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Trojan A, Lone YC, Briceno I, Trojan J. Anti-Gene IGF-I Vaccines in Cancer Gene Therapy: A Review of a Case of Glioblastoma. Curr Med Chem 2024; 31:1983-2002. [PMID: 38031775 DOI: 10.2174/0109298673237968231106095141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 06/27/2023] [Accepted: 10/10/2023] [Indexed: 12/01/2023]
Abstract
OBJECTIVE Vaccines for the deadliest brain tumor - glioblastoma (GBM) - are generally based on targeting growth factors or their receptors, often using antibodies. The vaccines described in the review were prepared to suppress the principal cancer growth factor - IGF-I, using anti-gene approaches either of antisense (AS) or of triple helix (TH) type. Our objective was to increase the median survival of patients treated with AS and TH cell vaccines. METHODOLOGY The cells were transfected in vitro by both constructed IGF-I AS and IGF-I TH expression episomal vectors; part of these cells was co-cultured with plant phytochemicals, modulating IGF-I expression. Both AS and TH approaches completely suppressed IGF-I expression and induced MHC-1 / B7 immunogenicity related to the IGF-I receptor signal. RESULTS This immunogenicity proved to be stronger in IGF-I TH than in IGF-I AS-prepared cell vaccines, especially in TH / phytochemical cells. The AS and TH vaccines generated an important TCD8+ and TCD8+CD11b- immune response in treated GBM patients and increased the median survival of patients up to 17-18 months, particularly using TH vaccines; in some cases, 2- and 3-year survival was reported. These clinical results were compared with those obtained in therapies targeting other growth factors. CONCLUSION The anti-gene IGF-I vaccines continue to be applied in current GBM personalized medicine. Technical improvements in the preparation of AS and TH vaccines to increase MHC-1 and B7 immunogenicity have, in parallel, allowed to increase in the median survival of patients.
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Affiliation(s)
- Annabelle Trojan
- INSERM UMR 1197, Cancer Center & University of Paris / Saclay, PO Box: 94802 Villejuif, France
- Faculty of Medicine, University of Cartagena, PO Box: 130014 Cartagena de Indias, Colombia
| | - Yu-Chun Lone
- INSERM UMR 1197, Cancer Center & University of Paris / Saclay, PO Box: 94802 Villejuif, France
- CEDEA / ICGT - Center of Oncological Diseases Diagnosis, PO Box: 110231 Bogota, Colombia
| | - Ignacio Briceno
- Faculty of Medicine, University of La Sabana, PO Box: 250008 Chia, Colombia
| | - Jerzy Trojan
- INSERM UMR 1197, Cancer Center & University of Paris / Saclay, PO Box: 94802 Villejuif, France
- CEDEA / ICGT - Center of Oncological Diseases Diagnosis, PO Box: 110231 Bogota, Colombia
- National Academy of Medicine - ANM, PO Box: 75272 Paris, France
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Fusing Artificial Cell Compartments and Lipid Domains Using Optical Traps: A Tool to Modulate Membrane Composition and Phase Behaviour. MICROMACHINES 2020; 11:mi11040388. [PMID: 32272670 PMCID: PMC7230983 DOI: 10.3390/mi11040388] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 03/25/2020] [Accepted: 03/28/2020] [Indexed: 01/26/2023]
Abstract
New technologies for manipulating biomembranes have vast potential to aid the understanding of biological phenomena, and as tools to sculpt novel artificial cell architectures for synthetic biology. The manipulation and fusion of vesicles using optical traps is amongst the most promising due to the level of spatiotemporal control it affords. Herein, we conduct a suite of feasibility studies to show the potential of optical trapping technologies to (i) modulate the lipid composition of a vesicle by delivering new membrane material through fusion events and (ii) manipulate and controllably fuse coexisting membrane domains for the first time. We also outline some noteworthy morphologies and transitions that the vesicle undergoes during fusion, which gives us insight into the mechanisms at play. These results will guide future exploitation of laser-assisted membrane manipulation methods and feed into a technology roadmap for this emerging technology.
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Chakraborty D, Pati S, Bose S, Dhar S, Dutta S, Sa G. Cancer immunotherapy: present scenarios and the future of immunotherapy. THE NUCLEUS 2019. [DOI: 10.1007/s13237-019-00273-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
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Shi M, Su L, Hao S, Guo X, Xiang J. Fusion Hybrid of Dendritic Cells and Engineered Tumor Cells Expressing Interleukin-12 Induces Type 1 Immune Responses against Tumor. TUMORI JOURNAL 2019; 91:531-8. [PMID: 16457153 DOI: 10.1177/030089160509100614] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Aims and Background Dendritic cell (DC)-tumor fusion hybrid vaccinees that facilitate antigen presentation represent a novel powerful strategy in cancer immunotherapy. Preclinical studies have demonstrated that IL-12 promotes specific antitumor immunity mediated by T cells in several types of tumors. In the present study, we investigated the antitumor immunity derived from vaccination of fusion hybrids between DCs and engineered J558/IL-12 myeloma cells secreting Th1 cytokine IL-12. Methods The expression vector pcDNA-IL-12 was generated and transfected into J558 myeloma cells and then bone marrow-derived DCs were fused with engineered J558/IL-12 cells. The antitumor immunity derived from vaccination of the fusion hybrid DC/J558/IL-12 was evaluated in vitro and in vivo. Results DC/J558/IL-12 cells secreted recombinant IL-12 (1.6 ng/mL), and inoculation of BALB/c mice with DC/J558/IL-12 hybrid induced a Th1 dominant immune response and resulted in tumor regression. Immunization of mice with engineered DC/J558/IL-12 hybrid elicited stronger J558 tumor-specific cytotoxic T lymphocyte (CTL) responses in vitro as well as more potent protective immunity against J558 tumor challenge in vivo than immunization with the mixture of DCs and J558/IL-12, J558/IL-12 and J558, respectively. Furthermore, the antitumor immunity mediated by DC/J558/1L-12 tumor cell vaccination in vivo appeared to be dependent on CD8+ CTL. Conclusions These results demonstrate that the engineered fusion hybrid vaccines that combine Th1 cytokine gene-modified tumor cells with DCs may be an attractive strategy for cancer immunotherapy.
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Affiliation(s)
- Meiqing Shi
- Research Unit, Saskatchewan Cancer Agency, Department of Oncology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
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Abstract
With the spotlight on cancer immunotherapy and the expanding use of immune checkpoint inhibitors, strategies to improve the response rate and duration of current cancer immunotherapeutics are highly sought. In that sense, investigators around the globe have been putting spurs on the development of effective cancer vaccines in humans after decades of efforts that led to limited clinical success. In more than three decades of research in pursuit of targeted and personalized immunotherapy, several platforms have been incorporated into the list of cancer vaccines from live viral or bacterial agents harboring antigens to synthetic peptides with the hope of stronger and durable immune responses that will tackle cancers better. Unlike adoptive cell therapy, cancer vaccines can take advantage of using a patient's entire immune system that can include more than engineered receptors or ligands in developing antigen-specific responses. Advances in molecular technology also secured the use of genetically modified genes or proteins of interest to enhance the chance of stronger immune responses. The formulation of vaccines to increase chances of immune recognition such as nanoparticles for peptide delivery is another area of great interest. Studies indicate that cancer vaccines alone may elicit tumor-specific cellular or humoral responses in immunologic assays and even regression or shrinkage of the cancer in select trials, but novel strategies, especially in combination with other cancer therapies, are under study and are likely to be critical to achieve and optimize reliable objective responses and survival benefit. In this review, cancer vaccine platforms with different approaches to deliver tumor antigens and boost immunity are discussed with the intention of summarizing what we know and what we need to improve in the clinical trial setting.
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Affiliation(s)
- Hoyoung M. Maeng
- Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Jay A. Berzofsky
- Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
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Stefanski HE, Mathur A. Decreased Expression and Function of Vß6+ and Vß14+ T Cells is Associated with Decreased Th1 Cytokine Production in Mice with Plasma Cell Tumors. TUMORI JOURNAL 2018; 82:22-6. [PMID: 8623498 DOI: 10.1177/030089169608200104] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Aims and background We have found that polyclonally stimulated T cells from mice bearing ascitic plasma cell tumors demonstrate specific decreases in Th1 cytokine production. In this study we investigated whether loss of Th1 responses in the plasma cell tumor system was associated with alterations in the Vß T cell receptor repertoire. Methods We examined the cell surface expression of specific Vß expressing splenic CD4+ or CD8+ T cells from normal and tumor bearing mice using direct three-color flowcytometry. In order to determine the Th phenotype of Vß expressing T cells, we enriched for Vß6, Vß14 or Vß8.1,8.2 cells, polyclonally stimulated them and measured the levels of the cytokines interleukin-4 (IL-4), IL-2 and interferon-gamma (IFN-gamma). Results We find that there is a statistically significant decrease in the frequency of Vß6+ and Vß14+ CD8+ T cells in mice bearing a plasma cell tumor (B53) as compared to normals (p<0.05). Stimulated Vß6+ and Vß14+ T cells exhibit an exclusively Th1 phenotype. Stimulated Vß6+ and Vß14+ T cells from B53 mice are deficient in production of the Th1 cytokines. In contrast, stimulated Vß8.1,8.2+ T cells, which are not altered in B53 mice, reveal a Th2 phenotype. Conclusions The significance of this study is our demonstration that decreased expression and function of Vß6+ and Vß14+ T cells may be, at least in part, responsible for the decrease in the production of IL-2 and/or IFN-gamma observed in hosts with tumors.
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Affiliation(s)
- H E Stefanski
- Department of Oral Science, University of Minnesota, Minneapolis, MN, USA
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Jones HP, Aldridge B, Boss-Williams K, Weiss JM. A role for B cells in facilitating defense against an NK cell-sensitive lung metastatic tumor is revealed by stress. J Neuroimmunol 2017; 313:99-108. [PMID: 29153616 DOI: 10.1016/j.jneuroim.2017.10.017] [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: 02/02/2017] [Revised: 10/27/2017] [Accepted: 10/28/2017] [Indexed: 11/28/2022]
Abstract
Stressors impair immune defenses and pose risks among cancer patients. Natural Killer cells are not the sole immune defense against tumor development. Utilizing an NK-sensitive tumor model, this study evaluated immune effects to stress and determined whether lung metastasis resulted from B cells' inability to augment tumorlytic function. Lung metastasis directly correlated with delayed lung B cell accumulation compared to NK, and T cells. Decreased interleukin-12 cytokine and CD80+ molecule expression by B cells correlated with decreased tumor lysis and increased tumor development. Thus, tumor defenses in the lung given stress exposure can depend on the B cell function.
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Affiliation(s)
- Harlan P Jones
- Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX, USA; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
| | - Beau Aldridge
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA
| | - Katherine Boss-Williams
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA
| | - Jay M Weiss
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA
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Yeheskely-Hayon D, Minai L, Golan L, Dann EJ, Yelin D. Optically induced cell fusion using bispecific nanoparticles. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2013; 9:3771-3777. [PMID: 23788508 DOI: 10.1002/smll.201300696] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/05/2013] [Revised: 04/15/2013] [Indexed: 06/02/2023]
Abstract
Redirecting the immune system to eliminate tumor cells is a promising alternative to traditional cancer therapies, most often requiring direct interaction between an immune system effector cell and its target. Herein, a novel approach for selective attachment of malignant cells to antigen-presenting cells by using bispecific nanoparticles is presented. The engaged cell pairs are then irradiated by a sequence of resonant femtosecond pulses, which results in widespread cell fusion and the consequent formation of hybrid cells. The dual role of gold nanoparticles as conjugating agents and fusion promoters offers a simple yet effective means for specific fusion between different cells. This technology could be useful for a variety of in vitro and in vivo applications that call for selective fusion between cells within a large heterogenic cell population.
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Affiliation(s)
- Daniella Yeheskely-Hayon
- Department of Biomedical Engineering, Technion-Israel Institute of Technology, 32000 Haifa, Israel.
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Browning MJ. Antigen presenting cell/ tumor cell fusion vaccines for cancer immunotherapy. Hum Vaccin Immunother 2013; 9:1545-8. [PMID: 23475129 DOI: 10.4161/hv.24235] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Fusions of antigen presenting cells and tumor cells have been investigated in animal models and phase I/II clinical trials as candidate cancer vaccines. In animal studies there have been numerous reports of induction of protective immunity against a wide range of tumor types. Results of clinical trials have been less dramatic, but tumor-specific immune responses have been reported in many patients, with clinical responses to the vaccination in a subset. In this commentary article, I review the current status of antigen presenting cell/tumor cell fusion vaccines for cancer immunotherapy.
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Affiliation(s)
- Michael J Browning
- Department of Infection; Immunity and Inflammation; University of Leicester; Leicester, UK; Department of Immunology; Leicester Royal Infirmary; Leicester, UK
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SHAO HONGFANG, YU QI, BO XIAOMING, DUAN ZHIGUANG. Analysis of oncology research from 2001 to 2010: A scientometric perspective. Oncol Rep 2013; 29:1441-52. [DOI: 10.3892/or.2013.2239] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2012] [Accepted: 12/21/2012] [Indexed: 11/05/2022] Open
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Shashidharamurthy R, Bozeman EN, Patel J, Kaur R, Meganathan J, Selvaraj P. Immunotherapeutic strategies for cancer treatment: a novel protein transfer approach for cancer vaccine development. Med Res Rev 2012; 32:1197-1219. [PMID: 23059764 DOI: 10.1002/med.20237] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Cancer cells have developed numerous ways to escape immune surveillance and gain unlimited proliferative capacity. Currently, several chemotherapeutic agents and radiotherapy, either alone or in combination, are being used to treat malignancies. However, both of these therapies are associated with several limitations and detrimental side effects. Therefore, recent scientific investigations suggest that immunotherapy is among the most promising new approaches in modern cancer therapy. The focus of cancer immunotherapy is to boost both acquired and innate immunity against malignancies by specifically targeting tumor cells, and leaving healthy cells and tissues unharmed. Cellular, cytokine, gene, and monoclonal antibody therapies have progressively become promising immunotherapeutic approaches that are being tested for several cancers in preclinical models as well as in the clinic. In this review, we discuss recent advances in these immunotherapeutic approaches, focusing on new strategies that allow the expression of specific immunostimulatory molecules on the surface of tumor cells to induce robust antitumor immunity.
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Affiliation(s)
- Rangaiah Shashidharamurthy
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA
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Dasanu CA, Sethi N, Ahmed N. Immune alterations and emerging immunotherapeutic approaches in lung cancer. Expert Opin Biol Ther 2012; 12:923-37. [PMID: 22559147 DOI: 10.1517/14712598.2012.685715] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Subjects with lung cancer were shown to present a variety of immune abnormalities including cellular immune dysfunction, cytokine alterations, and antigen presentation defects. As discouraging results are commonly seen with the existing therapies in lung cancer, more innovative treatment strategies are needed. AREAS COVERED The authors review comprehensively the immune abnormalities in individuals with lung cancer, describe the lung cancer immunotherapy candidates that are most advanced in their clinical development, and summarize recent data from clinical trials of these agents. EXPERT OPINION Enhancing the immune system represents an appealing avenue for lung cancer therapy. Several immunomodulating agents have activity in this regard including ipilimumab, a monoclonal antibody against the CTLA-4, and talactoferrin, a dendritic cell activator. In addition, a significant activity was shown with belagenpumatucel-L, a whole-cell-based vaccine that blocks the action of TGF-β2. Other promising vaccines are protein-specific vaccines against tumor antigens such as MAGE-A3, EGF, and MUC1. Although some of these immunotherapies may have lackluster performance as single agents in advanced disease, more impressive results are seen in combination with chemotherapy agents. Given their proven activity in lung cancer, these immunotherapies may soon become a powerful addition to the oncologist's toolbox.
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Affiliation(s)
- Constantin A Dasanu
- St. Francis Hospital and Medical Center, Department of Hematology-Oncology, Medical Oncology and Blood Disorders, Gothic Park, 43 Woodland Street, Suite G-80, Hartford, CT 06105, USA.
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Pedrazzoli F, Chrysantzas I, Dezzani L, Rosti V, Vincitorio M, Sitar G. Cell fusion in tumor progression: the isolation of cell fusion products by physical methods. Cancer Cell Int 2011; 11:32. [PMID: 21933375 PMCID: PMC3187729 DOI: 10.1186/1475-2867-11-32] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2011] [Accepted: 09/20/2011] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Cell fusion induced by polyethylene glycol (PEG) is an efficient but poorly controlled procedure for obtaining somatic cell hybrids used in gene mapping, monoclonal antibody production, and tumour immunotherapy. Genetic selection techniques and fluorescent cell sorting are usually employed to isolate cell fusion products, but both procedures have several drawbacks. RESULTS Here we describe a simple improvement in PEG-mediated cell fusion that was obtained by modifying the standard single-step procedure. We found that the use of two PEG undertreatments obtains a better yield of cell fusion products than the standard method, and most of these products are bi- or trinucleated polykaryocytes. Fusion rate was quantified using fluorescent cell staining microscopy. We used this improved cell fusion and cell isolation method to compare giant cells obtained in vitro and giant cells obtained in vivo from patients with Hodgkin's disease and erythroleukemia. CONCLUSIONS In the present study we show how to improve PEG-mediated cell fusion and that cell separation by velocity sedimentation offers a simple alternative for the efficient purification of cell fusion products and to investigate giant cell formation in tumor development.
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Affiliation(s)
- Filippo Pedrazzoli
- Department of Internal Medicine IRCCS Policlinico San Matteo, viale Golgi 19, Pavia 27100 Italy and University of Pavia, Strada Nuova, Pavia 27100; Italy
| | - Iraklis Chrysantzas
- Department of Internal Medicine IRCCS Policlinico San Matteo, viale Golgi 19, Pavia 27100 Italy and University of Pavia, Strada Nuova, Pavia 27100; Italy
| | - Luca Dezzani
- Department of Internal Medicine IRCCS Policlinico San Matteo, viale Golgi 19, Pavia 27100 Italy and University of Pavia, Strada Nuova, Pavia 27100; Italy
| | - Vittorio Rosti
- Department of Internal Medicine IRCCS Policlinico San Matteo, viale Golgi 19, Pavia 27100 Italy and University of Pavia, Strada Nuova, Pavia 27100; Italy
| | - Massimo Vincitorio
- Department of Internal Medicine IRCCS Policlinico San Matteo, viale Golgi 19, Pavia 27100 Italy and University of Pavia, Strada Nuova, Pavia 27100; Italy
| | - Giammaria Sitar
- Department of Internal Medicine IRCCS Policlinico San Matteo, viale Golgi 19, Pavia 27100 Italy and University of Pavia, Strada Nuova, Pavia 27100; Italy
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Cathelin D, Nicolas A, Bouchot A, Fraszczak J, Labbé J, Bonnotte B. Dendritic cell-tumor cell hybrids and immunotherapy: what's next? Cytotherapy 2011; 13:774-85. [PMID: 21299362 DOI: 10.3109/14653249.2011.553593] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Dendritic cells (DC) are professional antigen-presenting cells currently being used as a cellular adjuvant in cancer immunotherapy strategies. Unfortunately, DC-based vaccines have not demonstrated spectacular clinical results. DC loading with tumor antigens and DC differentiation and activation still require optimization. An alternative technique for providing antigens to DC consists of the direct fusion of dendritic cells with tumor cells. These resulting hybrid cells may express both major histocompatibility complex (MHC) class I and II molecules associated with tumor antigens and the appropriate co-stimulatory molecules required for T-cell activation. Initially tested in animal models, this approach has now been evaluated in clinical trials, although with limited success. We summarize and discuss the results from the animal studies and first clinical trials. We also present a new approach to inducing hybrid formation by expression of viral fusogenic membrane glycoproteins.
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Affiliation(s)
- Dominique Cathelin
- Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 866, France.
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Moviglia GA, Carrizo AG, Varela G, Gaeta CA, Paes de Lima A, Farina P, Molina H. Preliminary report on tumor stem cell/B cell hybridoma vaccine for recurrent glioblastoma multiforme. Hematol Oncol Stem Cell Ther 2010; 1:3-13. [PMID: 20063522 DOI: 10.1016/s1658-3876(08)50054-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Glioblastoma multiforme (GBM), the most aggressive glioma, presents with a rapid evolution and relapse within the first year, which is attributed to the persistence of tumor stem cells (TSC) and the escape of immune surveillance. Mixed leukocyte culture (MLC) cytoimplant has been shown to function as a powerful intratumor pro-inflammatory cytokine pump. Tumor B-cell hybridoma (TBH) vaccines have been shown to function as antigen-presenting cells. We evaluated the toxicity and efficiency of each treatment alone and in combination. PATIENTS AND METHODS In an open study, 12 consecutive patients were evenly divided into 3 groups, each group receiving 3 different treatments. Patients in Group 1 were treated, after diagnosis, with debulking surgery (DS)+radiotherapy (Rx), and after the first relapse underwent DS+MLC treatment. Patients in Group 2 were similarly treated but after the first relapse underwent DS+MLC+TBH. Finally, patients in Group 3 were similarly treated but after the first relapse underwent DS+TBH. Nestin PAP stain assessed TSC participation in TBH. RESULTS Treatment with MLC had strong and rapid therapeutic effects, but was limited in duration and induced various degrees of brain inflammation. Treatment with MLC+TBH acted synergistically, provoking a rapid, strong and lasting therapeutic response but also generating different degrees of brain inflammation. A lasting therapeutic effect without generating high degrees of brain inflammation occurred in patients treated with TBH vaccine alone. CONCLUSION TSC vaccine consisting of TBH alone seems to have potent adjuvant reactions overcoming both persistence of tumor stem cells and immune escape of GBM without provoking an encephalitic reaction.
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Sterry W. Perspectives in dermatology: dermatologic oncology. J DERMATOL TREAT 2009. [DOI: 10.1080/09546630050517603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
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Bilbao G, Curiel DT. Section Review Oncologic, Endocrine & Metabolic: Gene therapy for cancer therapeutics. Expert Opin Ther Pat 2008. [DOI: 10.1517/13543776.6.12.1267] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Hou S, Kou G, Fan X, Wang H, Qian W, Zhang D, Li B, Dai J, Zhao J, Ma J, Li J, Lin B, Wu M, Guo Y. Eradication of hepatoma and colon cancer in mice with Flt3L gene therapy in combination with 5-FU. Cancer Immunol Immunother 2007; 56:1605-13. [PMID: 17361437 PMCID: PMC11030779 DOI: 10.1007/s00262-007-0306-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2006] [Accepted: 02/23/2007] [Indexed: 10/23/2022]
Abstract
We developed a recombinant defective adenovirus with an insert of gene encoding extracellular domain of mouse Flt3L (Ad-mFlt3L) under control of cytomegalovirus promoter to investigate the biological efficacy of Flt3L in combination with chemotherapeutical drug, 5-FU, in eliciting an effective anti-cancer immunity in mouse hepatoma and colon cancer model systems. The constructed Ad-mFlt3L efficiently infected hepatoma and colon cancer cells both in vitro and in vivo, leading to a high production of mFlt3L proteins in association with accumulation of DCs, NK cells and lymphocytes in local tumor tissues. Administration of Ad-mFlt3L can protect bone marrow injury caused by 5-Fu and stimulates proliferation and maturation of lymphocytes, APCs and NKs. Intratumoral injection of Ad-mFlt3L followed by an intraperitoneal administration of 5-Fu significantly inhibited tumor growth and cured established tumors. Adenovirus mediated Flt3L gene therapy synergies with chemotherapeutic drug, 5-Fu, in elicitation of long-lasting antitumor immunity. The tumor specific immunity can be adoptively transferred into naïve animals successfully by transfusion of CD3+CD8+ T cells from the treated mice. The data suggests that adenovirus mediated Flt3L gene therapy in combination with 5-Fu chemotherapy may open a new avenue for development of anti-cancer chemogenetherapy.
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Affiliation(s)
- Sheng Hou
- International Joint Cancer Institute and Institute of Hepatobiliary Surgery, The Second Military Medical University, New Library Building 10th-11th Floor, 800 Xiang Yin Road, Shanghai, 200433 People’s Republic of China
- Shanghai Center for Cell Engineering and Antibody, Research Building, 399 Libing Road, Shanghai, 201203 People’s Republic of China
| | - Geng Kou
- International Joint Cancer Institute and Institute of Hepatobiliary Surgery, The Second Military Medical University, New Library Building 10th-11th Floor, 800 Xiang Yin Road, Shanghai, 200433 People’s Republic of China
- Shanghai Center for Cell Engineering and Antibody, Research Building, 399 Libing Road, Shanghai, 201203 People’s Republic of China
| | - Xiaoqiang Fan
- International Joint Cancer Institute and Institute of Hepatobiliary Surgery, The Second Military Medical University, New Library Building 10th-11th Floor, 800 Xiang Yin Road, Shanghai, 200433 People’s Republic of China
| | - Hao Wang
- International Joint Cancer Institute and Institute of Hepatobiliary Surgery, The Second Military Medical University, New Library Building 10th-11th Floor, 800 Xiang Yin Road, Shanghai, 200433 People’s Republic of China
- Shanghai Center for Cell Engineering and Antibody, Research Building, 399 Libing Road, Shanghai, 201203 People’s Republic of China
| | - Weizhu Qian
- International Joint Cancer Institute and Institute of Hepatobiliary Surgery, The Second Military Medical University, New Library Building 10th-11th Floor, 800 Xiang Yin Road, Shanghai, 200433 People’s Republic of China
- Shanghai Center for Cell Engineering and Antibody, Research Building, 399 Libing Road, Shanghai, 201203 People’s Republic of China
| | - Dapeng Zhang
- International Joint Cancer Institute and Institute of Hepatobiliary Surgery, The Second Military Medical University, New Library Building 10th-11th Floor, 800 Xiang Yin Road, Shanghai, 200433 People’s Republic of China
| | - Bohua Li
- International Joint Cancer Institute and Institute of Hepatobiliary Surgery, The Second Military Medical University, New Library Building 10th-11th Floor, 800 Xiang Yin Road, Shanghai, 200433 People’s Republic of China
- Shanghai Center for Cell Engineering and Antibody, Research Building, 399 Libing Road, Shanghai, 201203 People’s Republic of China
| | - Jianxin Dai
- International Joint Cancer Institute and Institute of Hepatobiliary Surgery, The Second Military Medical University, New Library Building 10th-11th Floor, 800 Xiang Yin Road, Shanghai, 200433 People’s Republic of China
| | - Jian Zhao
- International Joint Cancer Institute and Institute of Hepatobiliary Surgery, The Second Military Medical University, New Library Building 10th-11th Floor, 800 Xiang Yin Road, Shanghai, 200433 People’s Republic of China
| | - Jing Ma
- International Joint Cancer Institute and Institute of Hepatobiliary Surgery, The Second Military Medical University, New Library Building 10th-11th Floor, 800 Xiang Yin Road, Shanghai, 200433 People’s Republic of China
| | - Jing Li
- International Joint Cancer Institute and Institute of Hepatobiliary Surgery, The Second Military Medical University, New Library Building 10th-11th Floor, 800 Xiang Yin Road, Shanghai, 200433 People’s Republic of China
- Shanghai Center for Cell Engineering and Antibody, Research Building, 399 Libing Road, Shanghai, 201203 People’s Republic of China
| | - Birong Lin
- Shanghai Center for Cell Engineering and Antibody, Research Building, 399 Libing Road, Shanghai, 201203 People’s Republic of China
| | - Mengchao Wu
- International Joint Cancer Institute and Institute of Hepatobiliary Surgery, The Second Military Medical University, New Library Building 10th-11th Floor, 800 Xiang Yin Road, Shanghai, 200433 People’s Republic of China
| | - Yajun Guo
- International Joint Cancer Institute and Institute of Hepatobiliary Surgery, The Second Military Medical University, New Library Building 10th-11th Floor, 800 Xiang Yin Road, Shanghai, 200433 People’s Republic of China
- Shanghai Center for Cell Engineering and Antibody, Research Building, 399 Libing Road, Shanghai, 201203 People’s Republic of China
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20
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Doherty PC, Tripp RA, Sixbey JW. Evasion of host immune responses by tumours and viruses. CIBA FOUNDATION SYMPOSIUM 2007; 187:245-56; discussion 256-60. [PMID: 7796674 DOI: 10.1002/9780470514672.ch16] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Viruses and tumours use various mechanisms to avoid immune surveillance. Oncogenic viruses have achieved a balance with the immune system through evolutionary time to ensure long-term persistence. Mutations that promote escape mechanisms favouring tumour growth to the detriment of host survival through reproductive age offer no selective advantage and will not generally be maintained in the viral genome that persists in nature. Conventional (non-oncogenic) and tumour viruses interact with various immune mediators and T cells in different ways. Oncogenic viruses cannot operate solely in the context of a lytic cycle, though this may be characteristic of the initial phase of infection that is limited by the acute immune response. Some oncogenic viruses interact with normal cellular growth control and signalling mechanisms. Synthesis of key viral proteins may be tightly controlled in replicating cells that are subject to T cell surveillance, such as basal epithelia, while productive infection occurs in non-proliferating progeny that are lost under normal physiological conditions, such as desquamating epithelia. Tumorigenesis may be an aberrant consequence of the molecular mechanisms needed to maintain this pattern of viral growth regulation in the context of the cell cycle. Vaccines designed to limit the acute phase of infection with cell-free oncogenic viruses should be as effective as those for conventional viruses.
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Affiliation(s)
- P C Doherty
- Department of Immunology, St Jude Children's Research Hospital, Memphis, TN 38104, USA
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21
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Fusions of dendritic cells and C6 cells transfected with TGF-β1 antisense in treatment of intracranial gliomas. Chin J Cancer Res 2007. [DOI: 10.1007/s11670-007-0113-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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22
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Walewska R, Teobald I, Dunnion D, Abdulmajed H, Aldred M, Sadler J, Chapman C, Browning M. Preclinical development of hybrid cell vaccines for multiple myeloma. Eur J Haematol 2007; 78:11-20. [PMID: 17302859 DOI: 10.1111/j.1600-0609.2006.00769.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Immunotherapy may provide alternative or supplementary treatment of multiple myeloma (MM). We propose that hybrid cells, formed by fusing professional antigen-presenting cells with malignant plasma cells, would induce immune responses capable of mediating tumour regression. The human B-lymphoblastoid cell line, HMy2, was fused in vitro with CD138+ bead-separated myeloma plasma cells from five patients with MM. The hybrid cell lines generated in these studies grew stably in tissue culture, and maintained their phenotypic and functional characteristics, providing self-renewing cell lines with potential for therapeutic vaccination. The hybrid cells stimulated allogeneic and autologous T-cell proliferative responses in vitro to a considerably greater degree than their respective parent myeloma plasma cells, and directly activated both CD4+ and CD8+ T-cell responses. The enhanced T-cell stimulation correlated with expression of CD80 on the hybrid cells, and was inhibited by CTLA4-Ig fusion protein. The hybrid cell lines expressed several tumour-associated antigens known to be expressed in myeloma. These data show that self-replicating cell lines with enhanced immunostimulatory properties and potential for therapeutic vaccination can be generated by in vitro fusion of ex vivo myeloma cells and B-lymphoblastoid cell lines.
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Affiliation(s)
- Renata Walewska
- Department of Infection, Immunity & Inflammation, University of Leicester, Leicester, UK
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23
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Nguyen van Binh P, Duc HT. Analyses and perspectives in cancer immunotherapy. Biomed Pharmacother 2006; 60:621-8. [PMID: 16978826 DOI: 10.1016/j.biopha.2006.07.092] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2006] [Accepted: 07/28/2006] [Indexed: 01/15/2023] Open
Abstract
Since the last two decades, rapid progress has been made in the field of cancer immunotherapy relevant to manipulation of adaptative cytotoxic T lymphocytes (CTLs) and innate immunity natural killer (NK) cells as well as antibodies. Many possibilities are now offered for therapeutic purposes contributing to better approaches in treatment of cancer.
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Affiliation(s)
- P Nguyen van Binh
- Inserm, U602, Micro-environnement et Physiopathologie de la Différenciation, Hôpital Paul-Brousse, 16, avenue Paul-Vaillant-Couturier, 94807 Villejuif cedex, France
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24
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Shu S, Cochran AJ, Huang RR, Morton DL, Maecker HT. Immune responses in the draining lymph nodes against cancer: implications for immunotherapy. Cancer Metastasis Rev 2006; 25:233-42. [PMID: 16770535 DOI: 10.1007/s10555-006-8503-7] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Regional lymph nodes are the first site for melanoma metastases. The sentinel node (SN), on the direct lymphatic drainage pathway, which usually harbors first metastases, demonstrates significant suppression in its ability to respond to antigenic stimulation. This down-regulation of SN immunity is likely the basis of its susceptibility to tumor metastases, suggesting a potential role of the immune system in the control of malignant tumors. Despite immune dysfunction in the SN, phase II trials of systemic post-operative immunotherapy with a polyvalent melanoma vaccine developed at the John Wayne Cancer Institute showed improved 5-year overall survival in patients with melanoma metastatic to regional nodes. However, most immunotherapy clinical trials have failed to demonstrate a significant clinical response, and analyses of immune responses to tumor-associated antigens that correlate clinical responses have not been established. Therefore, refinements in assay methodologies and improvements in vaccine designs are critical to the success of cancer immunotherapy. Antigen presentation by dendritic cells (DCs) is the most potent means to initiate a T cell immunity. Dendritic cell-based immunotherapies have been vigorously attempted in the past decade. To improve the immunogenicity of cancer vaccines, we recently generated heterokaryons of DCs and tumor cells by electrofusion. The fusion hybrids retained their full antigen-presenting capacity and all natural tumor antigens. In pre-clinical animal experiments, a single injection of the DC-tumor fusion hybrids was sufficient to mediate the regression of tumors established in the lung, skin and brain. Most interestingly, successful therapy required the delivery of fusion hybrids directly into lymphoid organs such as lymph nodes. A clinical trial is now being carried out to test the immunogenicity and therapeutic effects of fusion hybrids for the treatment of metastatic melanoma.
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Affiliation(s)
- Suyu Shu
- Center for Surgery Research, The Cleveland Clinic Foundation, Cleveland, OH, USA.
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25
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Sasaki A, Iwashita Y, Shibata K, Matsumoto T, Ohta M, Kitano S. Prognostic value of preoperative peripheral blood monocyte count in patients with hepatocellular carcinoma. Surgery 2006; 139:755-64. [PMID: 16782430 DOI: 10.1016/j.surg.2005.10.009] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2005] [Revised: 10/13/2005] [Accepted: 10/18/2005] [Indexed: 12/17/2022]
Abstract
BACKGROUND The prognostic significance of the leukocyte subsets in peripheral blood has not yet been investigated in hepatocellular carcinoma patients. We sought to clarify the prognostic value of preoperative peripheral blood leukocyte subset counts, especially the absolute monocyte count, in HCC patients who have undergone hepatic resection. METHODS We retrospectively examined the relation between the preoperative absolute number of peripheral monocytes and clinicopathologic factors or long-term prognosis in 198 patients with hepatocellular carcinoma who underwent curative resection. RESULTS Univariate analysis indicated a significantly worse 5-year disease-free survival rate in patients with a peripheral blood monocyte count > 300/mm(3) (14.8%) than in patients with a count < or = 300/mm(3) (29.2%). There were no significant differences between patients in disease-free survival based on the lymphocyte or neutrophil count. According to multivariate analysis, preoperative peripheral blood monocyte count > 300/mm(3), alpha-fetoprotein level > 100 ng/mL, aspartate aminotransferase level > 100 IU/mL, and presence of microvascular invasion were independent risk factors for disease-free survival of less than 5 years. The peripheral blood monocyte count was higher in patients of male sex or those with a noncirrhotic liver, microvascular invasion, major hepatic resection, older age (>65 years), large tumor (> or =50 mm), or increased platelet count (>100,000/mm(3)) than in patients without these characteristics. CONCLUSIONS Our findings indicate that the preoperative absolute count (>300/mm(3)) of peripheral blood monocytes may be related to tumor progression and that it is an independent risk factor for recurrence of hepatocellular carcinoma after resection. Postoperative adjuvant chemotherapy might be necessary in patients with elevation of the preoperative absolute count of peripheral blood monocytes.
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Affiliation(s)
- Atsushi Sasaki
- Department of Surgery I, Oita University Faculty of Medicine, Oita, Japan.
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26
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Quéant S, Sarde CO, Gobert MG, Kadouche J, Roseto A. Antitumor response against myeloma cells by immunization with mouse syngenic dendritoma. Hybridoma (Larchmt) 2005; 24:182-8. [PMID: 16120023 DOI: 10.1089/hyb.2005.24.182] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
In order to generate an immune response against myeloma cells in an homogenous murine model, a stable hybrid cell line (DCSp) was established through the syngenic fusion between mouse dendritic cells (DC) and mouse Sp2/0 myeloma cells. DCSp cells behaved as potent T cell stimulators and were able to induce Sp2/0 specific cytotoxicity. When mice were immunized with irradiated hybrids before SP2/0 injection, they exhibited a significantly higher rate of survival as compared with controls. When tumors were detected, their emergence was not delayed, and time elapsed between tumor clinical perception and death remained unchanged. A humoral immune response was also always associated. We assume that this stable dendritoma cell line can be considered a valuable tool for myeloma studies in an homogenous mouse model. The efficiency of dendritoma as a weapon against tumor cells and the benefit of syngeny in experimental models are discussed.
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Affiliation(s)
- S Quéant
- Immunocytologie et Oncologie Moléculaire, Université de Technologie de Compiègne, Compiègne, France
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27
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Weise JB, Maune S, Görögh T, Kabelitz D, Arnold N, Pfisterer J, Hilpert F, Heiser A. A dendritic cell based hybrid cell vaccine generated by electrofusion for immunotherapy strategies in HNSCC. Auris Nasus Larynx 2005; 31:149-53. [PMID: 15121224 DOI: 10.1016/j.anl.2004.01.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2003] [Revised: 12/15/2003] [Accepted: 01/16/2004] [Indexed: 11/22/2022]
Abstract
OBJECTIVE Hybrid cells generated from dendritic cells (DC) and tumor cells provide tumor-associated antigens (TAA) in a polyvalent mode and therefore they have aroused interest in cancer immunotherapy. The present study was designed to investigate the hybrid cell generation and optimize its implementation for a TAA-target treatment of head and neck squamous cell carcinoma (HNSCC). METHODS Hybrid cells from mature DC and laryngeal carcinoma cell line UTSCC-19A were generated by electrofusion. Fusion efficiency and viability were determined by flow cytometry, light and fluorescence microscopy analyses. RESULTS The gradual electrofusion process constituted real human tumor and dendritic cell hybrids characterized by polynuclear cells and double staining as a result of overlay of red (HLA-DR:R-PE) and green (HEA:FITC) fluorescence. Furthermore, analyses have proven viability of fusion results, and factors influencing fusion yield were determined. CONCLUSION Physical fusion of mature dendritic cells with laryngeal carcinoma cells provides a dendritic cell based hybrid cell vaccine as a quantitative prerequisite for anti-cancer vaccination. Specific cytotoxic T-lymphocytes need to be induced before hybrid cell application in clinical studies.
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Affiliation(s)
- Jan Bernd Weise
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Kiel, Arnold-Heller-Strasse 14, D-24105 Kiel, Germany.
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28
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Peng BG, Liang LJ, He Q, Kuang M, Lia JM, Lu MD, Huang JF. Tumor vaccine against recurrence of hepatocellular carcinoma. World J Gastroenterol 2005; 11:700-4. [PMID: 15655825 PMCID: PMC4250742 DOI: 10.3748/wjg.v11.i5.700] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of autologous tumor vaccine on recurrence of hepatocellular carcinoma (HCC).
METHODS: Sixty patients with HCC who had undergone curative resection, were randomly divided into HCC vaccine group and control group. Three vaccinations at 2-wk intervals were performed after curative hepatic resection. Delayed-type- hypersensitivity (DTH) test was performed before and after vaccination. Primary endpoints were the time of recurrence.
RESULTS: Four patients in control group and 6 patients in HCC vaccine group were withdrawn from the study. The vaccine containing human autologous HCC fragments showed no essential adverse effect in a phase II clinical trial and 17 of 24 patients developed a DTH response against the fragments. Three of 17 DTH-positive response patients and 5 of 7 DTH- negative response patients had recurrences after curative resection. After the operation, 1-, 2- and 3-year recurrence rates of HCC vaccine group were 16.7%, 29.2% and 33.3%, respectively. But, 1-, 2- and 3-year recurrence rates of the control group were 30.8%, 53.8% and 61.5%, respectively. The time before the first recurrence in the vaccinated patients was significantly longer than that in the control patients (P<0.05).
CONCLUSION: Autologous tumor vaccine is of promise in decreasing recurrence of human HCC.
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Affiliation(s)
- Bao-Gang Peng
- Hepatobiliary Surgery Department, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong Province, China.
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29
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Ritchie DS, Yang J, Hermans IF, Ronchese F. B-Lymphocytes activated by CD40 ligand induce an antigen-specific anti-tumour immune response by direct and indirect activation of CD8(+) T-cells. Scand J Immunol 2005; 60:543-51. [PMID: 15584965 DOI: 10.1111/j.0300-9475.2004.01517.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
In this report, we describe the ability of CD40-ligand (CD40L)-activated, antigen-loaded B-cells to initiate antigen-specific anti-tumour immune responses in vivo. Mice immunized by means of intravenous administration of CD40L-activated B-cells loaded with an MHC class-I-binding peptide, and challenged with a tumour cell line expressing the same class-I epitope, showed a marked delay in tumour growth, compared to non-immunized controls or to mice receiving either freshly isolated B-cells or B-cells activated with lipopolysaccharide or interleukin-4. The ability of CD40L-activated B-cells to induce antigen-specific T-cell activation appeared to be through a combination of cross-presentation of antigen from activated B-cells to resident antigen-presenting cells and direct T-cell activation by the administered B-cells themselves. Immunization with CD40L-activated B-cells may, therefore, represent a means by which to stimulate anti-tumour CD8(+) T-cell responses in vivo.
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Affiliation(s)
- D S Ritchie
- Malaghan Institute of Medical Research, Wellington School of Medicine, Wellington, New Zealand.
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Xia D, Li F, Xiang J. Engineered fusion hybrid vaccine of IL-18 gene-modified tumor cells and dendritic cells induces enhanced antitumor immunity. Cancer Biother Radiopharm 2005; 19:322-30. [PMID: 15285878 DOI: 10.1089/1084978041424990] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Dendritic cell (DC)-tumor fusion hybrid vaccines that facilitate antigen presentation represent a novel powerful strategy in cancer immunotherapy. In our study, we investigated the antitumor immunity derived from the vaccination of fusion hybrids between engineered J558/IL-18 myeloma cells secreting Th1 cytokine IL-18 and DCs. DC/J558/IL-18 could secret a higher level of IL-18 than DCs, efficiently expressed J558 tumor antigen P1A, and enhanced ability of allogeneic T cell stimulation when compared to J558/IL-18. Our data showed that the immunization of BALB/c mice with DC/J558/IL-18 hybrids induced the most potent protective immunity against 1 x 10(6) cells with a J558 tumor challenge, compared to those immunized with the mixture of DCs and J558/IL-18, J558/IL-18, or J558. Furthermore, the immunization of mice with engineered DC/J558/IL-18 hybrids elicited stronger NK activity and J558 tumor-specific cytotoxic T lymphocyte (CTL) responses in vitro. In addition, DC/J558/IL-18 tumor cells into syngeneic mice induced a Th1 dominant immune response to J558 and resulted in tumor regression, which indicated that the antitumor effect mediated by DC/J558/IL-18 appeared to be dependent on TH1 cytokine production. These results demonstrate that the engineered fusion hybrid vaccines that combine Th1 gene-modified tumor with DCs may be an attractive strategy for cancer immunotherapy.
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Affiliation(s)
- Dajing Xia
- Research Unit, Saskatchewan Cancer Agency, Departments of Oncology, Microbiology, and Immunology, College of Medicine, University of Saskatchewan, 20 Campus Drive, Saskatoon, Saskatchewan S7N 4H4, Canada
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31
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Suzuki T, Fukuhara T, Tanaka M, Nakamura A, Akiyama K, Sakakibara T, Koinuma D, Kikuchi T, Tazawa R, Maemondo M, Hagiwara K, Saijo Y, Nukiwa T. Vaccination of Dendritic Cells Loaded with Interleukin-12-Secreting Cancer Cells Augments In vivo Antitumor Immunity: Characteristics of Syngeneic and Allogeneic Antigen-Presenting Cell Cancer Hybrid Cells. Clin Cancer Res 2005. [DOI: 10.1158/1078-0432.58.11.1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Abstract
Cancer immunotherapy by fusion of antigen-presenting cells and tumor cells has been shown to induce potent antitumor immunity. In this study, we characterized syngeneic and allogeneic, murine macrophage/dendritic cell (DC)-cancer fusion cells for the antitumor effects. The results showed the superiority of allogeneic cells as fusion partners in both types of antigen-presenting cells in an in vivo immunotherapy model. A potent induction of tumor-specific CTLs was observed in these immunized conditions. In addition, the immunization with DC-cancer fusion cells was better than that with macrophage-cancer fusion cells. Both syngeneic and allogeneic DC-cancer fusion cells induced higher levels of IFN-γ production than macrophage-cancer fusion cells. Interestingly, allogeneic DC-cancer fusion cells were superior in that they efficiently induced Th1-type cytokines but not the Th2-type cytokines interleukin (IL)-10 and IL-4, whereas syngeneic DC-cancer fusion cells were powerful inducers of both Th1 and Th2 cytokines. These results suggest that allogeneic DCs are suitable as fusion cells in cancer immunotherapy. To further enhance the antitumor immunity in the clinical setting, we prepared DCs fused with IL-12 gene-transferred cancer cells and thus generated IL-12-secreting DC-cancer fusion cells. Immunization with these gene-modified DC-cancer fusion cells was able to elicit a markedly enhanced antitumor effect in the in vivo therapeutic model. This novel IL-12-producing fusion cell vaccine might be one promising intervention for future cancer immunotherapy.
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Affiliation(s)
- Takuji Suzuki
- 1Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer
| | - Tatsuro Fukuhara
- 1Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer
| | - Masashi Tanaka
- 1Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer
| | - Akira Nakamura
- 1Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer
| | - Kenichi Akiyama
- 1Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer
| | - Tomohiro Sakakibara
- 1Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer
| | - Daizo Koinuma
- 1Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer
| | - Toshiaki Kikuchi
- 1Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer
| | - Ryushi Tazawa
- 1Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer
| | - Makoto Maemondo
- 1Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer
| | - Koichi Hagiwara
- 3Department of Respiratory Medicine, Saitama Medical School, Saitama, Japan
| | - Yasuo Saijo
- 2Department of Molecular Medicine and Gene Transfer Research, Graduate School of Medicine, Tohoku University, Sendai, Japan; and
| | - Toshihiro Nukiwa
- 1Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer
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Cimino AM, Palaniswami P, Kim AC, Selvaraj P. Cancer vaccine development: protein transfer of membrane-anchored cytokines and immunostimulatory molecules. Immunol Res 2004; 29:231-40. [PMID: 15181285 DOI: 10.1385/ir:29:1-3:231] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Many tumor cells escape host-immune recognition by the downregulation or lack of immunostimulatory molecules. Expression of immunostimulatory molecules on tumor cells by gene transfer can be used to induce an antitumor immune response. However, we have previously shown that protein transfer of glycosyl-phosphatidylinositol (GPI)-linked costimulatory molecules is a successful alternative to traditional gene transfer in preparing such a tumor vaccine. Vaccination with membranes modified by protein transfer to express GPI-linked B7.1 (CD80), a costimulatory adhesion molecule, induces protective immunity in mice and allogeneic antitumor T-cell proliferation in humans in vitro. Our goal is to develop an optimal tumor vaccine using tumor membranes modified by protein transfer to target and stimulate antigen-presenting cells (APCs) and T cells. We have investigated the efficacy of expressing GPI-anchored cytokine molecules on the surface of tumor cells. Expression of interleukin-12 (IL-12) on tumor-cell membranes in a GPI-anchored form induces a strong antitumor immune response that is comparable to the effects of secretory IL-12. Because many cytokines act synergistically, we are testing the membrane expression and immunostimulatory effects of cytokines individually as well as in combination to determine potential complementary effects of coexpression on the antitumor immune response. Ultimately, the protein-transfer vaccination may be used in humans alone or in multimodal combination therapies to induce tumor regression and to serve as a protective measure to prevent postsurgical secondary metastases.
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Affiliation(s)
- Ashley M Cimino
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Woodruff Memorial Research Building, 1639 Pierce Drive, Atlanta, GA 30322, USA
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Abstract
There is a continuing need for innovative, alternative therapies for hepatocellular carcinoma (HCC). Immunotherapy for cancer is attractive because of the exquisite specificity of the immune response. Activation of an HCC-specific response can be accomplished by strategies targeting tumor-associated self-antigens (for example, alpha-fetoprotein [AFP]). Gene array studies have added to the list of HCC-specific gene products that can be targeted. Alternatively, the immune response can be targeted against viral antigens in those patients infected with hepatitis B or C virus. Uncharacterized and mutated antigens can also be targeted with whole tumor cell or tumor lysate-based immunization strategies or with vectors coding for genes that make the tumor immunogenic, allowing the immune system to naturally evolve specificity against immunogenic target antigens. Strategies being investigated in animal models include increasing tumor immunogenicity by targeting cytokines or costimulatory molecules to tumor; immunization with tumor cells fused with antigen-presenting cells; adoptive transfer of viral antigen-specific T cells; and targeting AFP-expressing HCC cells by DNA, adenovirus, peptide, and dendritic cell (DC) strategies. Strategies that have been tested in human clinical trials include adoptive transfer of lymphocytes and autologous tumor-pulsed DC as well as 2 AFP-based strategies: AFP-derived peptides in Montanide and AFP peptides pulsed onto autologous DC. These trials, testing novel immune-based interventions in HCC subjects, have resulted in immunologic responses and have impacted recurrence and survival in HCC subjects.
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Affiliation(s)
- Lisa H Butterfield
- Departments of Medicine, Surgery and Immunology, University of Pittsburgh, Hillman Cancer Center, Research Pavilion, Room 1.19, 5117 Centre Avenue, Pittsburgh, Pennsylvania 15213, USA.
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Abstract
Although tumor vaccines have been studied for decades, there is no vaccine approved as a clinical product. Nevertheless, recent advances in immunology and tumor biology justify a renewed interest. First, cancer cells express many antigens that can be recognized by the immune system, some with high tumor selectivity. Second, knowledge about immune regulation, including the importance of costimulatory signals, has been successfully applied to the studies of tumors. Third, mechanisms of how tumors can escape from immunological control have been identified, setting the stage to discover agents to decrease their impact. Rejection of established mouse tumors has been accomplished as a result of therapeutic tumor vaccination and there are encouraging findings from vaccine trials in humans.
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Ogawa F, Iinuma H, Okinaga K. Dendritic cell vaccine therapy by immunization with fusion cells of interleukin-2 gene-transduced, spleen-derived dendritic cells and tumour cells. Scand J Immunol 2004; 59:432-9. [PMID: 15140052 DOI: 10.1111/j.0300-9475.2004.01411.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
We examined the preventive and therapeutic effects of fusion cells prepared from spleen-derived dendritic cells (DCs) transduced with the interleukin-2 (IL-2) gene and QRsP fibrosarcoma cells in a mouse lung metastasis model. The IL-2 or LacZ gene was introduced into spleen-derived DCs using an adenoviral vector. Irradiated QRsP tumour cells were fused with IL-2 gene-transduced DCs (fusion/IL-2) or LacZ gene-transduced DCs (fusion/LacZ) by polyethylene glycol. These fusion cells expressed major histocompatibility complexes (MHC) class I and II, CD86, CD11c and CD8alpha. Splenocytes from mice vaccinated with fusion cells showed increased production of interferon-gamma (IFN-gamma) and cytotoxic T-lymphocyte (CTL) activity as compared with those vaccinated with DCs or tumour cells alone, and CTL levels were higher in fusion/IL-2-vaccinated mice than in fusion/LacZ-vaccinated mice. In our experiments on the protective and therapeutic effects on lung metastasis, mice vaccinated with fusion/IL-2 fusion/LacZ or fusion showed a significant reduction in pulmonary metastasis compared with those given DCs, tumour or phosphate-buffered saline. The introduction of the IL-2 gene into fusion cells produced more potent preventive and therapeutic effects. These results suggest that immunization with fusion cells prepared from spleen-derived DCs and tumour cells is capable of inducing preventive and therapeutic anti-tumour immunity against lung metastasis, and modification by the IL-2 gene may increase anti-tumour efficacy.
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Affiliation(s)
- F Ogawa
- Department of Surgery, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan
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Abstract
Hybrid cells generated by fusing allogenic-presenting cells, such as dendritic cells, with tumor cells are a new tool in cancer immunotherapy which are designed to enhance the immunogenicity of antigenic tumors by presenting the whole spectrum of tumor-associated antigens, by providing the co-stimulatory molecules required for T-cell activation, and by the expression of allogenic MHC molecules for recruitment and activation of T-cell help. This approach has been successfully tested in animal models as well as in clinical phaseI/II trials with various tumors. Besides clinical repsonses, induction of tumor-specific cytolytic Tcells were observed. The electrofusion protocol described here has the advantage of high fusion efficiency, high hybrid-cell viability, as well as high reproducibility, and can be used for various tumor cell types after minor adjustments are made to the instrument settings in order to process large numbers of dendritic cells with consistent efficiencies.
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Affiliation(s)
- Uwe Trefzer
- Department of Dermatology and Allergy, Charité Humboldt University Medical School, Schumannstrase, 20/21, 10117, Berlin, Germany
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37
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Affiliation(s)
- Theodore F Logan
- Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indiana Cancer Pavilion, 535 Barnhill Drive, Indianapolis, IN 46202-5289, USA
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38
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Gerloni M, Rizzi M, Castiglioni P, Zanetti M. T cell immunity using transgenic B lymphocytes. Proc Natl Acad Sci U S A 2004; 101:3892-7. [PMID: 15004284 PMCID: PMC374340 DOI: 10.1073/pnas.0400138101] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Adaptive immunity exists in all vertebrates and plays a defense role against microbial pathogens and tumors. T cell responses begin when precursor T cells recognize antigen on specialized antigen-presenting cells and differentiate into effector cells. Currently, dendritic cells are considered the only cells capable of stimulating T lymphocytes. Here, we show that mature naïve B lymphocytes can be genetically programmed by using nonviral DNA and turned into powerful antigen-presenting cells with a dual capacity of synthesis and presentation of antigen to T cells in vivo. A single i.v. injection of transgenic lymphocytes activates T cell responses reproducibly and specifically even at very low cell doses (approximately 10(2)). We also demonstrate that T cell priming can occur in the absence of dendritic cells and results in immunological memory with protective effector functions. These findings disclose aspects in the regulation of adaptive immunity and indicate possibilities for vaccination against viruses and cancer in humans.
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Affiliation(s)
- Mara Gerloni
- Department of Medicine and Cancer Center, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0837, USA
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39
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Nakamura T, Peng KW, Vongpunsawad S, Harvey M, Mizuguchi H, Hayakawa T, Cattaneo R, Russell SJ. Antibody-targeted cell fusion. Nat Biotechnol 2004; 22:331-6. [PMID: 14990955 DOI: 10.1038/nbt942] [Citation(s) in RCA: 99] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2003] [Accepted: 12/11/2003] [Indexed: 12/22/2022]
Abstract
Membrane fusion has many potential applications in biotechnology. Here we show that antibody-targeted cell fusion can be achieved by engineering a fusogenic viral membrane glycoprotein complex. Three different single-chain antibodies were displayed at the extracellular C terminus of the measles hemagglutinin (H) protein, and combinations of point mutations were introduced to ablate its ability to trigger fusion through the native viral receptors CD46 and SLAM. When coexpressed with the measles fusion (F) protein, using plasmid cotransfection or bicistronic adenoviral vectors, the retargeted H proteins could mediate antibody-targeted cell fusion of receptor-negative or receptor-positive index cells with receptor-positive target cells. Adenoviral expression vectors mediating human epidermal growth factor receptor (EGFR)-targeted cell fusion were potently cytotoxic against EGFR-positive tumor cell lines and showed superior antitumor potency against EGFR-positive tumor xenografts as compared with control adenoviruses expressing native (untargeted) or CD38-targeted H proteins.
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Affiliation(s)
- Takafumi Nakamura
- Molecular Medicine Program, Mayo Foundation, 200 First St. SW, Rochester, Minnesota 55905, USA
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40
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Gabrijel M, Repnik U, Kreft M, Grilc S, Jeras M, Zorec R. Quantification of cell hybridoma yields with confocal microscopy and flow cytometry. Biochem Biophys Res Commun 2004; 314:717-23. [PMID: 14741694 DOI: 10.1016/j.bbrc.2003.12.154] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The fusion of antigen presenting and cancer cells leads to the formation of hybrid cells, which are considered a potential vaccine for treating cancer. The quality assessment of hybrid cell vaccines is crucial for the introduction of this new treatment. Flow cytometry was the method used recently, since it is faster in comparison to classical microscopy. Here we describe a rapid confocal microscopy based approach to quantify hybrid cell yields. The extent of fusion rate was determined by confocal microscopy by counting dual fluorescent cells and by measuring the area of co-localized pixels. Results of both methods showed high degree of correlation. The same samples were also analyzed by flow cytometry. Fusion rates determined with both techniques showed significant correlation. In conclusion, using confocal microscopy we developed a sensitive and a rapid method to assess the yield of hybridomas in a large number of electrofused cells.
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Affiliation(s)
- Mateja Gabrijel
- Celica Biomedical Sciences Center, Stegne 21, 1000, Ljubljana, Slovenia
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41
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Trefzer U, Herberth G, Wohlan K, Milling A, Thiemann M, Sherev T, Sparbier K, Sterry W, Walden P. Vaccination with hybrids of tumor and dendritic cells induces tumor-specific T-cell and clinical responses in melanoma stage III and IV patients. Int J Cancer 2004; 110:730-40. [PMID: 15146563 DOI: 10.1002/ijc.20191] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Hybrid cell vaccination was developed as therapeutic approach that aims at stimulating tumor-specific cytotoxic T-cell responses in cancer patients using hybrids of autologous tumor and allogeneic dendritic cells. We tested this concept and the efficacy of the vaccines in inducing clinical and immunologic responses in a clinical trial with melanoma stage III and IV patients. Of the 17 patients evaluated, 1 experienced a complete response, 1 a partial response and 6 stable disease with remarkably long survival times. In 11 of 14 patients analyzed, high-frequency T-cell responses to various tumor-associated T-cell epitope were induced and detectable in the peripheral blood. These immune responses were detected in clinical response patients as well as nonresponders. Failures of clinical responses in all the cases investigated correlated with loss of antigen expression and presentation. Hybrid cell vaccination thus proves effective in inducing tumor-specific T-cell responses in cancer patients.
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Affiliation(s)
- Uwe Trefzer
- Department of Dermatology and Allergy, Charité, University Medicine Berlin, Humboldt University, Berlin, Germany
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Haenssle HA, Krause SW, Emmert S, Zutt M, Kretschmer L, Schmidberger H, Andreesen R, Soruri A. Hybrid Cell Vaccination in Metastatic Melanoma. J Immunother 2004; 27:147-55. [PMID: 14770086 DOI: 10.1097/00002371-200403000-00008] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Hybrid cell vaccination with cell fusion products (CFPs) of autologous tumor cells and mature allogenic MHC II bearing dendritic cells has been described to induce cytotoxic T lymphocyte (CTL)-mediated immune responses. The aim of this study was to assess safety, antitumor activity, and immune responses of a CFP-vaccine in patients with disseminated malignant melanoma. In a phase I/II study, we treated 11 patients by monthly intracutaneous or subcutaneous application of a CFP vaccine generated by electrofusion of autologous melanoma cells with mature allogenic dendritic cells. In addition, patients received subcutaneous low-dose interleukin-2 injections for 6 days after each vaccination. No serious adverse effects were observed. Ten patients showed progressive disease and one patient had a short-lasting stable disease. None of the patients developed a positive delayed-type hypersensitivity reaction against irradiated autologous melanoma cells. In 2 patients, who were monitored in more detail, we found no evidence of induction of a specific antimelanoma T-cell response by analyzing the proliferation, cytokine secretion, and cytotoxicity of their T cells toward autologous melanoma cells. No unequivocal beneficial effects of the used CFP vaccine could be demonstrated.
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Affiliation(s)
- Holger A Haenssle
- Department of Dermatology, Georg-August-University Goettingen, Germany.
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Abstract
A novel cancer vaccine consisting of fixed autologous cancer tissue-fragments, microparticles encapsulating cytokines, and an adjuvant was developed. In a Phase I/IIa clinical trial, vaccination to patients after resection of hepatocellular carcinoma induced significantly longer time before the first recurrence than that in historical control patients operated in the same department (P < 0.05). This formulation will be promising against recurrence of many types of human cancers.
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Affiliation(s)
- Tadao Ohno
- RIKEN Cell Bank, RIKEN (The Institute of Physical and Chemical Research), Koyadai 3-1-1, Tsukuba Science City, Ibaraki 305-0074, Japan.
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Iwashita Y, Tahara K, Goto S, Sasaki A, Kai S, Seike M, Chen CL, Kawano K, Kitano S. A phase I study of autologous dendritic cell-based immunotherapy for patients with unresectable primary liver cancer. Cancer Immunol Immunother 2003; 52:155-61. [PMID: 12649744 PMCID: PMC11032976 DOI: 10.1007/s00262-002-0360-9] [Citation(s) in RCA: 90] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2002] [Accepted: 10/23/2002] [Indexed: 02/06/2023]
Abstract
BACKGROUND/AIMS To evaluate the safety and feasibility of immunotherapy based on autologous dendritic cells (DC) for patients with unresectable primary liver cancer (PLC). METHODS A total of ten patients were enrolled and immunized with DCs. Autologous DCs were generated ex vivo in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). Cells were then pulsed with tumor lysate (TL), tumor necrosis factor-alpha (TNF-alpha) and keyhole limpet hemocyanin (KLH). Non-adherent cells were collected on day 9 and cells were administered into the inguinal lymph node. Each patient received 1-10 x 10(6) cells four times at weekly intervals. RESULTS Immunization was well tolerated in all patients without significant toxicity. DC vaccination induced delayed-type hypersensitivity (DTH) against KLH in seven out of ten patients. In one patient, one of the two liver tumors (tumor in segment 7, 13 mm in diameter) decreased in size to 7 mm and showed necrotic change on computed tomography examination after eight immunizations. In two patients, serum levels of tumor markers decreased after vaccination. CONCLUSION The present clinical trial suggested that immunization by TL-pulsed DCs is feasible in patients with unresectable PLC without any toxicity. Further improvement in the clinical results of immunotherapy might be expected by modifying the therapeutic protocol.
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Affiliation(s)
- Yukio Iwashita
- />Department of Surgery I, Oita Medical University, Hasama-machi, 879-5593 Oita, Japan
| | - Kouichirou Tahara
- />Department of Surgery I, Oita Medical University, Hasama-machi, 879-5593 Oita, Japan
| | - Shigeru Goto
- />Department of Surgery I, Oita Medical University, Hasama-machi, 879-5593 Oita, Japan
| | - Atsushi Sasaki
- />Department of Surgery I, Oita Medical University, Hasama-machi, 879-5593 Oita, Japan
| | - Seiichiro Kai
- />Department of Surgery I, Oita Medical University, Hasama-machi, 879-5593 Oita, Japan
| | - Masataka Seike
- />Department of Medicine I, Oita Medical University, Oita, Japan
| | - Chao-Long Chen
- />Department of Surgery, Chang Gung Memorial Hospital, Kaohsiung, Taiwan R.O.C
| | - Katsunori Kawano
- />Department of Surgery I, Oita Medical University, Hasama-machi, 879-5593 Oita, Japan
| | - Seigo Kitano
- />Department of Surgery I, Oita Medical University, Hasama-machi, 879-5593 Oita, Japan
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Goddard RV, Prentice AG, Copplestone JA, Kaminski ER. In vitro dendritic cell-induced T cell responses to B cell chronic lymphocytic leukaemia enhanced by IL-15 and dendritic cell-B-CLL electrofusion hybrids. Clin Exp Immunol 2003; 131:82-9. [PMID: 12519390 PMCID: PMC1808593 DOI: 10.1046/j.1365-2249.2003.02047.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
HLA class II-restricted proliferative and cytotoxic T cell (CTL) responses to B cell chronic lymphocytic leukaemia (B-CLL) can be generated using autologous dendritic cells (DCs) pulsed with tumour cell lysate. In this study a number of different approaches were used to optimize further the in vitro system. First, the effects of a variety of maturation agents were studied. The addition of TNF-alpha, polyriboinosinic polyribocytidylic acid (Poly(I:C)) and LPS to autologous DCs resulted in the emergence of only a small percentage of CD83+ DCs, IFN-alpha having no demonstrable effect. Only the addition of Poly(I:C) to DCs resulted in modestly increased specific cytotoxicity to B-CLL targets, IFN-alpha and LPS having no effect. Secondly, T cells were pretreated with IL-15, prior to culturing with lysate-pulsed autologous DCs. A significant increase in T cell activation (P = 0.038), IFN-gamma secretion (P = 0.030) and specific cytotoxicity to B-CLL targets (P = 0.006) was demonstrated compared to untreated T cells. Thirdly, monocyte derived DCs electrofused with B-CLL B cells were compared with lysate-pulsed DCs. T cells stimulated by fused DCs generated higher levels of specific cytotoxicity to autologous B-CLL B cell targets than those stimulated by lysate pulsed DCs (P = 0.013). Blocking studies demonstrated inhibition of this cytotoxicity by both anti-CD4 (P = 0.062) and anti-CD8 monoclonal antibodies (P = 0.018), suggesting the generation of both HLA class I- and HLA class II-restricted CTL responses. In summary, in vitro B-CLL-specific T cell responses can be enhanced further by preincubating T cells with IL-15 and using autologous fused DC-B-CLL hybrids instead of autologous lysate-pulsed DCs. These preliminary data require confirmation with larger numbers of patients. Such an approach, however, may eventually provide effective immunotherapy for treatment of B-CLL.
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Affiliation(s)
- R V Goddard
- Plymouth Postgraduate Medical School, Derriford Combined Laboratory, Derriford Hospital, Plymouth, Devon, UK
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46
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Krause SW, Neumann C, Soruri A, Mayer S, Peters JH, Andreesen R. The treatment of patients with disseminated malignant melanoma by vaccination with autologous cell hybrids of tumor cells and dendritic cells. J Immunother 2002; 25:421-8. [PMID: 12218780 DOI: 10.1097/00002371-200209000-00006] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Malignant melanoma has been shown to be susceptible to T cell-mediated immunity and, therefore, is a candidate for vaccination approaches. Clinical trials using dendritic cells (DC) loaded with peptides corresponding to tumor antigens are ongoing in several institutions, and some promising results have already been published. However, every single peptide-based vaccine can only be used in a patient with a given single HLA type, and this strategy is not appropriate for patients with rare HLA types or with tumors without defined antigens. A clinical pilot study in patients with disseminated melanoma refractory to standard therapy was initiated using a different approach. The authors generated autologous monocyte-derived DC and fused these DC with gamma-irradiated primary autologous tumor cells by incubation in polyethylene glycol. In previous experiments, the authors had shown that these fused cell products are potent inducers of a T-cell response in a mixed lymphocyte tumor cell culture. Seventeen patients were immunized with the cell product by s.c. injection in monthly intervals without any serious side effects. Of these patients, one had a partial response with decrease in size of all evaluable tumor manifestations. In one patient, some of the metastases were regressing despite an overall progressive disease, and one patient achieved disease stabilization for six months. In the responding patient, in parallel to tumor regression, circumscript hair depigmentation occurred. These data show, that a hybrid vaccine of DC and tumor cells can be safely applied and can induce tumor regressions, however, the clinical efficacy of the approach in its present form is insufficient.
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Affiliation(s)
- Stefan W Krause
- Department of Hematology and Oncology, University of Regensburg, Germany.
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Liu Y, Zhang W, Chan T, Saxena A, Xiang J. Engineered fusion hybrid vaccine of IL-4 gene-modified myeloma and relative mature dendritic cells enhances antitumor immunity. Leuk Res 2002; 26:757-63. [PMID: 12191571 DOI: 10.1016/s0145-2126(02)00002-4] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Dendritic cell (DC)-tumor fusion hybrid vaccine which facilitates antigen presentation represents a new powerful strategy in cancer therapy. In the present study, we investigated the antitumor immunity derived from vaccination of fusion hybrids between wild-type J558 or engineered J558-IL-4 myeloma cells secreting cytokine interleukin-4 (IL-4) and immature DCs (DC(IMAT)) or relative mature DCs (DC(RMAT)). DC(RMAT) displayed an up-regulated expression of immune molecules (Ia(d), CD40, CD54, CD80 and CD86) and certain cytokines/chemokines, and enhanced ability of allogeneic T cell stimulation when compared to DC(IMAT). These DCs were fused with myeloma cells by polyethylene glycol (PEG). The fusion efficiency was approximately 20%. Our data showed that immunization of C57BL/6 mice with DC(RMAT)/J558 hybrids induced protective immunity against a high dose of J558 tumor challenge (1x10(6) cells) in 3 out of 10 immunized mice, compared with no protection seen in mice immunized with DC(IMAT)/J558 hybrids. Furthermore, immunization of mice with engineered DC(RMAT)/J558-IL-4 hybrids elicited stronger J558 tumor-specific cytotoxic T lymphocyte (CTL) responses in vitro and induced more efficient protective immunity (10/10 mice; tumor free) against J558 tumor challenge in vivo than DC(RMAT)/J558 hybrid vaccines. The results demonstrate the importance of DC maturation in DC-tumor hybrid vaccines and indicate that the engineered fusion hybrid vaccines which combine gene-modified tumor and DC vaccines may be an attractive strategy for cancer immunotherapy.
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Affiliation(s)
- Yongqing Liu
- Research Unit, Departments of Oncology and Pathology, College of Medicine, Saskatchewan Cancer Agency, University of Saskatchewan, 20 Campus Drive, Saskatoon, Saskatchewan, Canada S7N 4H4
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Chapoval AI, Zhu G, Chen L. Immunoglobulin fusion proteins as a tool for evaluation of T-cell costimulatory molecules. Mol Biotechnol 2002; 21:259-64. [PMID: 12102550 DOI: 10.1385/mb:21:3:259] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Costimulatory signal(s) in addition to engagement of T cell receptor is important for optimal activation of T lymphocytes. During last decade several dozens of new costimulatory molecules, including 4-1BB, CD40, OX40, CD27, and ICOS, have been identified. It is likely that in Post-Genome Era more molecules with potential costimulatory properties will be brought to our attention. We describe here a simple and reliable strategy for evaluating the functional activities of potential costimulatory molecules using soluble fusion protein between extracellular portion of costimulatory ligand and Fc portion of mouse IgG2a.
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Peng BG, Liu SQ, Kuang M, He Q, Totsuka S, Huang L, Huang J, Lu MD, Liang LJ, Leong KW, Ohno T. Autologous fixed tumor vaccine: a formulation with cytokine-microparticles for protective immunity against recurrence of human hepatocellular carcinoma. Jpn J Cancer Res 2002; 93:363-8. [PMID: 11985784 PMCID: PMC5927015 DOI: 10.1111/j.1349-7006.2002.tb01265.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
We developed a tumor vaccine consisting of fixed hepatocellular carcinoma (HCC) cells/tissue fragments, biodegradable microparticles encapsulating granulocyte-macrophage-colony stimulating factor and interleukin-2, and an adjuvant. The vaccine protected 33% of syngeneic mice from HCC cell challenge. The vaccine containing human autologous HCC fragments showed essentially no adverse effect in a phase I/IIa clinical trial and 8/12 patients developed a delayed-type hypersensitivity (DTH) response against the fragments. Although 2 of 4 DTH-response-negative patients had recurrence after curative resection, the DTH-response-positive patients had no recurrence. The time before the first recurrence in the vaccinated patients was significantly longer than that in 24 historical control patients operated in the same department (P < 0.05). This formulation is a promising candidate to prevent recurrence of human HCC.
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Affiliation(s)
- Bao Gang Peng
- RIKEN Cell Bank, RIKEN, The Institute of Physical and Chemical Research, Tsukuba Science City, Ibaraki 305-0074, Japan
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50
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Abstract
This review summarizes and discusses a new vaccine strategy based on xenogeneic homologous molecules by the breaking of immune tolerance against the growth factors or their receptors associated with tumor growth in a cross-reaction between the xenogeneic homologs and self-molecules. The xenogeneic vaccine may circumvent the fact that few tumor-specific antigens have been identified in human solid tumors and that the host usually shows immune tolerance to self-molecules as antigens. It may be of importance for the further exploration of the applications of xenogeneic homologous genes identified in human and other animal genome sequence projects in cancer therapy.
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Affiliation(s)
- Yu-Quan Wei
- Center for Biotherapy of Cancer and Cancer Research Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PRC.
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