|
1
|
Galili U. Self-Tumor Antigens in Solid Tumors Turned into Vaccines by α-gal Micelle Immunotherapy. Pharmaceutics 2024; 16:1263. [PMID: 39458595 PMCID: PMC11510312 DOI: 10.3390/pharmaceutics16101263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Revised: 09/02/2024] [Accepted: 09/23/2024] [Indexed: 10/28/2024] Open
Abstract
A major reason for the failure of the immune system to detect tumor antigens (TAs) is the insufficient uptake, processing, and presentation of TAs by antigen-presenting cells (APCs). The immunogenicity of TAs in the individual patient can be markedly increased by the in situ targeting of tumor cells for robust uptake by APCs, without the need to identify and characterize the TAs. This is feasible by the intra-tumoral injection of α-gal micelles comprised of glycolipids presenting the carbohydrate-antigen "α-gal epitope" (Galα1-3Galβ1-4GlcNAc-R). Humans produce a natural antibody called "anti-Gal" (constituting ~1% of immunoglobulins), which binds to α-gal epitopes. Tumor-injected α-gal micelles spontaneously insert into tumor cell membranes, so that multiple α-gal epitopes are presented on tumor cells. Anti-Gal binding to these epitopes activates the complement system, resulting in the killing of tumor cells, and the recruitment of multiple APCs (dendritic cells and macrophages) into treated tumors by the chemotactic complement cleavage peptides C5a and C3a. In this process of converting the treated tumor into a personalized TA vaccine, the recruited APC phagocytose anti-Gal opsonized tumor cells and cell membranes, process the internalized TAs and transport them to regional lymph-nodes. TA peptides presented on APCs activate TA-specific T cells to proliferate and destroy the metastatic tumor cells presenting the TAs. Studies in anti-Gal-producing mice demonstrated the induction of effective protection against distant metastases of the highly tumorigenic B16 melanoma following injection of natural and synthetic α-gal micelles into primary tumors. This treatment was further found to synergize with checkpoint inhibitor therapy by the anti-PD1 antibody. Phase-1 clinical trials indicated that α-gal micelle immunotherapy is safe and can induce the infiltration of CD4+ and CD8+ T cells into untreated distant metastases. It is suggested that, in addition to converting treated metastases into an autologous TA vaccine, this treatment should be considered as a neoadjuvant therapy, administering α-gal micelles into primary tumors immediately following their detection. Such an immunotherapy will convert tumors into a personalized anti-TA vaccine for the period prior to their resection.
Collapse
Affiliation(s)
- Uri Galili
- Department of Medicine, Rush University Medical Center, Chicago, IL 60612, USA
| |
Collapse
|
|
2
|
Brandi N, Renzulli M. The Synergistic Effect of Interventional Locoregional Treatments and Immunotherapy for the Treatment of Hepatocellular Carcinoma. Int J Mol Sci 2023; 24:ijms24108598. [PMID: 37239941 DOI: 10.3390/ijms24108598] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 05/05/2023] [Accepted: 05/08/2023] [Indexed: 05/28/2023] Open
Abstract
Immunotherapy has remarkably revolutionized the management of advanced HCC and prompted clinical trials, with therapeutic agents being used to selectively target immune cells rather than cancer cells. Currently, there is great interest in the possibility of combining locoregional treatments with immunotherapy for HCC, as this combination is emerging as an effective and synergistic tool for enhancing immunity. On the one hand, immunotherapy could amplify and prolong the antitumoral immune response of locoregional treatments, improving patients' outcomes and reducing recurrence rates. On the other hand, locoregional therapies have been shown to positively alter the tumor immune microenvironment and could therefore enhance the efficacy of immunotherapy. Despite the encouraging results, many unanswered questions still remain, including which immunotherapy and locoregional treatment can guarantee the best survival and clinical outcomes; the most effective timing and sequence to obtain the most effective therapeutic response; and which biological and/or genetic biomarkers can be used to identify patients likely to benefit from this combined approach. Based on the current reported evidence and ongoing trials, the present review summarizes the current application of immunotherapy in combination with locoregional therapies for the treatment of HCC, and provides a critical evaluation of the current status and future directions.
Collapse
Affiliation(s)
- Nicolò Brandi
- Department of Radiology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, 40138 Bologna, Italy
| | - Matteo Renzulli
- Department of Radiology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, 40138 Bologna, Italy
| |
Collapse
|
|
3
|
Galili U. Biosynthesis of α-Gal Epitopes (Galα1-3Galβ1-4GlcNAc-R) and Their Unique Potential in Future α-Gal Therapies. Front Mol Biosci 2021; 8:746883. [PMID: 34805272 PMCID: PMC8601398 DOI: 10.3389/fmolb.2021.746883] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 09/21/2021] [Indexed: 11/19/2022] Open
Abstract
The α-gal epitope is a carbohydrate antigen which appeared early in mammalian evolution and is synthesized in large amounts by the glycosylation enzyme α1,3galactosyltransferase (α1,3GT) in non-primate mammals, lemurs, and New-World monkeys. Ancestral Old-World monkeys and apes synthesizing α-gal epitopes underwent complete extinction 20–30 million years ago, and their mutated progeny lacking α-gal epitopes survived. Humans, apes, and Old-World monkeys which evolved from the surviving progeny lack α-gal epitopes and produce the natural anti-Gal antibody which binds specifically to α-gal epitopes. Because of this reciprocal distribution of the α-gal epitope and anti-Gal in mammals, transplantation of organs from non-primate mammals (e.g., pig xenografts) into Old-World monkeys or humans results in hyperacute rejection following anti-Gal binding to α-gal epitopes on xenograft cells. The in vivo immunocomplexing between anti-Gal and α-gal epitopes on molecules, pathogens, cells, or nanoparticles may be harnessed for development of novel immunotherapies (referred to as “α-gal therapies”) in various clinical settings because such immune complexes induce several beneficial immune processes. These immune processes include localized activation of the complement system which can destroy pathogens and generate chemotactic peptides that recruit antigen-presenting cells (APCs) such as macrophages and dendritic cells, targeting of antigens presenting α-gal epitopes for extensive uptake by APCs, and activation of recruited macrophages into pro-reparative macrophages. Some of the suggested α-gal therapies associated with these immune processes are as follows: 1. Increasing efficacy of enveloped-virus vaccines by synthesizing α-gal epitopes on vaccinating inactivated viruses, thereby targeting them for extensive uptake by APCs. 2. Conversion of autologous tumors into antitumor vaccines by expression of α-gal epitopes on tumor cell membranes. 3. Accelerating healing of external and internal injuries by α-gal nanoparticles which decrease the healing time and diminish scar formation. 4. Increasing anti-Gal–mediated protection against zoonotic viruses presenting α-gal epitopes and against protozoa, such as Trypanosoma, Leishmania, and Plasmodium, by vaccination for elevating production of the anti-Gal antibody. The efficacy and safety of these therapies were demonstrated in transgenic mice and pigs lacking α-gal epitopes and producing anti-Gal, raising the possibility that these α-gal therapies may be considered for further evaluation in clinical trials.
Collapse
Affiliation(s)
- Uri Galili
- Department of Medicine, Rush University Medical Center, Chicago, IL, United States
| |
Collapse
|
|
4
|
Charneau J, Suzuki T, Shimomura M, Fujinami N, Nakatsura T. Peptide-Based Vaccines for Hepatocellular Carcinoma: A Review of Recent Advances. J Hepatocell Carcinoma 2021; 8:1035-1054. [PMID: 34513746 PMCID: PMC8424432 DOI: 10.2147/jhc.s291558] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 08/10/2021] [Indexed: 12/14/2022] Open
Abstract
Primary liver cancer is the sixth most commonly diagnosed cancer and the third leading cause of cancer-related deaths worldwide. After surgery, up to 70% of patients experience relapses. The current first-line therapy for advanced cases of hepatocellular carcinoma (HCC) comprises sorafenib and lenvatinib administered as single-drug therapies. Regorafenib, cabozantinib, and ramucirumab are administered as second-line therapies. Recently, it has been reported that using the immune checkpoint inhibitors atezolizumab (anti-PDL1 antibody) and bevacizumab (anti-VEGF antibody) leads to longer overall survival of unresectable cases, when compared with the use of sorafenib. The role of cancer immunity against HCC has attracted the attention of clinicians. In this review, we describe our phase I/II clinical trials of peptide vaccines targeting GPC3 in HCC and discuss the potential of peptide vaccines targeting common cancer antigens that are highly expressed in HCC, such as WT-I, AFP, ROBO1, and FOXM1. Further, we introduce recent cancer vaccines targeting neoantigens, which have attracted attention in recent times, as well as present our preclinical studies, the results of which might aid to initiate a neoantigen vaccine clinical trial, which would be the first of its kind in Japan.
Collapse
Affiliation(s)
- Jimmy Charneau
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa City, Japan
| | - Toshihiro Suzuki
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa City, Japan.,Department of Pharmacology, School of Medicine, Teikyo University, Tokyo, Japan
| | - Manami Shimomura
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa City, Japan
| | - Norihiro Fujinami
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa City, Japan
| | - Tetsuya Nakatsura
- Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa City, Japan
| |
Collapse
|
|
5
|
Galili U. Increasing Efficacy of Enveloped Whole-Virus Vaccines by In situ Immune-Complexing with the Natural Anti-Gal Antibody. MEDICAL RESEARCH ARCHIVES 2021; 9:2481. [PMID: 34853815 PMCID: PMC8631339 DOI: 10.18103/mra.v9i7.2481] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
The appearance of variants of mutated virus in course of the Covid-19 pandemic raises concerns regarding the risk of possible formation of variants that can evade the protective immune response elicited by the single antigen S-protein gene-based vaccines. This risk may be avoided by inclusion of several antigens in vaccines, so that a variant that evades the immune response to the S-protein of SARS-CoV-2 virus will be destroyed by the protective immune response against other viral antigens. A simple way for preparing multi-antigenic enveloped-virus vaccines is using the inactivated whole-virus as vaccine. However, immunogenicity of such vaccines may be suboptimal because of poor uptake of the vaccine by antigen-presenting-cells (APC) due to electrostatic repulsion by the negative charges of sialic-acid on both the glycan-shield of the vaccinating virus and on the carbohydrate-chains (glycans) of APC. In addition, glycan-shield can mask many antigenic peptides. These effects of the glycan-shield can be reduced and immunogenicity of the vaccinating virus markedly increased by glycoengineering viral glycans for replacing sialic-acid units on glycans with α-gal epitopes (Galα1-3Galβ1-4GlcNAc-R). Vaccination of humans with inactivated whole-virus presenting α-gal epitopes (virusα-gal) results in formation of immune-complexes with the abundant natural anti-Gal antibody that binds to viral α-gal epitopes at the vaccination site. These immune-complexes are targeted to APC for rigorous uptake due to binding of the Fc portion of immunecomplexed anti-Gal to Fcγ receptors on APC. The APC further transport the large amounts of internalized vaccinating virus to regional lymph nodes, process and present the virus antigenic peptides for the activation of many clones of virus specific helper and cytotoxic T-cells. This elicits a protective cellular and humoral immune response against multiple viral antigens and an effective immunological memory. The immune response to virusα-gal vaccine was studied in mice producing anti-Gal and immunized with inactivated influenza-virusα-gal. These mice demonstrated 100-fold increase in titer of the antibodies produced, a marked increase in T-cell response, and a near complete protection against challenge with a lethal dose of live influenza-virus, in comparison to a similar vaccine lacking α-gal epitopes. This glycoengineering can be achieved in vitro by enzymatic reaction with neuraminidase removing sialic-acid and with recombinant α1,3galactosyltransferase (α1,3GT) synthesizing α-gal epitopes, by engineering host-cells to contain several copies of the α1,3GT gene (GGTA1), or by transduction of this gene in a replication-defective adenovirus vector into host-cells. Theoretically, these methods for increased immunogenicity may be applicable to all enveloped viruses with N-glycans on their envelope.
Collapse
Affiliation(s)
- Uri Galili
- Department of Medicine, Rush Medical College, Chicago, IL, USA
| |
Collapse
|
|
6
|
Galili U. Amplifying immunogenicity of prospective Covid-19 vaccines by glycoengineering the coronavirus glycan-shield to present α-gal epitopes. Vaccine 2020; 38:6487-6499. [PMID: 32907757 PMCID: PMC7437500 DOI: 10.1016/j.vaccine.2020.08.032] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 07/22/2020] [Accepted: 08/12/2020] [Indexed: 12/16/2022]
Abstract
The many carbohydrate chains on Covid-19 coronavirus SARS-CoV-2 and its S-protein form a glycan-shield that masks antigenic peptides and decreases uptake of inactivated virus or S-protein vaccines by APC. Studies on inactivated influenza virus and recombinant gp120 of HIV vaccines indicate that glycoengineering of glycan-shields to present α-gal epitopes (Galα1-3Galβ1-4GlcNAc-R) enables harnessing of the natural anti-Gal antibody for amplifying vaccine efficacy, as evaluated in mice producing anti-Gal. The α-gal epitope is the ligand for the natural anti-Gal antibody which constitutes ~1% of immunoglobulins in humans. Upon administration of vaccines presenting α-gal epitopes, anti-Gal binds to these epitopes at the vaccination site and forms immune complexes with the vaccines. These immune complexes are targeted for extensive uptake by APC as a result of binding of the Fc portion of immunocomplexed anti-Gal to Fc receptors on APC. This anti-Gal mediated effective uptake of vaccines by APC results in 10-200-fold higher anti-viral immune response and in 8-fold higher survival rate following challenge with a lethal dose of live influenza virus, than same vaccines lacking α-gal epitopes. It is suggested that glycoengineering of carbohydrate chains on the glycan-shield of inactivated SARS-CoV-2 or on S-protein vaccines, for presenting α-gal epitopes, will have similar amplifying effects on vaccine efficacy. α-Gal epitope synthesis on coronavirus vaccines can be achieved with recombinant α1,3galactosyltransferase, replication of the virus in cells with high α1,3galactosyltransferase activity as a result of stable transfection of cells with several copies of the α1,3galactosyltransferase gene (GGTA1), or by transduction of host cells with replication defective adenovirus containing this gene. In addition, recombinant S-protein presenting multiple α-gal epitopes on the glycan-shield may be produced in glycoengineered yeast or bacteria expression systems containing the corresponding glycosyltransferases. Prospective Covid-19 vaccines presenting α-gal epitopes may provide better protection than vaccines lacking this epitope because of increased uptake by APC.
Collapse
MESH Headings
- Animals
- Antibodies, Viral/biosynthesis
- Antigens, Viral/genetics
- Antigens, Viral/immunology
- Antigens, Viral/metabolism
- Betacoronavirus/drug effects
- Betacoronavirus/immunology
- Betacoronavirus/pathogenicity
- COVID-19
- COVID-19 Vaccines
- Coronavirus Infections/genetics
- Coronavirus Infections/immunology
- Coronavirus Infections/prevention & control
- Coronavirus Infections/virology
- Dendritic Cells/drug effects
- Dendritic Cells/immunology
- Dendritic Cells/virology
- Genetic Engineering
- HIV Core Protein p24/chemistry
- HIV Core Protein p24/genetics
- HIV Core Protein p24/immunology
- HIV Envelope Protein gp120/chemistry
- HIV Envelope Protein gp120/genetics
- HIV Envelope Protein gp120/immunology
- Humans
- Immunogenicity, Vaccine
- Macrophages/drug effects
- Macrophages/immunology
- Macrophages/virology
- Mice
- Pandemics/prevention & control
- Pneumonia, Viral/immunology
- Pneumonia, Viral/prevention & control
- Pneumonia, Viral/virology
- Recombinant Fusion Proteins/chemistry
- Recombinant Fusion Proteins/genetics
- Recombinant Fusion Proteins/immunology
- SARS-CoV-2
- Spike Glycoprotein, Coronavirus/genetics
- Spike Glycoprotein, Coronavirus/immunology
- Spike Glycoprotein, Coronavirus/metabolism
- Trisaccharides/chemistry
- Trisaccharides/immunology
- Viral Vaccines/administration & dosage
- Viral Vaccines/biosynthesis
- Viral Vaccines/genetics
- Viral Vaccines/immunology
Collapse
Affiliation(s)
- Uri Galili
- Department of Medicine, Rush Medical School, Chicago, IL, USA.
| |
Collapse
|
|
7
|
Zhang Y, Schmidt-Wolf IGH. Ten-year update of the international registry on cytokine-induced killer cells in cancer immunotherapy. J Cell Physiol 2020; 235:9291-9303. [PMID: 32484595 DOI: 10.1002/jcp.29827] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 05/18/2020] [Indexed: 12/11/2022]
Abstract
Cytokine-induced killer (CIK) cells represent an exceptional T-cell population uniting a T cell and natural killer cell-like phenotype in their terminally differentiated CD3+ CD56+ subset, which features non-MHC-restricted tumor-killing activity. CIK cells have provided encouraging results in initial clinical studies and revealed synergistic antitumor effects when combined with standard therapeutic procedures. We established the international registry on CIK cells (IRCC) to collect and evaluate clinical trials for the treatment of cancer patients in 2010. Moreover, our registry set new standards on the reporting of results from clinical trials using CIK cells. In the present update, a total of 106 clinical trials including 10,225 patients were enrolled in IRCC, of which 4,889 patients in over 30 distinct tumor entities were treated with CIK cells alone or in combination with conventional or novel therapies. Significantly improved median progression-free survival and overall survival were shown in 27 trials, and 9 trials reported a significantly increased 5-year survival rate. Mild adverse effects and graft-versus-host diseases were also observed in the studies. Recently, more efforts have been put into the improvement of antitumoral efficacy by CIK cells including the administration of immune checkpoint inhibitors and modification with chimeric antigen receptorc. The minimal toxicity and multiple improvements on their tumor-killing activity both make CIK cells a favorable therapeutic tool in the clinical practice of cancer immunotherapy.
Collapse
Affiliation(s)
- Ying Zhang
- Department of Integrated Oncology, Center for Integrated Oncology (CIO), University Hospital Bonn, Bonn, Germany
| | - Ingo G H Schmidt-Wolf
- Department of Integrated Oncology, Center for Integrated Oncology (CIO), University Hospital Bonn, Bonn, Germany
| |
Collapse
|
|
8
|
Fu Y, Liu S, Zeng S, Shen H. From bench to bed: the tumor immune microenvironment and current immunotherapeutic strategies for hepatocellular carcinoma. J Exp Clin Cancer Res 2019; 38:396. [PMID: 31500650 PMCID: PMC6734524 DOI: 10.1186/s13046-019-1396-4] [Citation(s) in RCA: 297] [Impact Index Per Article: 49.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 08/27/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) ranks the most common primary liver malignancy and the third leading cause of tumor-related mortality worldwide. Unfortunately, despite advances in HCC treatment, less than 40% of HCC patients are eligible for potentially curative therapies. Recently, cancer immunotherapy has emerged as one of the most promising approaches for cancer treatment. It has been proven therapeutically effective in many types of solid tumors, such as non-small cell lung cancer and melanoma. As an inflammation-associated tumor, it's well-evidenced that the immunosuppressive microenvironment of HCC can promote immune tolerance and evasion by various mechanisms. Triggering more vigorous HCC-specific immune response represents a novel strategy for its management. Pre-clinical and clinical investigations have revealed that various immunotherapies might extend current options for needed HCC treatment. In this review, we provide the recent progress on HCC immunology from both basic and clinical perspectives, and discuss potential advances and challenges of immunotherapy in HCC.
Collapse
MESH Headings
- Adaptive Immunity
- Animals
- Antineoplastic Agents, Immunological/pharmacology
- Antineoplastic Agents, Immunological/therapeutic use
- Biomarkers, Tumor
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/therapy
- Clinical Trials as Topic
- Combined Modality Therapy/methods
- Humans
- Immunity, Innate
- Immunotherapy/adverse effects
- Immunotherapy/methods
- Liver Neoplasms/immunology
- Liver Neoplasms/pathology
- Liver Neoplasms/therapy
- Lymphocytes, Tumor-Infiltrating/immunology
- Lymphocytes, Tumor-Infiltrating/metabolism
- Lymphocytes, Tumor-Infiltrating/pathology
- Translational Research, Biomedical
- Treatment Outcome
- Tumor Microenvironment/immunology
Collapse
Affiliation(s)
- Yaojie Fu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
| | - Shanshan Liu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
| | - Shan Zeng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
| | - Hong Shen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
| |
Collapse
|
|
9
|
Cao J, Kong FH, Liu X, Wang XB. Immunotherapy with dendritic cells and cytokine-induced killer cells for hepatocellular carcinoma: A meta-analysis. World J Gastroenterol 2019; 25:3649-3663. [PMID: 31367163 PMCID: PMC6658393 DOI: 10.3748/wjg.v25.i27.3649] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 04/18/2019] [Accepted: 06/07/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) has been revealed as the second most common cause of cancer-related deaths worldwide. The introduction of cell-based immunotherapy, including dendritic cells (DCs) and cytokine-induced killer cells (CIKs), has brought HCC patients an effective benefit. However, the efficacy and necessity of cellular immunotherapy after different interventional therapy remains to be further explored. AIM To investigate the efficacy of cellular immunotherapy, involving DCs and CIKs, combined with different conventional treatments of HCC. METHODS We performed a literature search on PubMed and Web of Science up to February 15, 2019. Long-term efficacy (overall survival and recurrence) and short-term adverse effects were investigated to assess the effectiveness of immunotherapy with DCs and/or CIKs. Review Manager 5.3 was used to perform the analysis. RESULTS A total of 22 studies involving 3756 patients selected by eligibility inclusion criteria were forwarded for meta-analysis. Combined with the conventional clinical treatment, immunotherapy with DCs and/or CIKs was demonstrated to significantly improve overall survival at 6 mo [risk ratio (RR) = 1.07; 95% confidence interval (CI): 1.01-1.13, P = 0.02], 1 year (RR = 1.12; 95%CI: 1.07-1.17, P < 0.00001), 3 years (RR = 1.23; 95%CI: 1.15-1.31, P < 0.00001) and 5 years (RR = 1.26; 95%CI: 1.15-1.37, P < 0.00001). Recurrence rate was significantly reduced by cellular immunotherapy at 6 mo (RR = 0.50; 95%CI: 0.36-0.69, P < 0.0001) and 1 year (RR = 0.82; 95%CI: 0.75-0.89, P < 0.00001). Adverse effect assessment addressed that immunotherapy with DCs and/or CIKs was accepted as a safe, feasible treatment. CONCLUSION Combination immunotherapy with DCs, CIKs and DC/CIK with various routine treatments for HCC was evidently suggested to improve patients' prognosis by increasing overall survival and reducing cancer recurrence.
Collapse
Affiliation(s)
- Jing Cao
- Department of Surgery, Technical University of Munich, Munich 80333, Germany
| | - Fan-Hua Kong
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Xi Liu
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Xiao-Bo Wang
- Department of Surgery, Technical University of Munich, Munich 80333, Germany
| |
Collapse
|
|
10
|
Huang Y, Huang Y, He J, Wang H, Luo Y, Li Y, Liu J, Zhong L, Zhao Y. PEGylated immunoliposome-loaded endoglin single-chain antibody enhances anti-tumor capacity of porcine α1,3GT gene. Biomaterials 2019; 217:119231. [PMID: 31254933 DOI: 10.1016/j.biomaterials.2019.119231] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Revised: 05/22/2019] [Accepted: 05/27/2019] [Indexed: 12/31/2022]
Abstract
Tumor could not be completely removed due to the absence of immune storm against tumor. The porcine α1,3 galactosyltransferase (α1,3 GT) induce the hyperacute rejection by synthesizing Galα1-3Galβ1-(3)4GlcNAc-R (αGal) on the surface of graft endothelial cells (ECs) during xeno-transplantation. This study aimed to develop anti-endoglin single-chain Fv fragments (ENG-scFv) conjugated PEGylated immunoliposomes (iLPs) to induce immune storm against tumor. Immune fluorescence was performed to detect the binding of ENG-scFv to human ENG, the endosomal/lysosomal escape of ENG-scFv-iLPs/α1,3 GT, and αGal expression in hENG-HEK293 cells. In vitro MTT assay was performed to measure ENG-scFv-iLPs/α1,3 GT cytotoxicity. NOD/SCID mouse born A549 tumor model was used to evaluate the therapeutic potency of ENG-scFv-iLPs/α1,3 GT. ENG-scFv-iLPs enabled efficient targeting delivery of α1,3 GT plasmid to ENG + tumors neovascular endothelial cells (TnECs), promoted endosomal/lysosomal escape due to the pH-sensitive ability, then synthesized carbohydrate epitope αGal on the surface of these cells to achieve the purpose of destroying the tumor. The mechanism of uptake for nanoparticles was energy driven, the clathrin-mediated endocytosis was the main endocytic pathway of the ENG-mAb-iLPs/α1,3 GT and lipid-raft-mediated of the ENG-scFv-iLPs/α1,3 GT, and macropinocytosis was also involved in intracellular entry. The inhibition of tumor angiogenesis and proliferation by ENG-scFv-iLPs/α1,3 GT was closely related to down-regulation of VEGF. Our findings establish an alternative therapeutic paradigm for scFv-conjugated nanoparticles to induce tumor cell apoptosis and inhibit tumor growth early. Such iLPs nanocarrier could efficiently release α1,3 GT to their distinct sites of action, where the endoglin + tumor neovascular endothelial cells (ENG + TnECs) exist, in a site-specific manner. Therefore, we believe that these scFv-targeted core-shell immunocomplexes are an important potential α1,3 GT delivery system for various solid tumor-targeted therapy.
Collapse
Affiliation(s)
- Yingying Huang
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Guangxi Medical University, Nanning, Guangxi, 530021, China; Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Yong Huang
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Guangxi Medical University, Nanning, Guangxi, 530021, China; Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Jian He
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Guangxi Medical University, Nanning, Guangxi, 530021, China; Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Huiling Wang
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Guangxi Medical University, Nanning, Guangxi, 530021, China; Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Yiqun Luo
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Guangxi Medical University, Nanning, Guangxi, 530021, China; Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Yanmei Li
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Guangxi Medical University, Nanning, Guangxi, 530021, China; Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Junjie Liu
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Guangxi Medical University, Nanning, Guangxi, 530021, China; Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi, 530021, China.
| | - Liping Zhong
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Guangxi Medical University, Nanning, Guangxi, 530021, China; Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi, 530021, China.
| | - Yongxiang Zhao
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Guangxi Medical University, Nanning, Guangxi, 530021, China; Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi, 530021, China.
| |
Collapse
|
|
11
|
Mo F, Xue D, Duan S, Liu A, Yang X, Hou X, Lu X. Novel fusion cells derived from tumor cells expressing the heterologous α-galactose epitope and dendritic cells effectively target cancer. Vaccine 2019; 37:926-936. [PMID: 30661833 DOI: 10.1016/j.vaccine.2019.01.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 11/17/2018] [Accepted: 01/04/2019] [Indexed: 11/18/2022]
Abstract
Tumor cells/dendritic cells (DCs) fusion cells (tumor/DC) represent a promising immunotherapeutic strategy but are still under performed in clinical trials for cancer treatment. To further boost their anticancer efficacy, here we developed a novel design for fusing dendritic cells with MDA-MB-231 cells expressing the heterologous α-galactose (α-gal) epitope and assessed its anticancer activities both in vitro and in vivo. The high expression of α-gal in MDA-MB-231 (Gal+)/DC correlated with enhanced DC activation. When applied to T cells, MDA-MB-231 (Gal+)/DC significantly stimulated T-cell proliferation and activation, promoted productions of cytokines IL-2 and IFN-γ, and enhanced T-cell-mediated cytotoxicity against MDA-MB-231 cells. MDA-MB-231 (Gal+)/DC inhibited proliferation and promoted apoptosis of tumor cells in vivo, prolonged mouse survival, and significantly boosted anticancer immunity by increasing CD4+ and CD8+ T cells systemically and elevating serum levels of cytokines and IgG. These results suggested that fusing dendritic cells with tumor cells expressing the heterologous α-gal epitope provides a novel therapeutic strategy for cancer treatment.
Collapse
Affiliation(s)
- Fengzhen Mo
- School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi 530021, China; Intenational Nanobody Research Center of Guangxi, Guangxi Medical University, Nanning, Guangxi 530021, China; Pharmaceutical College, Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Dabing Xue
- School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi 530021, China; Intenational Nanobody Research Center of Guangxi, Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Siliang Duan
- School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi 530021, China; Intenational Nanobody Research Center of Guangxi, Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Aiqun Liu
- Intenational Nanobody Research Center of Guangxi, Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Xiaomei Yang
- School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi 530021, China; Intenational Nanobody Research Center of Guangxi, Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Xiaoqiong Hou
- School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi 530021, China; Intenational Nanobody Research Center of Guangxi, Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Xiaoling Lu
- School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi 530021, China; Intenational Nanobody Research Center of Guangxi, Guangxi Medical University, Nanning, Guangxi 530021, China; National Center for International Research of Biological Targeting Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi 530021, China.
| |
Collapse
|
|
12
|
Lee JH, Lee JH, Lim YS, Yeon JE, Song TJ, Yu SJ, Gwak GY, Kim KM, Kim YJ, Lee JW, Yoon JH. Sustained efficacy of adjuvant immunotherapy with cytokine-induced killer cells for hepatocellular carcinoma: an extended 5-year follow-up. Cancer Immunol Immunother 2019; 68:23-32. [PMID: 30232520 PMCID: PMC6326973 DOI: 10.1007/s00262-018-2247-4] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 09/17/2018] [Indexed: 12/15/2022]
Abstract
Our earlier multicenter randomized controlled trial showed that adjuvant immunotherapy with cytokine-induced killer (CIK) cells resulted in longer recurrence-free survival (RFS) and overall survival (OS) as well in patients who received curative treatment for hepatocellular carcinoma (HCC). In the present study, we determined if the efficacy of CIK cell therapy continued after end of repeated CIK cell injections. We performed a follow-up study of our preceding trial. We included 226 patients: 114 patients in the immunotherapy group (injection of 6.4 × 109 CIK cells, 16 times during 60 weeks) and 112 patients in the control group (no treatment) after potentially curative treatment for HCC. In total, 162 patients (89 of the immunotherapy group and 73 of controls) underwent an extended follow-up for 60 months after randomization of the last patient. The primary endpoint was RFS, and secondary endpoints included OS. During follow-up time of median 68.5 months (interquartile range 45.0-82.2 months), the immunotherapy group continued to show a significantly lower risk of recurrence or death [hazard ratio (HR) 0.67; 95% confidence interval (CI) 0.48-0.94; P = 0.009 by one-sided log-rank test]. At 5 years, RFS rate was 44.8% in the immunotherapy group and 33.1% in the control group. The risk of all-cause death was also lower in the immunotherapy group compared to the control group (HR 0.33; 95% CI 0.15-0.76; P = 0.006). In patients who received curative treatment for HCC, the significant improvement in RFS and OS as a result of adjuvant CIK cell immunotherapy lasted over 5 years without boosting.
Collapse
Affiliation(s)
- Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea
| | - Joon Hyeok Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Young-Suk Lim
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Jong Eun Yeon
- The Liver Center, Korea University Guro Hospital, Seoul, South Korea
| | - Tae-Jin Song
- Department of Surgery, Korea University Ansan Hospital, Ansan, Gyeonggi-do, South Korea
| | - Su Jong Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea
| | - Geum-Youn Gwak
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Kang Mo Kim
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea
| | - Jae Won Lee
- Department of Statistics, Korea University, Seoul, South Korea
| | - Jung-Hwan Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea.
| |
Collapse
|
|
13
|
Wu MY, Yiang GT, Cheng PW, Chu PY, Li CJ. Molecular Targets in Hepatocarcinogenesis and Implications for Therapy. J Clin Med 2018; 7:213. [PMID: 30104473 PMCID: PMC6112027 DOI: 10.3390/jcm7080213] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Revised: 08/07/2018] [Accepted: 08/10/2018] [Indexed: 02/07/2023] Open
Abstract
Hepatocarcinogenesis comprises of multiple, complex steps that occur after liver injury and usually involve several pathways, including telomere dysfunction, cell cycle, WNT/β-catenin signaling, oxidative stress and mitochondria dysfunction, autophagy, apoptosis, and AKT/mTOR signaling. Following liver injury, gene mutations, accumulation of oxidative stress, and local inflammation lead to cell proliferation, differentiation, apoptosis, and necrosis. The persistence of this vicious cycle in turn leads to further gene mutation and dysregulation of pro- and anti-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, IL-10, IL-12, IL-13, IL-18, and transforming growth factor (TGF)-β, resulting in immune escape by means of the NF-κB and inflammasome signaling pathways. In this review, we summarize studies focusing on the roles of hepatocarcinogenesis and the immune system in liver cancer. In addition, we furnish an overview of recent basic and clinical studies to provide a strong foundation to develop novel anti-carcinogenesis targets for further treatment interventions.
Collapse
Affiliation(s)
- Meng-Yu Wu
- Department of Emergency Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan.
- Department of Emergency Medicine, School of Medicine, Tzu Chi University, Hualien 970, Taiwan.
| | - Giuo-Teng Yiang
- Department of Emergency Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan.
- Department of Emergency Medicine, School of Medicine, Tzu Chi University, Hualien 970, Taiwan.
| | - Pei-Wen Cheng
- Yuh-Ing Junior College of Health Care & Management, Kaohsiung 807, Taiwan.
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan.
| | - Pei-Yi Chu
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 231, Taiwan.
- Department of Pathology, Show Chwan Memorial Hospital, Changhua 500, Taiwan.
- National Institute of Cancer Research, National Health Research Institutes, Miaoli 704, Taiwan.
| | - Chia-Jung Li
- Research Assistant Center, Show Chwan Memorial Hospital, Changhua 500, Taiwan.
| |
Collapse
|
|
14
|
Effect of dendritic cell-based immunotherapy on hepatocellular carcinoma: A systematic review and meta-analysis. Cytotherapy 2018; 20:975-989. [PMID: 30072299 DOI: 10.1016/j.jcyt.2018.06.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 05/17/2018] [Accepted: 06/07/2018] [Indexed: 01/30/2023]
Abstract
BACKGROUND AIMS Dendritic cell (DC)-based immunotherapy has recently been reported frequently in the treatment of hepatocellular carcinoma (HCC); however, its efficacy remains controversial. In this study, we aimed to evaluate the clinical efficacy of DC-based immunotherapy on HCC by conducting a systematic review and meta-analysis. METHODS PubMed, Cochrane Library, Embase and Web of Science were searched to identify clinical trials on DC-based immunotherapy for HCC published up to January 31, 2018. The articles were selected according to pre-established inclusion criteria and methodologic quality, and publication bias were evaluated. RESULTS A total of 1276 cases from 19 clinical trials were included. Compared with traditional treatment, further DC-based therapy enhanced the CD4+ T/CD8+ T ratio (standardized mean difference: 0.68, 95% confidence interval [CI] 0.46-0.89, P < 0.001); increased the 1-year, 18-month and 5-year progression-free survival (PFS) rate and the 1-year, 18-month and 2-year overall survival (OS) rate (relative risk > 1, P < 0.05), prolonged the median PFS time (median survival ratio [MSR]: 1.98, 95% CI: 1.60-2.46, P < 0.001) and median OS time (MSR: 1.72, 95% CI: 1.51-1.96, P < 0.001). Adverse reactions were mild. CONCLUSIONS DC-based therapy not only enhanced anti-tumor immunity, improved the survival rate and prolonged the survival time of HCC patients, but it was also safe. These findings will provide encouraging information for further development of DC-based immunotherapy as an adjuvant treatment for HCC. However, the results must be interpreted with caution because of the small study numbers, publication bias and the various of study designs, pre-treatment and therapeutic processes of DCs.
Collapse
|
|
15
|
Shang N, Figini M, Shangguan J, Wang B, Sun C, Pan L, Ma Q, Zhang Z. Dendritic cells based immunotherapy. Am J Cancer Res 2017; 7:2091-2102. [PMID: 29119057 PMCID: PMC5665855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 09/14/2017] [Indexed: 06/07/2023] Open
Abstract
Dendritic cells (DCs) are the most potent antigen-presenting cells, and tumor antigen-loaded DCs (DC-vaccines) can activate tumor-specific cytotoxic T lymphocytes (CTLs) in lymphatic tissues. DC vaccination is a newly emerging and potent form of cancer immunotherapy and has clinically relevant mechanisms of action with great potential for the systemic treatment of cancers. However, clinical trials have demonstrated relatively poor therapeutic efficacy. The efficacy of DC-vaccines is strongly influenced by various techniques for the priming antigen loading onto DCs and their ability to migrate to the draining lymph nodes (LNs). Therefore, it is critical to improve DC-vaccines homing to draining LNs after administration in order to optimize DC-based therapy for individual patients. This review underlines 1) appropriate strategy to load tumor antigens onto DCs and 2) to optimize vaccine administration methods to ensure loaded DCs can migrate to LNs, in particular, Intraperitoneal (IP) injection. IP injection of DC-based vaccine may be a potential regimen for gastrointestinal tumors including hepatocellular carcinoma (HCC) and pancreatic adenocarcinoma (PDAC) since huge populations of LNs are present throughout the gastrointestinal track. Which might improve the subsequent migration to LNs.
Collapse
Affiliation(s)
- Na Shang
- Department of Radiology, Feinberg School of Medicine, Northwestern UniversityChicago, IL, USA
| | - Matteo Figini
- Department of Radiology, Feinberg School of Medicine, Northwestern UniversityChicago, IL, USA
| | - Junjie Shangguan
- Department of Radiology, Feinberg School of Medicine, Northwestern UniversityChicago, IL, USA
| | - Bin Wang
- Department of Radiology, Feinberg School of Medicine, Northwestern UniversityChicago, IL, USA
| | - Chong Sun
- Department of Radiology, Feinberg School of Medicine, Northwestern UniversityChicago, IL, USA
| | - Liang Pan
- Department of Radiology, Feinberg School of Medicine, Northwestern UniversityChicago, IL, USA
| | - Quanhong Ma
- Department of Radiology, Feinberg School of Medicine, Northwestern UniversityChicago, IL, USA
| | - Zhuoli Zhang
- Department of Radiology, Feinberg School of Medicine, Northwestern UniversityChicago, IL, USA
- Robert H. Lurie Comprehensive Cancer CenterChicago, IL, USA
| |
Collapse
|
|
16
|
Cai XR, Li X, Lin JX, Wang TT, Dong M, Chen ZH, Jia CC, Hong YF, Lin Q, Wu XY. Autologous transplantation of cytokine-induced killer cells as an adjuvant therapy for hepatocellular carcinoma in Asia: an update meta-analysis and systematic review. Oncotarget 2017; 8:31318-31328. [PMID: 28412743 PMCID: PMC5458210 DOI: 10.18632/oncotarget.15454] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Accepted: 11/12/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND High recurrence rate after curative treatment is the major problem for hepatocellular carcinoma (HCC). Cytokine-induced killer cells (CIKs) therapy was extensively studied among HCC patients. However, the value of CIKs therapy was controversial. A meta-analysis was performed to investigate the efficacy of adjuvant CIKs after invasive treatments among HCC patients. METHODS We searched online for literatures studying sequential CIKs therapy for HCC patients. Recurrence-free survival (RFS), progress-free survival (PFS) and overall survival (OS) were set as the main endpoints. Both overall and subgroup analysis were accomplished. RESULTS A total of 12 clinical trials with 1,387 patients were included. The pooled analysis showed a significant improvement of RFS, PFS and OS in CIK group (HR 0.56, 95% CI 0.47-0.67, p<0.00001 for RFS; HR 0.53, 95% CI 0.40-0.69, p<0.00001 for PFS; HR 0.59, 95% CI 0.46-0.77, p<0.0001 for OS). The proportion of CD4+ T cells increased significantly, while CD8+ T cells decreased significantly after CIKs therapy (WMD 4.07, 95% CI 2.58-5.56, p<0.00001; WMD -2.84, 95% CI -4.67 to -1.01, p=0.002, respectively). No significant differences of adverse events between CIK and non-CIK group existed. CONCLUSIONS Conventionally invasive therapies combined with CIKs therapy could improve the prognosis of HCC patients, especially for RFS and PFS, with mild side effects. Optimizing patient selection shall be the direction in future studies.
Collapse
Affiliation(s)
- Xiu-Rong Cai
- Department of Medical Oncology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, People's Republic of China
- Guangdong provincial Key Laboratory of Liver Disease Research, Guangzhou 510630, People's Republic of China
| | - Xing Li
- Department of Medical Oncology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, People's Republic of China
- Guangdong provincial Key Laboratory of Liver Disease Research, Guangzhou 510630, People's Republic of China
| | - Jin-Xiang Lin
- Department of Medical Oncology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, People's Republic of China
| | - Tian-Tian Wang
- Department of Medical Oncology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, People's Republic of China
- Guangdong provincial Key Laboratory of Liver Disease Research, Guangzhou 510630, People's Republic of China
| | - Min Dong
- Department of Medical Oncology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, People's Republic of China
- Guangdong provincial Key Laboratory of Liver Disease Research, Guangzhou 510630, People's Republic of China
| | - Zhan-Hong Chen
- Department of Medical Oncology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, People's Republic of China
- Guangdong provincial Key Laboratory of Liver Disease Research, Guangzhou 510630, People's Republic of China
| | - Chang-Chang Jia
- Guangdong provincial Key Laboratory of Liver Disease Research, Guangzhou 510630, People's Republic of China
- Cell-gene Therapy Translational Medicine Research Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, People's Republic of China
| | - Ying-Fen Hong
- Department of Medical Oncology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, People's Republic of China
- Guangdong provincial Key Laboratory of Liver Disease Research, Guangzhou 510630, People's Republic of China
| | - Qu Lin
- Department of Medical Oncology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, People's Republic of China
- Guangdong provincial Key Laboratory of Liver Disease Research, Guangzhou 510630, People's Republic of China
| | - Xiang-Yuan Wu
- Department of Medical Oncology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, People's Republic of China
- Guangdong provincial Key Laboratory of Liver Disease Research, Guangzhou 510630, People's Republic of China
| |
Collapse
|
|
17
|
Nakamoto Y. Promising new strategies for hepatocellular carcinoma. Hepatol Res 2017; 47:251-265. [PMID: 27558453 DOI: 10.1111/hepr.12795] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 08/16/2016] [Accepted: 08/19/2016] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer death worldwide. It usually arises based on a background of chronic liver diseases, defined as the hypercarcinogenic state. The current treatment options for HCC ranging from locoregional treatments to chemotherapies, including sorafenib, effectively regulate the limited sizes and numbers of the nodules. However, these treatments remain unsatisfactory because they have insufficient antitumor effects on the large and numerous nodules associated with HCC and because of a high recurrence rate in the surrounding inflamed liver. To develop novel and promising therapies with higher antitumor effects, recent progress in identifying molecular targets and developing immunological procedures for HCC are reviewed. The molecular targets discussed include the intracellular signaling pathways of protein kinase B/mammalian target of rapamycin and RAS/RAF/mitogen-activated protein kinase, Wnt/β-catenin and glutamine synthetase, insulin-like growth factor, signal transducer and activator of transcription 3, nuclear factor-κB and telomerase reverse transcriptase, and c-MET. Immunological studies have focused mainly on target identification, T cells, natural killer cells, dendritic cells, natural killer T cells, and vaccine development.
Collapse
Affiliation(s)
- Yasunari Nakamoto
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| |
Collapse
|
|
18
|
Noveiry BB, Hirbod-Mobarakeh A, Khalili N, Hourshad N, Greten TF, Abou-Alfa GK, Rezaei N. Specific immunotherapy in hepatocellular cancer: A systematic review. J Gastroenterol Hepatol 2017; 32:339-351. [PMID: 27206802 PMCID: PMC6377153 DOI: 10.1111/jgh.13449] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/07/2016] [Indexed: 01/27/2023]
Abstract
BACKGROUND AND AIM In recent years, several novel immunotherapeutic approaches were developed and investigated in patients with hepatocellular carcinoma (HCC). We designed this systematic review, to evaluate clinical efficacy of specific immunotherapy in patients with HCC, according to the guidelines of Border of Immune Tolerance Education and Research Network (BITERN) and Cochrane collaboration. METHODS We searched Medline, Scopus, CENTRAL, TRIP, DART, OpenGrey, and ProQuest through the 9th of December 2015. One author reviewed and retrieved citations from these seven databases for irrelevant and duplicate studies, and two other authors independently extracted data from the studies and rated their quality. We collated study findings and calculated a weighted treatment effect across studies using Review Manager. RESULTS We found 12144 references in seven databases of which 21 controlled studies with 1885 HCC patients in different stages were included in this systematic review after the primary and secondary screenings. Overall, patients undergoing specific immunotherapy had significantly higher overall survival than those in control group (HR = 0.59; 95% CI = 0.47-0.76, P < 0.0001). There was a significant difference in recurrence-free survival between patients undergoing specific immunotherapy and patients in control groups and patients in immunotherapy groups overall had less recurrence than control group (HR = 0.54; 95% CI = 0.46-0.63, P < 0.00001). CONCLUSIONS Results of this systematic review based on the available literature suggest that overall specific immunotherapeutic approaches could be beneficiary for the treatment of patients with HCC. This further supports the current and ongoing evaluations of specific immunotherapies in the field.
Collapse
Affiliation(s)
- Behnoud Baradaran Noveiry
- Border of Immune Tolerance Education and Research Network (BITERN), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Armin Hirbod-Mobarakeh
- Border of Immune Tolerance Education and Research Network (BITERN), Universal Scientific Education and Research Network (USERN), Tehran, Iran,Molecular Immunology Research Center, Department of Immunology, School of Medicine, Tehran, Iran,Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nastaran Khalili
- Border of Immune Tolerance Education and Research Network (BITERN), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Niloufar Hourshad
- Border of Immune Tolerance Education and Research Network (BITERN), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Tim F Greten
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland
| | - Ghassan K Abou-Alfa
- Memorial Sloan Kettering Cancer Center, New York, USA,Weill Cornell Medical College, New York, USA
| | - Nima Rezaei
- Border of Immune Tolerance Education and Research Network (BITERN), Universal Scientific Education and Research Network (USERN), Tehran, Iran,Molecular Immunology Research Center, Department of Immunology, School of Medicine, Tehran, Iran,Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran,Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Sheffield, UK
| |
Collapse
|
|
19
|
Qiu Y, Yun MM, Dong X, Xu M, Zhao R, Han X, Zhou E, Yun F, Su W, Liu C, Zhao H, Tong X, Gao J, Ouyang X, Yun S. Combination of cytokine-induced killer and dendritic cells pulsed with antigenic α-1,3-galactosyl epitope-enhanced lymphoma cell membrane for effective B-cell lymphoma immunotherapy. Cytotherapy 2016; 18:91-8. [PMID: 26549382 DOI: 10.1016/j.jcyt.2015.09.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2015] [Revised: 09/14/2015] [Accepted: 09/21/2015] [Indexed: 01/01/2023]
Abstract
BACKGROUND AIMS Refractory B-cell lymphomas are difficult to successfully treat with current chemotherapeutic regimens; however, immunotherapy may be an effective form of treatment for these patients. METHODS Fourteen refractory lymphoma patients (age, 29-74 y) were enrolled in the trial. α-1,3-galactosyl (α-Gal) epitopes were synthesized on lymphoma cell membranes with the use of bovine recombinant α-1,3-galactosyltransferase (α-GT) and neuraminidase to enhance tumor immunogenicity. Subsequent incubation of processed cell membranes with autologous dendritic cells (DCs) in the presence of human serum containing abundant natural anti-α-Gal immunoglobulin G led to the effective phagocytosis of tumor membranes by DCs. The pulsed DCs and autologous cytokine-induced killer cells were then co-cultured to promote maximum cytotoxicity to lymphoma cells and were infused back into the donor lymphoma patients. Therapeutic responses were assessed by clinical observation, laboratory tests and a computed tomography scan at 6 months after treatment. RESULTS Complete and partial remission occurred in four and three patients, respectively. The disease status remained unchanged in five patients, and disease progression was observed in two patients. No serious side effects or autoimmune diseases were observed in any participants. Serum lactate dehydrogenase and β2-macroglobulin decreased in 11 and 14 patients, respectively. All patients showed robust systemic cytotoxicity in response to tumor lysate as measured by interferon-γ expression in peripheral blood mononuclear cells after treatment (P < 0.001). The number of peripheral immune effector cells (CD3(+)/CD4(+), CD8(+)/CD28(+) and CD16(+)/CD56(+) cells) increased significantly (P < 0.05) 3 months after treatment. CONCLUSIONS Lymphoma cell-specific α-Gal immunotherapy is safe, effective and has great potential for the treatment of refractory B-cell lymphoma.
Collapse
Affiliation(s)
- Ying Qiu
- Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Mark M Yun
- Heart of England National Health Service Foundation Trust, Bordesley Green, East Birmingham, UK
| | - Xuebin Dong
- Guy's and St Thomas' Hospital National Health Service Foundation Trust, London, UK
| | - Mingbao Xu
- Beijing Armed Police General Hospital, Beijing, China
| | - Ruidong Zhao
- Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Xia Han
- Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Erxia Zhou
- Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Feiyu Yun
- Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Wuyun Su
- Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Caixia Liu
- Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Haiyan Zhao
- Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Xin Tong
- Second Hospital of Lanzhou University, Lanzhou, China
| | - Jin Gao
- Jing-Meng Stem Cell Company, Beijing, China
| | - Xiaohui Ouyang
- Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Sheng Yun
- Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China.
| |
Collapse
|
|
20
|
Galili U. Natural anti-carbohydrate antibodies contributing to evolutionary survival of primates in viral epidemics? Glycobiology 2016; 26:1140-1150. [PMID: 27567275 DOI: 10.1093/glycob/cww088] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2016] [Revised: 08/09/2016] [Accepted: 08/16/2016] [Indexed: 12/17/2022] Open
Abstract
Humans produce multiple natural antibodies against carbohydrate antigens on gastrointestinal bacteria. Two such antibodies appeared in primates in recent geological times. Anti-Gal, abundant in humans, apes and Old-World monkeys, appeared 20-30 million years ago (mya) following inactivation of the α1,3GT gene (GGTA1). This gene encodes in other mammals the enzyme α1,3galactosyltransferase (α1,3GT) that synthesizes α-gal epitopes (Galα1-3Galβ1-4GlcNAc-R) which bind anti-Gal. Anti-Neu5Gc, found only in humans, appeared in hominins <6 mya, following elimination of N-glycolylneuraminic-acid (Neu5Gc) because of inactivation of CMAH, the gene encoding hydroxylase that converts N-acetylneuraminic-acid (Neu5Ac) into Neu5Gc. These antibodies, were initially produced in few individuals that acquired random mutations inactivating the corresponding genes and eliminating α-gal epitopes or Neu5Gc, which became nonself antigens. It is suggested that these evolutionary selection events were induced by epidemics of enveloped viruses, lethal to ancestral Old World primates or hominins. Such viruses presented α-gal epitopes or Neu5Gc, synthesized in primates that conserved active GGTA1 or CMAH, respectively, and were lethal to their hosts. The natural anti-Gal or anti-Neu5Gc antibodies, produced in offspring lacking the corresponding carbohydrate antigens, neutralized and destroyed viruses presenting α-gal epitopes or Neu5Gc. These antibodies further induced rapid, effective immune responses against virus antigens, thus preventing infections from reaching lethal stages. These epidemics ultimately resulted in extinction of primate populations synthesizing these carbohydrate antigens and their replacement with offspring populations lacking the antigens and producing protective antibodies against them. Similar events could mediate the elimination of various carbohydrate antigens, thus preventing the complete extinction of other vertebrate species.
Collapse
Affiliation(s)
- Uri Galili
- University of Massachusetts Medical School, Worcester, MA, USA
| |
Collapse
|
|
21
|
Yegin EG, Oymaci E, Karatay E, Coker A. Progress in surgical and nonsurgical approaches for hepatocellular carcinoma treatment. Hepatobiliary Pancreat Dis Int 2016; 15:234-56. [PMID: 27298100 DOI: 10.1016/s1499-3872(16)60097-8] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a complex and heterogeneous malignancy, frequently occurs in the setting of a chronically diseased organ, with multiple confounding factors making its management challenging. HCC represents one of the leading causes of cancer-related mortality globally with a rising trend of incidence in some of the developed countries, which indicates the need for better surgical and nonsurgical management strategies. DATA SOURCES PubMed database was searched for relevant articles in English on the issue of HCC management. RESULTS Surgical resection represents a potentially curative option for appropriate candidates with tumors detected at earlier stages and with well-preserved liver function. The long-term outcome of surgery is impaired by a high rate of recurrence. Surgical approaches are being challenged by local ablative therapies such as radiofrequency ablation and microwave ablation in selected patients. Liver transplantation offers potential cure for HCC and also correction of underlying liver disease, and minimizes the risk of recurrence, but is reserved for patients within a set of criteria proposed for a prudent allocation in the shortage of donor organs. Transcatheter locoregional therapies have become the palliative standard allowing local control for intermediate stage patients with noninvasive multinodular or large HCC who are beyond the potentially curative options. The significant survival benefit with the multikinase inhibitor sorafenib for advanced HCC has shifted the direction of research regarding systemic treatment toward molecular therapies targeting the disregulated pathways of hepatocarcinogenesis. Potential benefit is suggested from simultaneous or sequential multimodal therapies, and optimal combinations are being investigated. Despite the striking progress in preclinical studies of HCC immunotherapy and gene therapy, extensive clinical trials are required to achieve successful clinical applications of these innovative approaches. CONCLUSION Treatment decisions have become increasingly complex for HCC with the availability of multiple surgical and nonsurgical therapeutic options and require a comprehensive, multidisciplinary approach.
Collapse
Affiliation(s)
- Ender Gunes Yegin
- Department of Gastroenterology, Bozyaka Training and Research Hospital, Izmir 35170, Turkey.
| | | | | | | |
Collapse
|
|
22
|
Albertini MR, Ranheim EA, Zuleger CL, Sondel PM, Hank JA, Bridges A, Newton MA, McFarland T, Collins J, Clements E, Henry MB, Neuman HB, Weber S, Whalen G, Galili U. Phase I study to evaluate toxicity and feasibility of intratumoral injection of α-gal glycolipids in patients with advanced melanoma. Cancer Immunol Immunother 2016; 65:897-907. [PMID: 27207605 DOI: 10.1007/s00262-016-1846-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Accepted: 05/08/2016] [Indexed: 12/14/2022]
Abstract
Effective uptake of tumor cell-derived antigens by antigen-presenting cells is achieved pre-clinically by in situ labeling of tumor with α-gal glycolipids that bind the naturally occurring anti-Gal antibody. We evaluated toxicity and feasibility of intratumoral injections of α-gal glycolipids as an autologous tumor antigen-targeted immunotherapy in melanoma patients (pts). Pts with unresectable metastatic melanoma, at least one cutaneous, subcutaneous, or palpable lymph node metastasis, and serum anti-Gal titer ≥1:50 were eligible for two intratumoral α-gal glycolipid injections given 4 weeks apart (cohort I: 0.1 mg/injection; cohort II: 1.0 mg/injection; cohort III: 10 mg/injection). Monitoring included blood for clinical, autoimmune, and immunological analyses and core tumor biopsies. Treatment outcome was determined 8 weeks after the first α-gal glycolipid injection. Nine pts received two intratumoral injections of α-gal glycolipids (3 pts/cohort). Injection-site toxicity was mild, and no systemic toxicity or autoimmunity could be attributed to the therapy. Two pts had stable disease by RECIST lasting 8 and 7 months. Tumor nodule biopsies revealed minimal to no change in inflammatory infiltrate between pre- and post-treatment biopsies except for 1 pt (cohort III) with a post-treatment inflammatory infiltrate. Two and four weeks post-injection, treated nodules in 5 of 9 pts exhibited tumor cell necrosis without neutrophilic or lymphocytic inflammatory response. Non-treated tumor nodules in 2 of 4 evaluable pts also showed necrosis. Repeated intratumoral injections of α-gal glycolipids are well tolerated, and tumor necrosis was seen in some tumor nodule biopsies after tumor injection with α-gal glycolipids.
Collapse
Affiliation(s)
- Mark R Albertini
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA.
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
- Medical Service, William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.
- University of Wisconsin Clinical Sciences Center, Room K6/530, 600 Highland Avenue, Madison, WI, 53792, USA.
| | - Erik A Ranheim
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
- Department of Pathology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Cindy L Zuleger
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Paul M Sondel
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Jacquelyn A Hank
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Alan Bridges
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
- Medical Service, William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
| | - Michael A Newton
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
- Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Thomas McFarland
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | | | - Erin Clements
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
| | - Mary Beth Henry
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Heather B Neuman
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Sharon Weber
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Giles Whalen
- Department of Surgery, University of Massachusetts Medical School, Worcester, MA, USA
| | - Uri Galili
- Department of Surgery, University of Massachusetts Medical School, Worcester, MA, USA
| |
Collapse
|
|
23
|
Abstract
Advanced hepatocellular carcinoma (HCC) is a serious therapeutic challenge and targeted therapies only provide a modest benefit in terms of overall survival. Novel approaches are urgently needed for the treatment of this prevalent malignancy. Evidence demonstrating the antigenicity of tumour cells, the discovery that immune checkpoint molecules have an essential role in immune evasion of tumour cells, and the impressive clinical results achieved by blocking these inhibitory receptors, are revolutionizing cancer immunotherapy. Here, we review the data on HCC immunogenicity, the mechanisms for HCC immune subversion and the different immunotherapies that have been tested to treat HCC. Taking into account the multiplicity of hyperadditive immunosuppressive forces acting within the HCC microenvironment, a combinatorial approach is advised. Strategies include combinations of systemic immunomodulation and gene therapy, cell therapy or virotherapy.
Collapse
|
|
24
|
Tsuchiya N, Sawada Y, Endo I, Uemura Y, Nakatsura T. Potentiality of immunotherapy against hepatocellular carcinoma. World J Gastroenterol 2015; 21:10314-10326. [PMID: 26420958 PMCID: PMC4579878 DOI: 10.3748/wjg.v21.i36.10314] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Revised: 05/21/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, is the fifth most common cancer worldwide and the second leading cause of cancer-related death. Despite the high incidence, treatment options remain limited for advanced HCC, and as a result prognosis continues to be poor. Current therapeutic options, surgery, chemotherapy and radiotherapy, have only modest efficacy. New treatment modalities to prolong survival and to minimize the risk of adverse response are desperately needed for patients with advanced HCC. Tumor immunotherapy is a promising, novel treatment strategy that may lead to improvements in both treatment-associated toxicity and outcome. The strategies have developed in part through genomic studies that have yielded candidate target molecules and in part through basic biology studies that have defined the pathways and cell types regulating immune response. Here, we summarize the various types of HCC immunotherapy and argue that the newfound field of HCC immunotherapy might provide critical advantages in the effort to improve prognosis of patients with advanced HCC. Already several immunotherapies, such as tumor-associated antigen therapy, immune checkpoint inhibitors and cell transfer immunotherapy, have demonstrated safety and feasibility in HCC patients. Unfortunately, immunotherapy currently has low efficacy in advanced stage HCC patients; overcoming this challenge will place immunotherapy at the forefront of HCC treatment, possibly in the near future.
Collapse
|
|
25
|
Schmeel LC, Schmeel FC, Coch C, Schmidt-Wolf IGH. Cytokine-induced killer (CIK) cells in cancer immunotherapy: report of the international registry on CIK cells (IRCC). J Cancer Res Clin Oncol 2015; 141:839-49. [PMID: 25381063 DOI: 10.1007/s00432-014-1864-3] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Accepted: 10/21/2014] [Indexed: 01/05/2023]
Abstract
PURPOSE Cytokine-induced killer (CIK) cells represent an exceptional T cell population uniting a T cell and natural killer cell like phenotype in their terminally differentiated CD3(+)CD56(+) subset, which features non-MHC-restricted tumor-killing activity. CIK cells are expandable from peripheral blood mononuclear cells and mature following the addition of certain cytokines. CIK cells have provided encouraging results in initial clinical studies and revealed synergistic antitumor effects when combined with standard therapeutic procedures. METHODS Therefore, we established the international registry on CIK cells in order to collect and evaluate data about clinical trials using CIK cells for the treatment of cancer patients. Moreover, our registry is expected to set new standards on the reporting of results from clinical trials using CIK cells. Clinical responses, overall survival (OS), adverse reactions and immunologic effects were analyzed in 45 studies present in our database. These studies investigated 22 different tumor entities altogether enrolling 2,729 patients. RESULTS A mean response rate of 39 % and significantly increased OS, accompanied by an improved quality of life, were reported. Interestingly, side effects of CIK cell treatment were minor. Mild fevers, chills, headache and fatigue were, however, seen regularly after CIK cell infusion. Moreover, CIK cells revealed numerous immunologic effects such as changes in T cell subsets, tumor markers, cytokine secretion and HBV viral load. CONCLUSION Due to their easy availability and potent antitumor activity, CIK cells emerged as a promising immunotherapy approach in oncology and may gain major importance on the prognosis of cancer.
Collapse
Affiliation(s)
- Leonard Christopher Schmeel
- Department of Internal Medicine III, Center for Integrated Oncology (CIO), University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Sigmund-Freud-Straße 25, 53105, Bonn, Germany
| | | | | | | |
Collapse
|
|
26
|
Monocyte-derived dendritic cells from cirrhotic patients retain similar capacity for maturation/activation and antigen presentation as those from healthy subjects. Cell Immunol 2015; 295:36-45. [PMID: 25734547 DOI: 10.1016/j.cellimm.2015.02.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2014] [Revised: 02/13/2015] [Accepted: 02/14/2015] [Indexed: 01/27/2023]
Abstract
UNLABELLED Few studies have investigated the impact of liver cirrhosis on dendritic cell function. The purpose of this study was to compare the activation and antigen-presentation capacity of monocyte-derived dendritic cells (MoDC) from cirrhotic patients (CIR) relative to healthy donors (HD). MoDC from CIR and HD were matured, phenotyped, irradiated and pulsed with 15mer peptides for two hepatocellular carcinoma-related antigens, alphafetoprotein and glypican-3, then co-cultured with autologous T-cells. Expanded T-cells were evaluated by interferon-gamma ELISPOT and intracellular staining. 15 CIR and 7 HD were studied. While CD14+ monocytes from CIR displayed enhanced M2 polarization, under MoDC-polarizing conditions, we identified no significant difference between HD and CIR in maturation-induced upregulation of co-stimulation markers. Furthermore, no significant differences were observed between CIR and HD in subsequent expansion of tumor antigen-specific IFNγ+ T-cells. CONCLUSION MoDCs isolated from cirrhotic individuals retain similar capacity for in vitro activation, maturation and antigen-presentation as those from healthy donors.
Collapse
|
|
27
|
Ding ZY, Wei YQ. Immunopathology of Hepatobiliary Tumors and Immunotherapy of Liver Cancers. CANCER IMMUNOLOGY 2015:199-215. [DOI: 10.1007/978-3-662-46410-6_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
28
|
Abstract
Newer immunotherapy agents may break the barrier that tumors create to evade the attack from the immune system. Dendritic cell vaccination has shown encouraging clinical activity and a favorable safety profile in advanced tumor stages. However, optimal cell maturation status, choice of tumor antigens and route of administration have not been established. Single or multiple peptides derived from tumor-associated antigens may also be used for cancer vaccination. Intratumoral delivery of oncolytic viruses expressing immunostimulating cytokines like GM-CSF have produced stimulating clinical results that need further verification. But it is probably T-cell checkpoint modulation with monoclonal antibodies that has attracted the highest expectations. Promising activity has been reported for tremelimumab, a CTLA-4 inhibitor, and a clinical trial testing the PD-1 antibody nivolumab is underway. Future progress will probably come from a better understanding of the mechanisms of cancer-related immunosuppression, improvement in agents and strategies and combination of the available therapeutic tools.
Collapse
Affiliation(s)
- Bruno Sangro
- Liver Unit, Clínica Universidad de Navarra, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD); Avda. Pio XII 36. 31008-Pamplona, Spain.,Liver Unit, Clínica Universidad de Navarra, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD); Avda. Pio XII 36. 31008-Pamplona, Spain
| | - Daniel Palmer
- The Department of Molecular & Clinical Cancer Medicine, University of Liverpool, Liverpool, L69 3GA, UK.,The Department of Molecular & Clinical Cancer Medicine, University of Liverpool, Liverpool, L69 3GA, UK
| | - Ignacio Melero
- Departments of Oncology & Immunology, Centro de Investigación Médica Aplicada y Clínica Universidad de Navarra. Avda. Pio XII, 55. 31008-Pamplona, Spain.,Departments of Oncology & Immunology, Centro de Investigación Médica Aplicada y Clínica Universidad de Navarra. Avda. Pio XII, 55. 31008-Pamplona, Spain
| |
Collapse
|
|
29
|
Song S, Yuan P, Li P, Wu H, Lu J, Wei W. Dynamic analysis of tumor-associated immune cells in DEN-induced rat hepatocellular carcinoma. Int Immunopharmacol 2014; 22:392-9. [PMID: 25066760 DOI: 10.1016/j.intimp.2014.07.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Revised: 06/16/2014] [Accepted: 07/08/2014] [Indexed: 12/14/2022]
Abstract
Hepatocellular carcinoma (HCC) is an aggressive disease with poor prognosis and limited methods to predict patient survival. Immune cells infiltrating tumors are known to impact tumor progression. Here, we analyzed the phenotype and function of dendritic cells (DCs), and the frequency of IL-10-producing regulatory B cells (Breg) and Foxp3(+) regulatory T cells (Treg) in different stages of N-nitrosodiethylamine (DEN)-induced rat HCC in order to understand their roles in this disease. 4weeks following DEN treatment, no significant differences in CD80 and CD86 expression were found on DCs from HCC rats and normal rats but 12 and 16weeks following DEN treatment, the expression of CD80, CD86 and MHCII on DCs of HCC rats was significantly decreased. We also found that the frequency of IL-10-producing Breg and CD4(+)CD25(+)Foxp3(+) Treg in HCC rats was obviously increased during all of these three stages. In addition, the bone-marrow derived DCs (BMDCs) from HCC rats displayed lower ability in activating T cells and an increase in IL-10 secretion. No differences in IL-12 level and endocytosis ability were found on BMDCs from HCC rats and normal rats. Our results suggest that the dysfunction of DCs and the increase of IL-10-producing Breg and Foxp3(+) Treg might play important roles in HCC progression.
Collapse
Affiliation(s)
- Shasha Song
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, PR China
| | - Pingfan Yuan
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, PR China
| | - Peipei Li
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, PR China
| | - Huaxun Wu
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, PR China
| | - Jingtao Lu
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, PR China.
| | - Wei Wei
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, PR China.
| |
Collapse
|
|
30
|
Jäkel CE, Schmidt-Wolf IGH. An update on new adoptive immunotherapy strategies for solid tumors with cytokine-induced killer cells. Expert Opin Biol Ther 2014; 14:905-16. [PMID: 24673175 DOI: 10.1517/14712598.2014.900537] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
INTRODUCTION Cytokine-induced killer (CIK) cells are mainly CD3(+)CD56(+) NKT cells exhibiting non-MHC-restricted cytotoxicity against a broad range of tumors. Much research is going on to improve CIK cell effectivity and to evaluate the clinical benefit of different combinations with conventional therapies. AREAS COVERED This review provides an update on in vitro/in vivo studies and clinical trials applying CIK cells for the treatment of solid tumors. This comprises attempts using additional cytokines, genetic engineering and combinations with different conventional and modern therapies. EXPERT OPINION Since our last review, much effort has been made to improve CIK cell cytotoxicity and clinical effectivity. Targeted CIK cell therapy and combinations of CIK cells with antiangiogenic drugs or oncolytic viruses are examples of recent outstanding achievements in the field of adoptive CIK cell therapy. The clinical application of CIK cells in combination with conventional therapies, especially, obtained promising results. However, the best combination and the optimal therapy schedule have yet to be defined.
Collapse
Affiliation(s)
- Clara E Jäkel
- University Hospital Bonn, Center for Integrated Oncology (CIO) , Bonn , Germany
| | | |
Collapse
|
|
31
|
Song S, Yuan P, Wu H, Chen J, Fu J, Li P, Lu J, Wei W. Dendritic cells with an increased PD-L1 by TGF-β induce T cell anergy for the cytotoxicity of hepatocellular carcinoma cells. Int Immunopharmacol 2014; 20:117-23. [PMID: 24606770 DOI: 10.1016/j.intimp.2014.02.027] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Revised: 01/21/2014] [Accepted: 02/19/2014] [Indexed: 11/28/2022]
Abstract
The effects of TGF-β on dendritic cells (DCs) in the tumor microenvironment are not well-understood. In this study, we investigated the effect of TGF-β on the induction of programmed death ligand-1 (PD-L1) expression in DCs and the underlying mechanism, and we further investigated the influence of the DCs with PD-L1 expression altered by TGF-β on T-cell immunity. We determined that TGF-β increased the expression of PD-L1 and signal transducers and activators of transcription 3 (STAT3) in DCs in both a time- and dose-dependent manner, and the expression of PD-L1 was decreased significantly after STAT3 blockade. In addition, TGF-β-treated DCs induced the apoptosis of T cells and increased the percentage of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs). Furthermore, the cytotoxicity of T cells against mice hepatocellular carcinoma cells (Hepa) was obviously suppressed. These results suggest that PD-L1 may play an important role in TGF-β-induced immune dysfunction, which finally results in a failure in the anti-tumor responses, and the TGF-β-STAT3-PD-L1 signaling pathway may contribute to novel therapeutic targets for the tumor based on DCs.
Collapse
Affiliation(s)
- Shasha Song
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, PR China
| | - Pingfan Yuan
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, PR China
| | - Huaxun Wu
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, PR China
| | - Jingyu Chen
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, PR China
| | - Jingjing Fu
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, PR China
| | - Peipei Li
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, PR China
| | - Jingtao Lu
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, PR China.
| | - Wei Wei
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, PR China.
| |
Collapse
|
|
32
|
Jäkel CE, Vogt A, Gonzalez-Carmona MA, Schmidt-Wolf IGH. Clinical studies applying cytokine-induced killer cells for the treatment of gastrointestinal tumors. J Immunol Res 2014; 2014:897214. [PMID: 24741629 PMCID: PMC3987941 DOI: 10.1155/2014/897214] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Accepted: 11/30/2013] [Indexed: 12/22/2022] Open
Abstract
Tumors of the gastrointestinal system represent a significant share of solid tumors worldwide. Despite the advances in diagnosis and treatment, the prognosis of gastrointestinal tumors is still very poor and improved therapies are indispensable. Cytokine-induced killer (CIK) cells are feasible for an immunotherapeutic approach as they are easily available and have an advantageous biologic profile; they are rapidly proliferating and their high cytotoxicity is non-MHC-restricted. We summarize and discuss twenty recent clinical studies applying CIK cells for the treatment of gastric, pancreatic, hepatocellular, and colorectal cancer. Autologous CIK cells were transfused intravenously, intraperitoneally, or via the common hepatic artery. In all studies side effects and toxicity of CIK cell therapy were mild and easily controllable. The combination of CIK cell therapy with conventional adjuvant or palliative therapies was superior to the standard therapy alone, indicating the benefit of CIK cell therapy for cancer patients. Thus, CIK cells represent a promising immunotherapy for the treatment of gastrointestinal tumors. The optimal treatment schedule and ideal combination with conventional therapies should be evaluated in further clinical studies.
Collapse
Affiliation(s)
- Clara E Jäkel
- Center for Integrated Oncology (CIO), University Medical Center Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany
| | - Annabelle Vogt
- Department of Internal Medicine I, University Medical Center Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany
| | - Maria A Gonzalez-Carmona
- Department of Internal Medicine I, University Medical Center Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany
| | - Ingo G H Schmidt-Wolf
- Center for Integrated Oncology (CIO), University Medical Center Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany
| |
Collapse
|
|
33
|
Wirth TC. Spontaneous and therapeutic immune responses in hepatocellular carcinoma: implications for current and future immunotherapies. Expert Rev Gastroenterol Hepatol 2014; 8:101-10. [PMID: 24410473 DOI: 10.1586/17474124.2014.862497] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Hepatocellular carcinoma (HCC) represents a major health problem in the world, ranking fifth in incidence and third in cancer-related deaths. Due to the unique immunosuppressive microenvironment of the liver, HCC develops in an immunotolerant niche posing an important obstacle to immunotherapy. A number of studies, however, have shown immunogenic properties of HCC by demonstrating spontaneous adaptive immune responses during tumor formation and progression. Furthermore, studies examining immune responses during HCC therapy have revealed that conventional treatments such as surgical resection, locoregional therapy and systemic therapy with antibodies, small molecules or chemotherapy induce adaptive immune responses that contribute to therapeutic effects. These observations have provided a basis for clinical trials involving adoptive transfers of T cells or natural killer cells, peptide and dendritic cell vaccinations or, more recently, virotherapy and inhibition of co-inhibitory molecules. Here, spontaneous and therapeutic immune responses in HCC and their implication for current and future immunotherapies are discussed.
Collapse
Affiliation(s)
- Thomas C Wirth
- Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, 30625 Hannover, Germany
| |
Collapse
|
|
34
|
Zhang YH, Dong XQ, Zou Y, Wu JL, Bai LP, Liu JH, Wang M. Role of TGF-β in metastasis of hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2013; 21:2508-2514. [DOI: 10.11569/wcjd.v21.i25.2508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of transforming growth factor-b (TGF-β) derived from regulatory T cells in metastasis of hepatocellular carcinoma.
METHODS: Forty-eight primary liver cancer patients without metastasis, 32 liver cancer patients with distant metastasis (17 cases of lung metastasis and 15 cases of brain metastasis), and 54 healthy subjects were included in this study. Serum concentrations of interleukin-10 (IL-10), IL-17A, tumor necrosis factor-α (TNF-α) and TGF-β were measured by ELISA. Levels of TGF-β in peripheral blood mononuclear cells (PBMCs) and regulatory T cells were determined by flow cytometry and RT-PCR, respectively.
RESULTS: Serum levels of TNF-α and TGF-β were significantly increased in liver cancer patients with metastasis compared with normal controls. Serum level of TGF-β was significantly higher in liver cancer patients with metastasis than in liver cancer without metastasis and normal controls (both P < 0.05). Furthermore, we confirmed that TGF-β in liver cancer patients with metastasis was derived from regulatory T cells by quantitative real-time PCR and flow cytometry.
CONCLUSION: TGF-β has a dual role in tumorigenesis; it acts as a tumor suppressor in early stage but promotes tumor cell invasion and metastasis in advanced stage. High level of TGF-β was found only in liver cancer patients with metastasis.
Collapse
|
|
35
|
Current World Literature. Curr Opin Allergy Clin Immunol 2012; 12:440-5. [DOI: 10.1097/aci.0b013e328356708d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
|