focus on anti-immunosuppression-based therapies. Small molecules, antibodies and immune cells are being considered as therapeutic agents, aimed to prevent cancer cell communication with neurons and leukocytes, targeting chemotactic and neurotransmitter signaling pathways linked to perineural invasion and metastasis.
Collapse
Affiliation(s)
- Rodolfo Daniel Cervantes-Villagrana
- Department of Pharmacology, Center for Research and Advanced Studies of the National Polytechnic Institute (CINVESTAV-IPN), 07360, Mexico City, Mexico.
| | - Damaris Albores-García
- Department of Environmental Health Sciences, Florida International University (FIU), Miami, Florida, 33199, USA
| | - Alberto Rafael Cervantes-Villagrana
- Laboratorio de investigación en Terapéutica Experimental, Unidad Académica de Ciencias Químicas, Área de Ciencias de la Salud, Universidad Autónoma de Zacatecas (UAZ), Zacatecas, México
| | - Sara Judit García-Acevez
- Dirección de Proyectos e Investigación, Grupo Diagnóstico Médico Proa, 06400 CDMX, Cuauhtémoc, México
| |
Collapse
|
|
19
|
Taniguchi M, Mizuno S, Yoshikawa T, Fujinami N, Sugimoto M, Kobayashi S, Takahashi S, Konishi M, Gotohda N, Nakatsura T. Peptide vaccine as an adjuvant therapy for glypican-3-positive hepatocellular carcinoma induces peptide-specific CTLs and improves long prognosis. Cancer Sci 2020; 111:2747-2759. [PMID: 32449239 PMCID: PMC7419030 DOI: 10.1111/cas.14497] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 05/12/2020] [Accepted: 05/14/2020] [Indexed: 12/20/2022] Open
Abstract
There is no established postoperative adjuvant therapy for hepatocellular carcinoma (HCC), and improvement of patient prognosis has been limited. We conducted long‐term monitoring of patients within a phase II trial that targeted a cancer antigen, glypican‐3 (GPC3), specifically expressed in HCC. We sought to determine if the GPC3 peptide vaccine was an effective adjuvant therapy by monitoring disease‐free survival and overall survival. We also tracked GPC3 immunohistochemical (IHC) staining, CTL induction, and postoperative plasma GPC3 for a patient group that was administered the vaccine (n = 35) and an unvaccinated patient group that underwent surgery only (n = 33). The 1‐y recurrence rate after surgery was reduced by approximately 15%, and the 5‐y and 8‐y survival rates were improved by approximately 10% and 30%, respectively, in the vaccinated group compared with the unvaccinated group. Patients who were positive for GPC3 IHC staining were more likely to have induced CTLs, and 60% survived beyond 5 y. Vaccine efficacy had a positive relationship with plasma concentration of GPC3; high concentrations increased the 5‐y survival rate to 75%. We thus expect GPC3 vaccination in patients with HCC, who are positive for GPC3 IHC staining and/or plasma GPC3 to induce CTL and have significantly improved long‐term prognosis.
Collapse
Affiliation(s)
- Masatake Taniguchi
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.,Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan.,Department of Medical Oncology and Translational Research, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Shoichi Mizuno
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Toshiaki Yoshikawa
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Norihiro Fujinami
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Motokazu Sugimoto
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Shin Kobayashi
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Shinichiro Takahashi
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Masaru Konishi
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Naoto Gotohda
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Tetsuya Nakatsura
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.,Department of Medical Oncology and Translational Research, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| |
Collapse
|
|
20
|
Recent Advances in Immunotherapy for Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12040775. [PMID: 32218257 PMCID: PMC7226090 DOI: 10.3390/cancers12040775] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 03/22/2020] [Accepted: 03/24/2020] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death since most patients are diagnosed at advanced stage and the current systemic treatment options using molecular-targeted drugs remain unsatisfactory. However, the recent success of cancer immunotherapies has revolutionized the landscape of cancer therapy. Since HCC is characterized by metachronous multicentric occurrence, immunotherapies that induce systemic and durable responses could be an appealing treatment option. Despite the suppressive milieu of the liver and tumor immunosurveillance escape mechanisms, clinical studies of checkpoint inhibitors in patients with advanced HCC have yielded promising results. Here, we provide an update on recent advances in HCC immunotherapies. First, we describe the unique tolerogenic properties of hepatic immunity and its interaction with HCC and then review the status of already or nearly available immune checkpoint blockade-based therapies as well as other immunotherapy strategies at the preclinical or clinical trial stage.
Collapse
|
|
21
|
Zongyi Y, Xiaowu L. Immunotherapy for hepatocellular carcinoma. Cancer Lett 2020; 470:8-17. [DOI: 10.1016/j.canlet.2019.12.002] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 11/25/2019] [Accepted: 12/01/2019] [Indexed: 02/08/2023]
|
|
22
|
Sun Y, Ma W, Yang Y, He M, Li A, Bai L, Yu B, Yu Z. Cancer nanotechnology: Enhancing tumor cell response to chemotherapy for hepatocellular carcinoma therapy. Asian J Pharm Sci 2019; 14:581-594. [PMID: 32104485 PMCID: PMC7032247 DOI: 10.1016/j.ajps.2019.04.005] [Citation(s) in RCA: 87] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Revised: 03/06/2019] [Accepted: 04/18/2019] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest cancers due to its complexities, reoccurrence after surgical resection, metastasis and heterogeneity. In addition to sorafenib and lenvatinib for the treatment of HCC approved by FDA, various strategies including transarterial chemoembolization, radiotherapy, locoregional therapy and chemotherapy have been investigated in clinics. Recently, cancer nanotechnology has got great attention for the treatment of various cancers including HCC. Both passive and active targetings are progressing at a steady rate. Herein, we describe the lessons learned from pathogenesis of HCC and the understanding of targeted and non-targeted nanoparticles used for the delivery of small molecules, monoclonal antibodies, miRNAs and peptides. Exploring current efficacy is to enhance tumor cell response of chemotherapy. It highlights the opportunities and challenges faced by nanotechnologies in contemporary hepatocellular carcinoma therapy, where personalized medicine is increasingly becoming the mainstay. Overall objective of this review is to enhance our understanding in the design and development of nanotechnology for treatment of HCC.
Collapse
Affiliation(s)
- Yongbing Sun
- National Engineering Research Center for solid preparation technology of Chinese Medicines, Jiangxi University of Traditional Chinese Medicines, Nanchang 330006, China
| | - Wen Ma
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Yuanyuan Yang
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Mengxue He
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
| | - Aimin Li
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
| | - Lei Bai
- Department of Chemical and Biomedical Engineering, West Virginia University, Morgantown 26506, USA
| | - Bin Yu
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Zhiqiang Yu
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| |
Collapse
|
|
23
|
Zhao J, Chen Y, Ding ZY, Liu JY. Safety and Efficacy of Therapeutic Cancer Vaccines Alone or in Combination With Immune Checkpoint Inhibitors in Cancer Treatment. Front Pharmacol 2019; 10:1184. [PMID: 31680963 PMCID: PMC6798079 DOI: 10.3389/fphar.2019.01184] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2019] [Accepted: 09/13/2019] [Indexed: 02/05/2023] Open
Abstract
Therapeutic cancer vaccines have proven to seldom induce dramatic clinical response when used alone, and therefore, they are being studied in combination with additional treatment modalities to achieve optimal treatment activities. Growing preclinical data show that combining vaccines and immune checkpoint inhibitors (ICIs) can prime intensified immunogenicity and modulate immunosuppressive tumor microenvironment. Herein, we focus on the safety and efficacy of approved and promising cancer vaccines alone or combined with ICIs in the treatment of several malignancies. Generally, the majority of clinical trials support the concept of synergy that combination therapy of vaccines and ICIs holds maximized potential to improve clinical outcomes. Importantly, the combination has acceptable safety and minimal additional toxicity compared with single-agent vaccines or ICIs. Additionally, the potential strategies of combining personalized tumor vaccines with ICIs will become priority option and future direction of vaccine development and application and the urgent need to develop effective biomarkers to screen appropriate patient populations and predict response to combination therapy.
Collapse
Affiliation(s)
- Jing Zhao
- Department of Biotherapy, Cancer Center, and National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, China
- Sichuan Clinical Research Center of Biotherapy, West China Hospital of Sichuan University, Chengdu, China
| | - Ye Chen
- Department of Biotherapy, Cancer Center, and National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, China
- Sichuan Clinical Research Center of Biotherapy, West China Hospital of Sichuan University, Chengdu, China
| | - Zhen-Yu Ding
- Department of Biotherapy, Cancer Center, and National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, China
- Sichuan Clinical Research Center of Biotherapy, West China Hospital of Sichuan University, Chengdu, China
| | - Ji-Yan Liu
- Department of Biotherapy, Cancer Center, and National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, China
- Sichuan Clinical Research Center of Biotherapy, West China Hospital of Sichuan University, Chengdu, China
| |
Collapse
|
|
24
|
Shimizu Y, Yoshikawa T, Kojima T, Shoda K, Nosaka K, Mizuno S, Wada S, Fujimoto Y, Sasada T, Kohashi K, Bando H, Endo I, Nakatsura T. Heat shock protein 105 peptide vaccine could induce antitumor immune reactions in a phase I clinical trial. Cancer Sci 2019; 110:3049-3060. [PMID: 31390678 PMCID: PMC6778658 DOI: 10.1111/cas.14165] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 08/02/2019] [Accepted: 08/05/2019] [Indexed: 01/06/2023] Open
Abstract
Heat shock protein 105 (HSP105) is overexpressed in many cancers, including colorectal cancer (CRC) and esophageal cancer (EC). We carried out a phase I clinical trial of HLA-A24- and HLA-A2-restricted HSP105 peptide vaccines in patients with CRC or EC. In this additional study of the trial, we examined the immunological efficacy of the novel vaccine. Thirty patients with advanced CRC or EC underwent HSP105 peptide vaccination. Immunological responses were evaluated by ex vivo and in vitro γ-interferon enzyme-linked immunospot assays and their correlation with patients' prognosis was analyzed. The HSP105 peptide vaccines induced peptide-specific CTLs in 15 of 30 patients. Among HLA-A24 patients (n = 15), 7 showed induction of CTLs only ex vivo, whereas among HLA-A2 patients (n = 15), 4 showed the induction ex vivo and 6 in vitro. Heat shock protein 105-specific CTL induction correlated with suppression of cancer progression and was revealed as a potential predictive biomarker for progression-free survival (P = .008; hazard ratio = 3.03; 95% confidence interval, 1.34-6.85) and overall survival (P = .025; hazard ratio = 2.72; 95% confidence interval, 1.13-6.52). Production of cytokines by HSP105 peptide-specific CTLs was observed at the injection sites (skin) and tumor tissues, suggesting that HSP105-specific CTLs not only accumulated at vaccination sites but also infiltrated tumors. Furthermore, we established 2 HSP105 peptide-specific CTL clones, which showed HSP105-specific cytokine secretion and cytotoxicity. Our results suggest that the HSP105 peptide vaccine could induce immunological effects in cancer patients and improve their prognosis.
Collapse
Affiliation(s)
- Yasuhiro Shimizu
- Division of Cancer ImmunotherapyExploratory Oncology Research and Clinical Trial CenterNational Cancer CenterKashiwaJapan
- Department of Gastroenterological SurgeryYokohama City University Graduate School of MedicineYokohamaJapan
| | - Toshiaki Yoshikawa
- Division of Cancer ImmunotherapyExploratory Oncology Research and Clinical Trial CenterNational Cancer CenterKashiwaJapan
| | - Takashi Kojima
- Department of GastroenterologyNational Cancer Center Hospital EastKashiwaJapan
| | - Kayoko Shoda
- Division of Cancer ImmunotherapyExploratory Oncology Research and Clinical Trial CenterNational Cancer CenterKashiwaJapan
| | - Kazuto Nosaka
- Division of Cancer ImmunotherapyExploratory Oncology Research and Clinical Trial CenterNational Cancer CenterKashiwaJapan
| | - Shoichi Mizuno
- Division of Cancer ImmunotherapyExploratory Oncology Research and Clinical Trial CenterNational Cancer CenterKashiwaJapan
| | - Satoshi Wada
- Division of Cancer ImmunotherapyKanagawa Cancer Center Research InstituteYokohamaJapan
| | - Yuki Fujimoto
- Division of Cancer ImmunotherapyKanagawa Cancer Center Research InstituteYokohamaJapan
| | - Tetsuro Sasada
- Division of Cancer ImmunotherapyKanagawa Cancer Center Research InstituteYokohamaJapan
| | - Kenichi Kohashi
- Department of Anatomic PathologyPathological ScienceKyusyu University Graduate School of MedicineFukuokaJapan
| | - Hideaki Bando
- Department of GastroenterologyNational Cancer Center Hospital EastKashiwaJapan
| | - Itaru Endo
- Department of Gastroenterological SurgeryYokohama City University Graduate School of MedicineYokohamaJapan
| | - Tetsuya Nakatsura
- Division of Cancer ImmunotherapyExploratory Oncology Research and Clinical Trial CenterNational Cancer CenterKashiwaJapan
| |
Collapse
|
|
25
|
Immunotherapy in Hepatocellular Carcinoma: Is There a Light at the End of the Tunnel? Cancers (Basel) 2019; 11:cancers11081078. [PMID: 31366113 PMCID: PMC6721326 DOI: 10.3390/cancers11081078] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 07/10/2019] [Accepted: 07/23/2019] [Indexed: 12/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer with dismal prognosis when diagnosed at advanced stages. Surgical resection of the primary tumor or orthotropic liver transplantation serves as a potential curative option. However, this approach is highly dependent on the hepatic reserve and baseline functional status of the patient. Liver directed therapies such as portal vein embolization (PVE), trans-arterial chemoembolization (TACE), and systemic chemotherapy are employed in non-surgical candidates. Sorafenib was the only approved systemic therapeutic agent for almost a decade until the recent approval of lenvatinib by the United States Food and Drug Administration (FDA) as an alternate first-line agent. Regorafenib, nivolumab, pembrolizumab and cabozantinib are approved by the FDA as second-line agents in patients who failed or could not tolerate sorafenib. Ramucirumab was recently FDA approved for the subset of patients that have high alfa-fetoprotein levels (>400 ng/mL). A better understanding of tumorigenesis and encouraging clinical trial results that evaluated immune-checkpoint inhibitors opened doors for immunotherapy in HCC. Immune checkpoint inhibitors have demonstrated a prolonged median overall and progression-free survival in a subset of patients with HCC. On-going translational and clinical research will hopefully provide us with a better understanding of tumor markers, genetic aberrations and other factors that determine the immunotherapy response in HCC. In this review, we sought to summarize the potential role and future directions of immunotherapy in the management of HCC.
Collapse
|
|
26
|
Role of glypicans in regulation of the tumor microenvironment and cancer progression. Biochem Pharmacol 2019; 168:108-118. [PMID: 31251939 DOI: 10.1016/j.bcp.2019.06.020] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Accepted: 06/20/2019] [Indexed: 12/28/2022]
Abstract
Glypicans are evolutionary conserved, cell surface heparan sulfate (HS) proteoglycans that are attached to the cell membrane via a glycosylphosphatidylinositol (GPI) anchor. Glypicans interact with a broad class of soluble and insoluble ligands, such as morphogens, growth factors, chemokines, receptors and components of the extracellular matrix (ECM). Such versatility comes from their ability to interact through both their HS chains and core protein. Glypicans are involved in cellular and tissue development, morphogenesis and cell motility. They exhibit differential expression in several cancers, acting as both tumor promoters and inhibitors in a cancer type-specific manner. They also influence tumor stroma by facilitating angiogenesis, ECM remodeling and alteration of immune cell functions. Glypicans have emerged as a new therapeutic moiety, whose functions can be exploited in the field of targeted therapies and precision medicine in cancer. This is demonstrated by the emergence of several anti-glypican antibody-based immunologics that have been recently developed and are being evaluated in clinical trials. This review will focus on glypican structure and function with an emphasis on their expression in various cancers. Discussion will also center on the potential of glypicans to be therapeutic targets for inhibition of cancer cell growth.
Collapse
|
|
27
|
Shimizu Y, Suzuki T, Yoshikawa T, Endo I, Nakatsura T. Next-Generation Cancer Immunotherapy Targeting Glypican-3. Front Oncol 2019; 9:248. [PMID: 31024850 PMCID: PMC6469401 DOI: 10.3389/fonc.2019.00248] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 03/18/2019] [Indexed: 12/16/2022] Open
Abstract
Glypican-3 (GPC3), a 65 kD protein consisting of 580 amino acids, is a heparan sulfate proteoglycan bound to the cell membrane by glycosylphosphatidylinositol. This protein is expressed in the liver and the kidney of healthy fetuses but is hardly expressed in adults, except in the placenta. Contrarily, GPC3 is specifically expressed in hepatocellular carcinoma (HCC), ovarian clear cell carcinoma, melanoma, squamous cell carcinoma of the lung, hepatoblastoma, nephroblastoma (Wilms tumor), yolk sac tumor, and some pediatric cancers. Although the precise function of GPC3 remains unclear, it has been strongly suggested that it is related to the malignant transformation of HCC. We identified GPC3 as a promising target for cancer immunotherapy and have been working on the development of cancer immunotherapeutic agents targeting it through clinical trials. In some trials, it was revealed that the GPC3 peptide vaccines we developed using human leukocyte antigen-A24- and A2-restricted GPC3-derived peptides could induce GPC3-specific cytotoxic T cells in most vaccinated patients and thereby improve their prognosis. To further improve the clinical efficacy of cancer immunotherapy targeting GPC3, we are also developing next-generation therapeutic strategies using T cells engineered to express antigen-specific T-cell receptor or chimeric antigen receptor. In addition, we have successfully monitored the levels of serum full-length GPC3 protein, which is somehow secreted in the blood. The utility of GPC3 as a biomarker for predicting tumor recurrence and treatment efficacy is now being considered. In this review article, we summarize the results of clinical trials carried out by our team and describe the novel agent targeting the cancer-specific shared antigen, GPC3.
Collapse
Affiliation(s)
- Yasuhiro Shimizu
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.,Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Toshihiro Suzuki
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Toshiaki Yoshikawa
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Tetsuya Nakatsura
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| |
Collapse
|
|
28
|
Abstract
Hepatocellular carcinoma (HCC) has an increasing incidence and dismal prognosis, with few systemic treatments approved, including several small molecule tyrosine kinase inhibitors. The application of immune checkpoint inhibitors (ICIs) to HCC has resulted in durable activity, and further evaluation is ongoing. In this review, we discuss the immunologic principles and the mechanism of action of the ICIs and present the relevant clinical data. Furthermore, we provide an overview of the current and emerging immunotherapeutic approaches for HCC, such as combination treatments, vaccines, and cellular therapies.
Collapse
Affiliation(s)
- Charalampos S Floudas
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Rm B2L312, 10 Center Drive, Bethesda, MD, 20892-1078, USA.
| | - Gagandeep Brar
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Rm B2L312, 10 Center Drive, Bethesda, MD, 20892-1078, USA
| | - Tim F Greten
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Rm B2L312, 10 Center Drive, Bethesda, MD, 20892-1078, USA
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| |
Collapse
|
|
29
|
Akazawa Y, Suzuki T, Yoshikawa T, Mizuno S, Nakamoto Y, Nakatsura T. Prospects for immunotherapy as a novel therapeutic strategy against hepatocellular carcinoma. World J Meta-Anal 2019; 7:80-95. [DOI: 10.13105/wjma.v7.i3.80] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 03/12/2019] [Accepted: 03/16/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly aggressive malignant disease, with a poor clinical prognosis. Many standard therapies are often considered for HCC treatment today; however, these conventional therapies often fail to achieve sufficiently effective clinical results. Today, HCC therapy is set to undergo a major revolution, owing to rapid developments in cancer immunotherapy, particularly immune checkpoint inhibitor therapy. Cancer immunotherapy is a novel and promising treatment strategy that differs significantly from conventional therapies in its approach to achieve antitumor effects. In fact, many cancer immunotherapies have been tested worldwide and shown to be effective against various types of cancer; HCC is no exception to this trend. For example, we identified a specific cancer antigen called glypican-3 (GPC3) and performed clinical trials of GPC3-targeted peptide vaccine immunotherapy in patients with HCC. Here, we present an overview of the immune mechanisms for development and progression of HCC, our GPC3-based immunotherapy, and immune checkpoint inhibitor therapy against HCC. Finally, we discuss the future prospects of cancer immunotherapy against HCC. We believe that this review and discussion of cancer immunotherapy against HCC could stimulate more interest in this promising strategy for cancer therapy and help in its further development.
Collapse
Affiliation(s)
- Yu Akazawa
- Toshiaki Yoshioka, Shoichi Mizuno, Tetsuya Nakatsura, Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, Japan
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
| | - Toshihiro Suzuki
- Toshiaki Yoshioka, Shoichi Mizuno, Tetsuya Nakatsura, Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, Japan
| | | | | | - Yasunari Nakamoto
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
| | | |
Collapse
|
|
30
|
Kitagawa K, Gonoi R, Tatsumi M, Kadowaki M, Katayama T, Hashii Y, Fujisawa M, Shirakawa T. Preclinical Development of a WT1 Oral Cancer Vaccine Using a Bacterial Vector to Treat Castration-Resistant Prostate Cancer. Mol Cancer Ther 2019; 18:980-990. [PMID: 30824610 DOI: 10.1158/1535-7163.mct-18-1105] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 12/28/2018] [Accepted: 02/22/2019] [Indexed: 11/16/2022]
Abstract
Previously, we constructed a recombinant Bifidobacterium longum displaying a partial mouse Wilms' tumor 1 (WT1) protein (B. longum 420) as an oral cancer vaccine using a bacterial vector and demonstrated that oral administration of B. longum 420 significantly inhibited tumor growth compared with the Db126 WT1 peptide vaccine in the TRAMP-C2, mouse castration-resistant prostate cancer (CRPC) syngeneic tumor model. The present study demonstrated that oral administration of 1.0×109 colony-forming units of B. longum 420 induced significantly higher cytotoxicity against TRAMP-C2 cells than intraperitoneal injection of 100 μg of Db126, and the in vivo antitumor activity of B. longum 420 in the TRAMP-C2 tumor model could be augmented by intraperitoneal injections of 250 μg of anti-PD-1 antibody. For the clinical development, we produced the B440 pharmaceutical formulation, which is lyophilized powder of inactivated B. longum 440 displaying the partially modified human WT1 protein. We confirmed that B. longum 440 could induce cellular immunity specific to multiple WT1 epitopes. In a preclinical dosage study, B440 significantly inhibited growth of the TRAMP-C2 tumors compared with that of the control groups (PBS and B. longum not expressing WT1) at all dosages (1, 5, and 10 mg/body of B440). These mouse doses were considered to correspond with practical oral administration doses of 0.2, 1, and 2 g/body for humans. Taken together, these results suggest that the B440 WT1 oral cancer vaccine can be developed as a novel oral immuno-oncology drug to treat CRPC as a monotherapy or as an adjunct to immune checkpoint inhibitors.
Collapse
Affiliation(s)
- Koichi Kitagawa
- Division of Advanced Medical Science, Kobe University Graduate School of Science, Technology and Innovation, Kobe, Japan.,Division of Translational Research for Biologics, Department of Internal Medicine Related, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Reina Gonoi
- Division of Advanced Medical Science, Kobe University Graduate School of Science, Technology and Innovation, Kobe, Japan
| | - Maho Tatsumi
- Division of Advanced Medical Science, Kobe University Graduate School of Science, Technology and Innovation, Kobe, Japan
| | - Masahide Kadowaki
- Division of Advanced Medical Science, Kobe University Graduate School of Science, Technology and Innovation, Kobe, Japan
| | - Takane Katayama
- Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
| | - Yoshiko Hashii
- Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
| | - Masato Fujisawa
- Department of Urology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Toshiro Shirakawa
- Division of Advanced Medical Science, Kobe University Graduate School of Science, Technology and Innovation, Kobe, Japan. .,Division of Translational Research for Biologics, Department of Internal Medicine Related, Kobe University Graduate School of Medicine, Kobe, Japan.,Department of Urology, Kobe University Graduate School of Medicine, Kobe, Japan
| |
Collapse
|
|
31
|
Brar G, Greten TF, Brown ZJ. Current frontline approaches in the management of hepatocellular carcinoma: the evolving role of immunotherapy. Therap Adv Gastroenterol 2018; 11:1756284818808086. [PMID: 30377451 PMCID: PMC6202741 DOI: 10.1177/1756284818808086] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 09/24/2018] [Indexed: 02/04/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a major cause of cancer-associated mortality worldwide and is expected to rise. Patients with early-stage disease may have a good prognosis with a 5-year survival rate of greater than 70%. However, the majority of patients are diagnosed with late-stage disease with a dismal overall survival rate of less than 16%. Therefore, there is a great need for advances in the treatment of advanced HCC, which for approximately the past decade, has been sorafenib. Immunotherapy is an evolving cancer treatment and has shown promise in treating patients with advanced HCC. In this review, we discuss the current standard of care for advanced HCC and then discuss the evolving role of immunotherapies.
Collapse
Affiliation(s)
- Gagandeep Brar
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Tim F. Greten
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Institutes of Health, Building 10, Room 3B43, Bethesda, MD 20892, USA
| | - Zachary J. Brown
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| |
Collapse
|
|
32
|
Combinatory therapy adopting nanoparticle-based cancer vaccination with immune checkpoint blockade for treatment of post-surgical tumor recurrences. J Control Release 2018; 285:56-66. [DOI: 10.1016/j.jconrel.2018.07.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 07/05/2018] [Accepted: 07/05/2018] [Indexed: 12/20/2022]
|
|
33
|
Ma W, Chen X, Yuan Y. T-cell-associated immunotherapy: a promising strategy for the treatment of hepatocellular carcinoma. Immunotherapy 2018; 9:523-525. [PMID: 28595519 DOI: 10.2217/imt-2017-0053] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Affiliation(s)
- Weijie Ma
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Xi Chen
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Yufeng Yuan
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| |
Collapse
|
|
34
|
Chen Z, Hu K, Feng L, Su R, Lai N, Yang Z, Kang S. Senescent cells re-engineered to express soluble programmed death receptor-1 for inhibiting programmed death receptor-1/programmed death ligand-1 as a vaccination approach against breast cancer. Cancer Sci 2018; 109:1753-1763. [PMID: 29675979 PMCID: PMC5989746 DOI: 10.1111/cas.13618] [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: 03/15/2018] [Revised: 04/11/2018] [Accepted: 04/12/2018] [Indexed: 01/02/2023] Open
Abstract
Various types of vaccines have been proposed as approaches for prevention or delay of the onset of cancer by boosting the endogenous immune system. We previously developed a senescent‐cell‐based vaccine, induced by radiation and veliparib, as a preventive and therapeutic tool against triple‐negative breast cancer. However, the programmed death receptor‐1/programmed death ligand‐1 (PD‐1/PD‐L1) pathway was found to play an important role in vaccine failure. Hence, we further developed soluble programmed death receptor‐1 (sPD1)‐expressing senescent cells to overcome PD‐L1/PD‐1‐mediated immune suppression while vaccinating to promote dendritic cell (DC) maturity, thereby amplifying T‐cell activation. In the present study, sPD1‐expressing senescent cells showed a particularly active status characterized by growth arrest and modified immunostimulatory cytokine secretion in vitro. As expected, sPD1‐expressing senescent tumor cell vaccine (STCV/sPD‐1) treatment attracted more mature DC and fewer exhausted‐PD1+ T cells in vivo. During the course of the vaccine studies, we observed greater safety and efficacy for STCV/sPD‐1 than for control treatments. STCV/sPD‐1 pre‐injections provided complete protection from 4T1 tumor challenge in mice. Additionally, the in vivo therapeutic study of mice with s.c. 4T1 tumor showed that STCV/sPD‐1 vaccination delayed tumorigenesis and suppressed tumor progression at early stages. These results showed that STCV/sPD‐1 effectively induced a strong antitumor immune response against cancer and suggested that it might be a potential strategy for TNBC prevention.
Collapse
Affiliation(s)
- Zehong Chen
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Oncology, Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Kang Hu
- Department of Oncology, Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Lieting Feng
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ruxiong Su
- Department of Pharmacy, Puning People's Hospital, Southern Medical University, Puning, China
| | - Nan Lai
- Department of Oncology, Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Zike Yang
- Department of Oncology, Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Shijun Kang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| |
Collapse
|
|
35
|
Oncofetal gene SALL4 reactivation by hepatitis B virus counteracts miR-200c in PD-L1-induced T cell exhaustion. Nat Commun 2018; 9:1241. [PMID: 29593314 PMCID: PMC5871883 DOI: 10.1038/s41467-018-03584-3] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 02/26/2018] [Indexed: 12/17/2022] Open
Abstract
A chronic viral or tumor microenvironment can push T cells to exhaustion by promoting coinhibitory ligand expression. However, how host factors control coinhibitory ligand expression and whether viral infection breaks this control during tumor progress is unknown. Here we show a close negative correlation between SALL4 or PD-L1 and miR-200c in tumors from 98 patients with HBV-related hepatocellular carcinoma. SALL4 or PD-L1 expression correlates negatively with miR-200c expression, and patients with lower levels of SALL4 or PD-L1 and higher miR-200c survive longer. Moreover, over-expression of miR-200c antagonizes HBV-mediated PD-L1 expression by targeting 3'-UTR of CD274 (encoding PD-L1) directly, and reverses antiviral CD8+ T cell exhaustion. MiR-200c transcription is inhibited by oncofetal protein SALL4, which is re-expressed through HBV-induced STAT3 activation in adulthood. We propose that an HBV-pSTAT3-SALL4-miR-200c axis regulates PD-L1. Therapeutic strategies to influence this axis might reverse virus-induced immune exhaustion.
Collapse
|
|
36
|
Shimizu Y, Suzuki T, Yoshikawa T, Tsuchiya N, Sawada Y, Endo I, Nakatsura T. Cancer immunotherapy-targeted glypican-3 or neoantigens. Cancer Sci 2018; 109:531-541. [PMID: 29285841 PMCID: PMC5834776 DOI: 10.1111/cas.13485] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 12/22/2017] [Accepted: 12/25/2017] [Indexed: 12/17/2022] Open
Abstract
Immune checkpoint inhibitors have ushered in a new era in cancer therapy, although other therapies or combinations thereof are still needed for many patients for whom these drugs are ineffective. In this light, we have identified glypican‐3 an HLA‐24, HLA‐A2 restriction peptide with extreme cancer specificity. In this paper, we summarize results from a number of related clinical trials showing that glypican‐3 peptide vaccines induce specific CTLs in most patients (UMIN Clinical Trials Registry: UMIN000001395, UMIN000005093, UMIN000002614, UMN000003696, and UMIN000006357). We also describe the current state of personalized cancer immunotherapy based on neoantigens, and assess, based on our own research and experience, the potential of such therapy to elicit cancer regression. Finally, we discuss the future direction of cancer immunotherapy.
Collapse
Affiliation(s)
- Yasuhiro Shimizu
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.,Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Toshihiro Suzuki
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Toshiaki Yoshikawa
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| | - Nobuhiro Tsuchiya
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.,Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Yu Sawada
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.,Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Tetsuya Nakatsura
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
| |
Collapse
|
|
37
|
Petrizzo A, Mauriello A, Luciano A, Rea D, Barbieri A, Arra C, Maiolino P, Tornesello M, Gigantino V, Botti G, Ciliberto G, Buonaguro FM, Tagliamonte M, Buonaguro L. Inhibition of tumor growth by cancer vaccine combined with metronomic chemotherapy and anti-PD-1 in a pre-clinical setting. Oncotarget 2018; 9:3576-3589. [PMID: 29423067 PMCID: PMC5790484 DOI: 10.18632/oncotarget.23181] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 10/25/2017] [Indexed: 11/29/2022] Open
Abstract
Tumor microenvironment (TME) is characterized by multiple immune suppressive mechanisms able to suppress anti-tumor effector cell immunity. Combinatorial strategies, including vaccine and immunomodulatory drugs, need to be developed for improved immunotherapy efficacy. A novel combinatorial approach was assessed in C57BL/6 mice injected with mouse melanoma B16F10 cells. A multi-peptide vaccine (PEPT) was combined with a low dose metronomic chemotherapy (MCT) and an anti-PD-1 checkpoint inhibitor (CI). Statistical analysis were performed with the unpaired two-sided Student's t-test and ANOVA. Animals treated with the multi-peptide vaccine combined with MCT or CI showed remarkable delay in tumor growth and prolonged survival as compared to control groups. The multi-pronged combination including PEPT+MCT+CI was able to prolong survival in all mice and inhibit tumor growth in 66.6% of mice. All animals which did not show tumor growth were re-challenged with the same melanoma cells and one of them showed complete tumor growth inhibition. The anti-tumor effect was associated with strong T cell immune response to vaccine mutated peptides and significant reduction of regulatory T cells. The combination of a vaccine with MCT and CI was highly efficient in potentiating the vaccine's anti-tumor effects. The approach is highly promising to be moved into clinical trial.
Collapse
Affiliation(s)
- Annacarmen Petrizzo
- Laboratory of Molecular Biology and Viral Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione Pascale, IRCCS, Naples, Italy
| | - Angela Mauriello
- Laboratory of Molecular Biology and Viral Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione Pascale, IRCCS, Naples, Italy
| | - Antonio Luciano
- Animal Facility, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione Pascale, IRCCS, Naples, Italy
| | - Domenica Rea
- Animal Facility, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione Pascale, IRCCS, Naples, Italy
| | - Antonio Barbieri
- Animal Facility, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione Pascale, IRCCS, Naples, Italy
| | - Claudio Arra
- Animal Facility, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione Pascale, IRCCS, Naples, Italy
| | - Piera Maiolino
- Pharmacy Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione Pascale, IRCCS, Naples, Italy
| | - Marialina Tornesello
- Laboratory of Molecular Biology and Viral Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione Pascale, IRCCS, Naples, Italy
| | - Vincenzo Gigantino
- Unit of Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione Pascale, IRCCS, Naples, Italy
| | - Gerardo Botti
- Unit of Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione Pascale, IRCCS, Naples, Italy
| | - Gennaro Ciliberto
- Scientific Directorate, Regina Elena National Cancer Institute, Rome, Italy
| | - Franco M. Buonaguro
- Laboratory of Molecular Biology and Viral Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione Pascale, IRCCS, Naples, Italy
| | - Maria Tagliamonte
- Laboratory of Molecular Biology and Viral Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione Pascale, IRCCS, Naples, Italy
| | - Luigi Buonaguro
- Laboratory of Molecular Biology and Viral Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione Pascale, IRCCS, Naples, Italy
| |
Collapse
|
|
38
|
Shirakawa T, Kitagawa K. Antitumor effect of oral cancer vaccine with Bifidobacterium delivering WT1 protein to gut immune system is superior to WT1 peptide vaccine. Hum Vaccin Immunother 2018; 14:159-162. [PMID: 29048978 PMCID: PMC5791589 DOI: 10.1080/21645515.2017.1382787] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 09/08/2017] [Accepted: 09/18/2017] [Indexed: 12/30/2022] Open
Abstract
Despite the revolutionary progress of immune checkpoint inhibitors (CPIs) for cancer immunotherapy, CPIs are effective only in a subset of patients. Combining CPIs and cancer vaccines to achieve better clinical outcomes is a reasonable approach since CPI enhances cancer vaccine-induced tumor-associated antigen (TAA) specific CTL. Among the various TAAs so far identified, WT1 protein is one of the most promising TAAs as a cancer vaccine target. Until now clinical trials of WT1 vaccine have demonstrated only modest clinical efficacy. These WT1 vaccines were based on peptides or dendritic cells (DCs), and there was no oral cancer vaccine. Recently, we developed a WT1 oral cancer vaccine using a recombinant Bifidobacterium displaying WT1 protein, which can efficiently deliver WT1 protein to the gut immune system, and we demonstrated that this oral cancer vaccine had a significant anti-tumor effect in a C1498-WT1 murine leukemia syngeneic tumor model. The WT1 protein displayed in this vaccine consists of about 70% of the WT1 amino acid sequence including multiple known CD4 and CD8 T-cell epitopes of WT1. In this commentary, we introduce our recent data indicating the superior anti-tumor effect of a WT1 oral cancer vaccine delivering WT1 protein to the gut immune system compared to a peptide vaccine.
Collapse
Affiliation(s)
- Toshiro Shirakawa
- Division of Advanced Medical Science, Kobe University Graduate School of Science, Technology and Innovation, Kobe, Japan
- Division of Translational Research for Biologics, Department of Internal Medicine Related, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Koichi Kitagawa
- Division of Translational Research for Biologics, Department of Internal Medicine Related, Kobe University Graduate School of Medicine, Kobe, Japan
| |
Collapse
|
|
39
|
Nikitovic D, Berdiaki A, Spyridaki I, Krasanakis T, Tsatsakis A, Tzanakakis GN. Proteoglycans-Biomarkers and Targets in Cancer Therapy. Front Endocrinol (Lausanne) 2018; 9:69. [PMID: 29559954 PMCID: PMC5845539 DOI: 10.3389/fendo.2018.00069] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 02/16/2018] [Indexed: 12/18/2022] Open
Abstract
Proteoglycans (PGs), important constituents of the extracellular matrix, have been associated with cancer pathogenesis. Their unique structure consisting of a protein core and glycosaminoglycan chains endowed with fine modifications constitutes these molecules as capable cellular effectors important for homeostasis and contributing to disease progression. Indeed, differential expression of PGs and their interacting proteins has been characterized as specific for disease evolvement in various cancer types. Importantly, PGs to a large extent regulate the bioavailability of hormones, growth factors, and cytokines as well as the activation of their respective receptors which regulate phenotypic diversibility, gene expression and rates of recurrence in specific tumor types. Defining and targeting these effectors on an individual patient basis offers ground for the development of newer therapeutic approaches which may act as either supportive or a substitute treatment to the standard therapy protocols. This review discusses the roles of PGs in cancer progression, developing technologies utilized for the defining of the PG "signature" in disease, and how this may facilitate the generation of tailor-made cancer strategies.
Collapse
Affiliation(s)
- Dragana Nikitovic
- Laboratory of Anatomy-Histology-Embryology, Medical School, University of Crete, Heraklion, Greece
| | - Aikaterini Berdiaki
- Laboratory of Anatomy-Histology-Embryology, Medical School, University of Crete, Heraklion, Greece
| | - Ioanna Spyridaki
- Laboratory of Anatomy-Histology-Embryology, Medical School, University of Crete, Heraklion, Greece
| | - Theodoros Krasanakis
- Laboratory of Anatomy-Histology-Embryology, Medical School, University of Crete, Heraklion, Greece
| | - Aristidis Tsatsakis
- Laboratory of Toxicology, Medical School, University of Crete, Heraklion, Greece
| | - George N Tzanakakis
- Laboratory of Anatomy-Histology-Embryology, Medical School, University of Crete, Heraklion, Greece
| |
Collapse
|
|
40
|
Zeng JZ, Liu Y, Huang F, He ZH, Sun H, Lu YD, Lei JH, Luo RC. Glypican-3-specific cytotoxic T lymphocytes induced by human leucocyte antigen-A*0201-restricted peptide effectively kill hepatocellular carcinoma cells in vitro. ASIAN PAC J TROP MED 2017; 10:1084-1089. [PMID: 29203107 DOI: 10.1016/j.apjtm.2017.10.013] [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] [Received: 08/25/2017] [Revised: 09/30/2017] [Accepted: 10/17/2017] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE To investigate potential human leucocyte antigen (HLA)-A2-restricted epitope peptides of glypican-3 (GPC3) and determine the cytotoxicity of peptide-specific cytotoxic T lymphocytes (CTLs) against hepatocellular carcinoma (HCC) cells. METHODS The potential HLA-A*0201-restricted GPC3 peptides were screened using computer algorithms, T2 cell-binding affinity and stability of peptide/HLA-A*0201 complex assay. The peptide-specific CTLs were generated and their cytotoxicity against GPC3+ SMMC 7721 and HepG2 cells was detected using IFN-γ based enzyme-linked immunospot and lactate dehydrogenase release assays in vitro. RESULTS A total of six peptides were identified for bindings to HAL-A2 and the GPC3 522-530 and GPC3 229-237 peptides with HLA-A*0201 molecules displayed high binding affinity and stability. The CTLs induced by the GPC3 522-530 or positive control GPC3 144-152 peptide responded to the peptide by producing IFN-γ, which were abrogated by treatment with anti-HLA-A2 antibody. The GPC3 522-530-specific CTLs responded to and killed SMMC 7721 and HepG2 cells, instead of GPC3-silenced SMMC 7721 or HepG2 cells. GPC3 522-530-specific CTLs response to HCC cells was blocked by anti-HLA-A2 antibody. CONCLUSIONS The GPC3 522-530 peptide contains antigen-determinant and its specific CTLs can effectively kill HCC in a HLA-A2-restricted and peptide-dependent manner. Our findings suggest that this peptide may be valuable for development of therapeutic vaccine.
Collapse
Affiliation(s)
- Jiang-Zheng Zeng
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510310, China; Department of Medical Oncology, The First Affiliated Hospital of Hainan Medical College, Hainan Medical College Cancer Institute, Haikou 570102, China
| | - Yu Liu
- Department of Breast and Thoracic Tumor Surgery, The First Affiliated Hospital of Hainan Medical College, Haikou 570102, China
| | - Fen Huang
- Department of Medical Oncology, The First Affiliated Hospital of Hainan Medical College, Hainan Medical College Cancer Institute, Haikou 570102, China
| | - Zhi-Hui He
- Department of Medical Oncology, The First Affiliated Hospital of Hainan Medical College, Hainan Medical College Cancer Institute, Haikou 570102, China
| | - Huamao Sun
- Department of Medical Oncology, The First Affiliated Hospital of Hainan Medical College, Hainan Medical College Cancer Institute, Haikou 570102, China
| | - Yan-Da Lu
- Department of Medical Oncology, The First Affiliated Hospital of Hainan Medical College, Hainan Medical College Cancer Institute, Haikou 570102, China
| | - Jun-Hua Lei
- Department of Medical Oncology, The First Affiliated Hospital of Hainan Medical College, Hainan Medical College Cancer Institute, Haikou 570102, China.
| | - Rong-Cheng Luo
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510310, China.
| |
Collapse
|
|
41
|
Zhou G, Sprengers D, Boor PPC, Doukas M, Schutz H, Mancham S, Pedroza-Gonzalez A, Polak WG, de Jonge J, Gaspersz M, Dong H, Thielemans K, Pan Q, IJzermans JNM, Bruno MJ, Kwekkeboom J. Antibodies Against Immune Checkpoint Molecules Restore Functions of Tumor-Infiltrating T Cells in Hepatocellular Carcinomas. Gastroenterology 2017. [PMID: 28648905 DOI: 10.1053/j.gastro.2017.06.017] [Citation(s) in RCA: 317] [Impact Index Per Article: 39.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Ligand binding to inhibitory receptors on immune cells, such as programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA4), down-regulates the T-cell-mediated immune response (called immune checkpoints). Antibodies that block these receptors increase antitumor immunity in patients with melanoma, non-small-cell lung cancer, and renal cell cancer. Tumor-infiltrating CD4+ and CD8+ T cells in patients with hepatocellular carcinoma (HCC) have been found to be functionally compromised. We analyzed HCC samples from patients to determine if these inhibitory pathways prevent T-cell responses in HCCs and to find ways to restore their antitumor functions. METHODS We collected HCC samples from 59 patients who underwent surgical resection from November 2013 through May 2017, along with tumor-free liver tissues (control tissues) and peripheral blood samples. We isolated tumor-infiltrating lymphocytes (TIL) and intra-hepatic lymphocytes. We used flow cytometry to quantify expression of the inhibitory receptors PD-1, hepatitis A virus cellular receptor 2 (TIM3), lymphocyte activating 3 (LAG3), and CTLA4 on CD8+ and CD4+ T cells from tumor, control tissue, and blood; we studied the effects of antibodies that block these pathways in T-cell activation assays. RESULTS Expression of PD-1, TIM3, LAG3, and CTLA4 was significantly higher on CD8+ and CD4+ T cells isolated from HCC tissue than control tissue or blood. Dendritic cells, monocytes, and B cells in HCC tumors expressed ligands for these receptors. Expression of PD-1, TIM3, and LAG3 was higher on tumor-associated antigen (TAA)-specific CD8+ TIL, compared with other CD8+ TIL. Compared with TIL that did not express these inhibitory receptors, CD8+ and CD4+ TIL that did express these receptors had higher levels of markers of activation, but similar or decreased levels of granzyme B and effector cytokines. Antibodies against CD274 (PD-ligand1 [PD-L1]), TIM3, or LAG3 increased proliferation of CD8+ and CD4+ TIL and cytokine production in response to stimulation with polyclonal antigens or TAA. Importantly, combining antibody against PD-L1 with antibodies against TIM3, LAG3, or CTLA4 further increased TIL functions. CONCLUSIONS The immune checkpoint inhibitory molecules PD-1, TIM3, and LAG3 are up-regulated on TAA-specific T cells isolated from human HCC tissues, compared with T cells from tumor-free liver tissues or blood. Antibodies against PD-L1, TIM3, or LAG3 restore responses of HCC-derived T cells to tumor antigens, and combinations of the antibodies have additive effects. Strategies to block PD-L1, TIM3, and LAG3 might be developed for treatment of primary liver cancer.
Collapse
MESH Headings
- Antibodies, Monoclonal/pharmacology
- Antibodies, Neutralizing/pharmacology
- Antigens, CD/immunology
- Antigens, CD/metabolism
- Antineoplastic Agents/pharmacology
- Antineoplastic Combined Chemotherapy Protocols/pharmacology
- CTLA-4 Antigen/antagonists & inhibitors
- CTLA-4 Antigen/immunology
- CTLA-4 Antigen/metabolism
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Proliferation/drug effects
- Cells, Cultured
- Coculture Techniques
- Cytokines/metabolism
- Hepatitis A Virus Cellular Receptor 2/antagonists & inhibitors
- Hepatitis A Virus Cellular Receptor 2/immunology
- Hepatitis A Virus Cellular Receptor 2/metabolism
- Humans
- Immunotherapy/methods
- Liver Neoplasms/drug therapy
- Liver Neoplasms/immunology
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Lymphocyte Activation/drug effects
- Lymphocytes, Tumor-Infiltrating/drug effects
- Lymphocytes, Tumor-Infiltrating/immunology
- Lymphocytes, Tumor-Infiltrating/metabolism
- Programmed Cell Death 1 Receptor/antagonists & inhibitors
- Programmed Cell Death 1 Receptor/immunology
- Programmed Cell Death 1 Receptor/metabolism
- Signal Transduction/drug effects
- T-Lymphocytes/drug effects
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
- Tumor Escape/drug effects
- Tumor Microenvironment
- Up-Regulation
- Lymphocyte Activation Gene 3 Protein
Collapse
Affiliation(s)
- Guoying Zhou
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Centre, Rotterdam, the Netherlands
| | - Dave Sprengers
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Centre, Rotterdam, the Netherlands
| | - Patrick P C Boor
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Centre, Rotterdam, the Netherlands
| | - Michail Doukas
- Department of Pathology, Erasmus MC-University Medical Centre, Rotterdam, the Netherlands
| | - Hannah Schutz
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Centre, Rotterdam, the Netherlands
| | - Shanta Mancham
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Centre, Rotterdam, the Netherlands
| | | | - Wojciech G Polak
- Department of Surgery, Erasmus MC-University Medical Centre, Rotterdam, the Netherlands
| | - Jeroen de Jonge
- Department of Surgery, Erasmus MC-University Medical Centre, Rotterdam, the Netherlands
| | - Marcia Gaspersz
- Department of Surgery, Erasmus MC-University Medical Centre, Rotterdam, the Netherlands
| | - Haidong Dong
- Department of Urology and Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Kris Thielemans
- Laboratory of Molecular and Cellular Therapy, Department of Immunology-Physiology, Vrije Universiteit, Brussels, and eTheRNA immunotherapies NV, Niel, Belgium
| | - Qiuwei Pan
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Centre, Rotterdam, the Netherlands
| | | | - Marco J Bruno
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Centre, Rotterdam, the Netherlands
| | - Jaap Kwekkeboom
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Centre, Rotterdam, the Netherlands.
| |
Collapse
|
|
42
|
PD-1/PD-L1 checkpoint blockades in non-small cell lung cancer: New development and challenges. Cancer Lett 2017; 405:29-37. [DOI: 10.1016/j.canlet.2017.06.033] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Revised: 06/21/2017] [Accepted: 06/28/2017] [Indexed: 11/18/2022]
|
|
43
|
Zhou F, Shang W, Yu X, Tian J. Glypican-3: A promising biomarker for hepatocellular carcinoma diagnosis and treatment. Med Res Rev 2017. [PMID: 28621802 DOI: 10.1002/med.21455] [Citation(s) in RCA: 248] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Liver cancer is the second leading cause of cancer-related deaths, and hepatocellular carcinoma (HCC) is the most common type. Therefore, molecular targets are urgently required for the early detection of HCC and the development of novel therapeutic approaches. Glypican-3 (GPC3), an oncofetal proteoglycan anchored to the cell membrane, is normally detected in the fetal liver but not in the healthy adult liver. However, in HCC patients, GPC3 is overexpressed at both the gene and protein levels, and its expression predicts a poor prognosis. Mechanistic studies have revealed that GPC3 functions in HCC progression by binding to molecules such as Wnt signaling proteins and growth factors. Moreover, GPC3 has been used as a target for molecular imaging and therapeutic intervention in HCC. To date, GPC3-targeted magnetic resonance imaging, positron emission tomography, and near-infrared imaging have been investigated for early HCC detection, and various immunotherapeutic protocols targeting GPC3 have been developed, including the use of humanized anti-GPC3 cytotoxic antibodies, treatment with peptide/DNA vaccines, immunotoxin therapies, and genetic therapies. In this review, we summarize the current knowledge regarding the structure, function, and biology of GPC3 with a focus on its clinical potential as a diagnostic molecule and a therapeutic target in HCC immunotherapy.
Collapse
Affiliation(s)
- Fubo Zhou
- Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, 100853, China
| | - Wenting Shang
- Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China
| | - Xiaoling Yu
- Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, 100853, China
| | - Jie Tian
- Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China
| |
Collapse
|
|
44
|
Combination of p53-DC vaccine and rAd-p53 gene therapy induced CTLs cytotoxic against p53-deleted human prostate cancer cells in vitro. Cancer Gene Ther 2017. [PMID: 28621316 DOI: 10.1038/cgt.2017.21] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Recently, the US FDA approved sipuleucel-T, which is composed of autologous DCs stimulated with a recombinant fusion protein of prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GM-CSF), as the first immunotherapeutic agent for metastatic castration resistant prostate cancer (mCRPC). However, sipuleucel-T demonstrated only modest efficacy in mCPRC patients. Researchers are now investigating the potential of p53 protein as a tumor-associated antigen (TAA) loaded in DC-based cancer vaccine. Approximately half of all tumors overexpress p53, and up to 20% of prostate cancer cells overexpresses p53. In this study, we evaluated the feasibility of combining p53-DC vaccine and rAd-p53 gene therapy, using the p53-overexpressing and non-expressing prostate cancer cells in vitro. We successfully generated the p53-DC vaccine by culturing autologous DCs infected with rAd-p53. This p53-DC vaccine can differentiate CTLs specifically cytotoxic to p53-overexpressing prostate cancer cells. In addition, rAd-p53 infection can induce overexpression of p53 and thus the cytotoxicity of CTLs differentiated by the p53-DC vaccine in p53 non-expressing prostate cancer cells. These findings suggest that this combination therapy using p53-DC vaccine and rAd-p53 gene therapy together may represent a new paradigm for the treatment of mCRPC.
Collapse
|
|
45
|
Cellular and molecular targets for the immunotherapy of hepatocellular carcinoma. Mol Cell Biochem 2017; 437:13-36. [PMID: 28593566 DOI: 10.1007/s11010-017-3092-z] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 06/01/2017] [Indexed: 02/06/2023]
|
|
46
|
Buonaguro FM, Buonaguro L. Cancer vaccines for hepatocellular carcinoma: future directions. Immunotherapy 2016; 8:391-3. [PMID: 26973120 DOI: 10.2217/imt-2015-0018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Affiliation(s)
- Franco M Buonaguro
- Lab of Molecular Biology & Viral Oncology, Department Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, 'Fondazione Pascale' - IRCCS, Naples, Italy
| | - Luigi Buonaguro
- Lab of Molecular Biology & Viral Oncology, Department Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, 'Fondazione Pascale' - IRCCS, Naples, Italy
| |
Collapse
|
|
47
|
Beyranvand Nejad E, Welters MJP, Arens R, van der Burg SH. The importance of correctly timing cancer immunotherapy. Expert Opin Biol Ther 2016; 17:87-103. [PMID: 27802061 DOI: 10.1080/14712598.2017.1256388] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
INTRODUCTION The treatment options for cancer-surgery, radiotherapy and chemotherapy-are now supplemented with immunotherapy. Previously underappreciated but now gaining strong interest are the immune modulatory properties of the three conventional modalities. Moreover, there is a better understanding of the needs and potential of the different immune therapeutic platforms. Key to improved treatment will be the combinations of modalities that complete each other's shortcomings. Area covered: Tumor-specific T-cells are required for optimal immunotherapy. In this review, the authors focus on the correct timing of different types of chemotherapeutic agents or immune modulators and immunotherapeutic drugs, not only for the activation and expansion of tumor-specific T-cells but also to support and enhance their anti-tumor efficacy. Expert opinion: At an early phase of disease, clinical success can be obtained using single treatment modalities but at later disease stages, combinations of several modalities are required. The gain in success is determined by a thorough understanding of the direct and indirect immune effects of the modalities used. Profound knowledge of these effects requires optimal tuning of immunomonitoring. This will guide the appropriate combination of treatments and allow for correct sequencing the order and interval of the different therapeutic modalities.
Collapse
Affiliation(s)
- Elham Beyranvand Nejad
- a Department of Medical Oncology , Leiden University Medical Center , Leiden , The Netherlands.,b Department of Immunohematology and Blood Transfusion , Leiden University Medical Center , Leiden , The Netherlands
| | - Marij J P Welters
- a Department of Medical Oncology , Leiden University Medical Center , Leiden , The Netherlands
| | - Ramon Arens
- b Department of Immunohematology and Blood Transfusion , Leiden University Medical Center , Leiden , The Netherlands
| | - Sjoerd H van der Burg
- a Department of Medical Oncology , Leiden University Medical Center , Leiden , The Netherlands
| |
Collapse
|
|
48
|
Is There Still Room for Cancer Vaccines at the Era of Checkpoint Inhibitors. Vaccines (Basel) 2016; 4:vaccines4040037. [PMID: 27827885 PMCID: PMC5192357 DOI: 10.3390/vaccines4040037] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2016] [Revised: 10/23/2016] [Accepted: 10/31/2016] [Indexed: 02/07/2023] Open
Abstract
Checkpoint inhibitor (CPI) blockade is considered to be a revolution in cancer therapy, although most patients (70%–80%) remain resistant to this therapy. It has been hypothesized that only tumors with high mutation rates generate a natural antitumor T cell response, which could be revigorated by this therapy. In patients with no pre-existing antitumor T cells, a vaccine-induced T cell response is a rational option to counteract clinical resistance. This hypothesis has been validated in preclinical models using various cancer vaccines combined with inhibitory pathway blockade (PD-1-PDL1-2, CTLA-4-CD80-CD86). Enhanced T cell infiltration of various tumors has been demonstrated following this combination therapy. The timing of this combination appears to be critical to the success of this therapy and multiple combinations of immunomodulating antibodies (CPI antagonists or costimulatory pathway agonists) have reinforced the synergy with cancer vaccines. Only limited results are available in humans and this combined approach has yet to be validated. Comprehensive monitoring of the regulation of CPI and costimulatory molecules after administration of immunomodulatory antibodies (anti-PD1/PD-L1, anti-CTLA-4, anti-OX40, etc.) and cancer vaccines should help to guide the selection of the best combination and timing of this therapy.
Collapse
|
|
49
|
Suzuki S, Sakata J, Utsumi F, Sekiya R, Kajiyama H, Shibata K, Kikkawa F, Nakatsura T. Efficacy of glypican-3-derived peptide vaccine therapy on the survival of patients with refractory ovarian clear cell carcinoma. Oncoimmunology 2016; 5:e1238542. [PMID: 27999758 PMCID: PMC5139642 DOI: 10.1080/2162402x.2016.1238542] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Revised: 09/13/2016] [Accepted: 09/13/2016] [Indexed: 12/23/2022] Open
Abstract
Compared with other epithelial ovarian carcinoma subtypes, ovarian clear cell carcinoma (OCCC) has been recognized to show chemoresistance. Therefore, new treatment modalities are required for patients with OCCC that is refractory to chemotherapy. The carcinoembryonic antigen glypican-3 (GPC3) is expressed by approximately half of OCCC and is a promising immunotherapeutic target. The purpose of this study was to evaluate the effect of GPC3 peptide vaccine against refractory OCCC patients. We conducted a phase II trial with a GPC3-derived peptide vaccine in OCCC patients. Immunological responses were analyzed by ex vivo IFNγ ELISPOT assay. We also evaluated control subjects, who received best supportive care without vaccinations during the same period. Thirty-two patients with refractory OCCC were enrolled between July 2010 and September 2015, and underwent GPC3 peptide vaccination. Fifteen patients were vaccinated less than six times because their general condition progressively deteriorated, and 17 patients were vaccinated at least six times. Three patients showed a partial response as the best overall response. The GPC3 peptide vaccine induced a GPC3-specific CTL response in 15 out of 24 patients who had PBMCs collected three times or more. The prognosis of palliative care patients without GPC3 peptide vaccinations was significantly poorer than that of those with GPC3 peptide vaccinations (post cancer-treatment survival: p = 0.002). Although the disease control rate was not high, our results suggest that GPC3 peptide vaccinations may hold a significant impact to prolong survival of patients with refractory OCCC, allowing them to maintain quality of life with no serious toxicities.
Collapse
Affiliation(s)
- Shiro Suzuki
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine , Showa-ku, Nagoya, Japan
| | - Jun Sakata
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine , Showa-ku, Nagoya, Japan
| | - Fumi Utsumi
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine , Showa-ku, Nagoya, Japan
| | - Ryuichiro Sekiya
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine , Showa-ku, Nagoya, Japan
| | - Hiroaki Kajiyama
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine , Showa-ku, Nagoya, Japan
| | - Kiyosumi Shibata
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine , Showa-ku, Nagoya, Japan
| | - Fumitaka Kikkawa
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine , Showa-ku, Nagoya, Japan
| | - Tetsuya Nakatsura
- Division of Cancer Immunotherapy, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center , Kashiwa, Chiba, Japan
| |
Collapse
|
|
50
|
Liu A, Dong L, Wei XL, Yang XH, Xiao JH, Liu ZQ. Development of amino- and dimethylcarbamate-substituted resorcinol as programmed cell death-1 (PD-1) inhibitor. Eur J Pharm Sci 2016; 88:50-8. [DOI: 10.1016/j.ejps.2016.03.023] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 03/26/2016] [Accepted: 03/27/2016] [Indexed: 10/22/2022]
|