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Tomasicchio M, Semple L, Esmail A, Meldau R, Randall P, Pooran A, Davids M, Cairncross L, Anderson D, Downs J, Malherbe F, Novitzky N, Panieri E, Oelofse S, Londt R, Naiker T, Dheda K. An autologous dendritic cell vaccine polarizes a Th-1 response which is tumoricidal to patient-derived breast cancer cells. Cancer Immunol Immunother 2018; 68:71-83. [PMID: 30283982 PMCID: PMC6326986 DOI: 10.1007/s00262-018-2238-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 08/23/2018] [Indexed: 12/17/2022]
Abstract
Breast cancer remains one of the leading causes of cancer-associated death worldwide. Conventional treatment is associated with substantial toxicity and suboptimal efficacy. We, therefore, developed and evaluated the in vitro efficacy of an autologous dendritic cell (DC) vaccine to treat breast cancer. We recruited 12 female patients with stage 1, 2, or 3 breast cancer and matured their DCs with autologous tumour-specific lysate, a toll-like receptor (TLR)-3 and 7/8 agonist, and an interferon-containing cocktail. The efficacy of the vaccine was evaluated by its ability to elicit a cytotoxic T-lymphocyte response to autologous breast cancer cells in vitro. Matured DCs (≥ 60% upregulation of CD80, CD86, CD83, and CCR7) produced high levels of the Th1 effector cytokine, IL12-p70 (1.2 ng/ml; p < 0.0001), compared to DCs pulsed with tumour lysate, or matured with an interferon-containing cocktail alone. We further showed that matured DCs enhance antigen-specific CD8 + T-cell responses to HER-2 (4.5%; p < 0.005) and MUC-1 (19%; p < 0.05) tetramers. The mature DCs could elicit a robust and dose-dependent antigen-specific cytotoxic T-lymphocyte response (65%) which was tumoricidal to autologous breast cancer cells in vitro compared to T-lymphocytes that were primed with autologous lysate loaded-DCs (p < 0.005). Lastly, we showed that the mature DCs post-cryopreservation maintained high viability, maintained their mature phenotype, and remained free of endotoxins or mycoplasma. We have developed a DC vaccine that is cytotoxic to autologous breast cancer cells in vitro. The tools and technology generated here will now be applied to a phase I/IIa clinical trial.
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Affiliation(s)
- Michele Tomasicchio
- Division of Pulmonology and UCT Lung Institute, Department of Medicine, Centre for Lung Infection and Immunity, Groote Schuur Hospital, University of Cape Town, Old Main Building, H46.41, Groote Schuur Drive, Observatory, Cape Town, 7925, South Africa
| | - Lynn Semple
- Division of Pulmonology and UCT Lung Institute, Department of Medicine, Centre for Lung Infection and Immunity, Groote Schuur Hospital, University of Cape Town, Old Main Building, H46.41, Groote Schuur Drive, Observatory, Cape Town, 7925, South Africa
| | - Aliasgar Esmail
- Division of Pulmonology and UCT Lung Institute, Department of Medicine, Centre for Lung Infection and Immunity, Groote Schuur Hospital, University of Cape Town, Old Main Building, H46.41, Groote Schuur Drive, Observatory, Cape Town, 7925, South Africa
| | - Richard Meldau
- Division of Pulmonology and UCT Lung Institute, Department of Medicine, Centre for Lung Infection and Immunity, Groote Schuur Hospital, University of Cape Town, Old Main Building, H46.41, Groote Schuur Drive, Observatory, Cape Town, 7925, South Africa
| | - Philippa Randall
- Division of Pulmonology and UCT Lung Institute, Department of Medicine, Centre for Lung Infection and Immunity, Groote Schuur Hospital, University of Cape Town, Old Main Building, H46.41, Groote Schuur Drive, Observatory, Cape Town, 7925, South Africa
| | - Anil Pooran
- Division of Pulmonology and UCT Lung Institute, Department of Medicine, Centre for Lung Infection and Immunity, Groote Schuur Hospital, University of Cape Town, Old Main Building, H46.41, Groote Schuur Drive, Observatory, Cape Town, 7925, South Africa
| | - Malika Davids
- Division of Pulmonology and UCT Lung Institute, Department of Medicine, Centre for Lung Infection and Immunity, Groote Schuur Hospital, University of Cape Town, Old Main Building, H46.41, Groote Schuur Drive, Observatory, Cape Town, 7925, South Africa
| | - Lydia Cairncross
- Department of General Surgery, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa
| | - David Anderson
- Division of Radiation Oncology, Department of Radiation Medicine, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa
| | - Jennifer Downs
- Department of General Surgery, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa
| | - Francois Malherbe
- Department of General Surgery, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa
| | - Nicolas Novitzky
- National Health Laboratory Services (NHLS), Groote Schuur Hospital, Haematology, Cape Town, South Africa.,Division of Haematology, University of Cape Town, Cape Town, South Africa
| | - Eugenio Panieri
- Department of General Surgery, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa
| | - Suzette Oelofse
- Division of Pulmonology and UCT Lung Institute, Department of Medicine, Centre for Lung Infection and Immunity, Groote Schuur Hospital, University of Cape Town, Old Main Building, H46.41, Groote Schuur Drive, Observatory, Cape Town, 7925, South Africa
| | - Rolanda Londt
- Division of Pulmonology and UCT Lung Institute, Department of Medicine, Centre for Lung Infection and Immunity, Groote Schuur Hospital, University of Cape Town, Old Main Building, H46.41, Groote Schuur Drive, Observatory, Cape Town, 7925, South Africa
| | - Thurandrie Naiker
- Department of General Surgery, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa
| | - Keertan Dheda
- Division of Pulmonology and UCT Lung Institute, Department of Medicine, Centre for Lung Infection and Immunity, Groote Schuur Hospital, University of Cape Town, Old Main Building, H46.41, Groote Schuur Drive, Observatory, Cape Town, 7925, South Africa. .,Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
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Koido S. Dendritic-Tumor Fusion Cell-Based Cancer Vaccines. Int J Mol Sci 2016; 17:ijms17060828. [PMID: 27240347 PMCID: PMC4926362 DOI: 10.3390/ijms17060828] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2016] [Revised: 05/19/2016] [Accepted: 05/23/2016] [Indexed: 12/20/2022] Open
Abstract
Dendritic cells (DCs) are potent antigen-presenting cells (APCs) that play a critical role in the induction of antitumor immunity. Therefore, various strategies have been developed to deliver tumor-associated antigens (TAAs) to DCs as cancer vaccines. The fusion of DCs and whole tumor cells to generate DC-tumor fusion cells (DC-tumor FCs) is an alternative strategy to treat cancer patients. The cell fusion method allows DCs to be exposed to the broad array of TAAs originally expressed by whole tumor cells. DCs then process TAAs endogenously and present them through major histocompatibility complex (MHC) class I and II pathways in the context of costimulatory molecules, resulting in simultaneous activation of both CD4⁺ and CD8⁺ T cells. DC-tumor FCs require optimized enhanced immunogenicity of both DCs and whole tumor cells. In this context, an effective fusion strategy also needs to produce immunogenic DC-tumor FCs. We discuss the potential ability of DC-tumor FCs and the recent progress in improving clinical outcomes by DC-tumor FC-based cancer vaccines.
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Affiliation(s)
- Shigeo Koido
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, 277-8567 Chiba, Japan.
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Kajihara M, Takakura K, Kanai T, Ito Z, Matsumoto Y, Shimodaira S, Okamoto M, Ohkusa T, Koido S. Advances in inducing adaptive immunity using cell-based cancer vaccines: Clinical applications in pancreatic cancer. World J Gastroenterol 2016; 22:4446-58. [PMID: 27182156 PMCID: PMC4858628 DOI: 10.3748/wjg.v22.i18.4446] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Revised: 04/01/2016] [Accepted: 04/15/2016] [Indexed: 02/06/2023] Open
Abstract
The incidence of pancreatic ductal adenocarcinoma (PDA) is on the rise, and the prognosis is extremely poor because PDA is highly aggressive and notoriously difficult to treat. Although gemcitabine- or 5-fluorouracil-based chemotherapy is typically offered as a standard of care, most patients do not survive longer than 1 year. Therefore, the development of alternative therapeutic approaches for patients with PDA is imperative. As PDA cells express numerous tumor-associated antigens that are suitable vaccine targets, one promising treatment approach is cancer vaccines. During the last few decades, cell-based cancer vaccines have offered encouraging results in preclinical studies. Cell-based cancer vaccines are mainly generated by presenting whole tumor cells or dendritic cells to cells of the immune system. In particular, several clinical trials have explored cell-based cancer vaccines as a promising therapeutic approach for patients with PDA. Moreover, chemotherapy and cancer vaccines can synergize to result in increased efficacies in patients with PDA. In this review, we will discuss both the effect of cell-based cancer vaccines and advances in terms of future strategies of cancer vaccines for the treatment of PDA patients.
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Baines A, Martin P, Rorie C. Current and Emerging Targeting Strategies for Treatment of Pancreatic Cancer. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2016; 144:277-320. [DOI: 10.1016/bs.pmbts.2016.09.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Reguzova AY, Karpenko LI, Mechetina LV, Belyakov IM. Peptide-MHC multimer-based monitoring of CD8 T-cells in HIV-1 infection and AIDS vaccine development. Expert Rev Vaccines 2014; 14:69-84. [PMID: 25373312 DOI: 10.1586/14760584.2015.962520] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
The use of MHC multimers allows precise and direct detecting and analyzing of antigen-specific T-cell populations and provides new opportunities to characterize T-cell responses in humans and animals. MHC-multimers enable us to enumerate specific T-cells targeting to viral, tumor and vaccine antigens with exceptional sensitivity and specificity. In the field of HIV/SIV immunology, this technique provides valuable information about the frequencies of HIV- and SIV-specific CD8(+) cytotoxic T lymphocytes (CTLs) in different tissues and sites of infection, AIDS progression, and pathogenesis. Peptide-MHC multimer technology remains a very sensitive tool in detecting virus-specific T -cells for evaluation of the immunogenicity of vaccines against HIV-1 in preclinical trials. Moreover, it helps to understand how immune responses are formed following vaccination in the dynamics from priming point until T-cell memory is matured. Here we review a diversity of peptide-MHC class I multimer applications for fundamental immunological studies in different aspects of HIV/SIV infection and vaccine development.
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Affiliation(s)
- Alena Y Reguzova
- State Research Center of Virology and Biotechnology "Vector", Koltsovo, Novosibirsk region, 630559, Russia
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Koido S, Homma S, Kan S, Takakura K, Namiki Y, Kobayashi H, Ito Z, Uchiyama K, Kajihara M, Arihiro S, Arakawa H, Okamoto M, Ohkusa T, Gong J, Tajiri H. Induction of antigen-specific cytotoxic T lymphocytes by fusion cells generated from allogeneic plasmacytoid dendritic and tumor cells. Int J Oncol 2014; 45:470-8. [PMID: 24819411 DOI: 10.3892/ijo.2014.2433] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Accepted: 04/17/2014] [Indexed: 11/06/2022] Open
Abstract
Previous work has demonstrated that fusion cells generated from autologous monocyte-derived dendritic cells (MoDCs) and whole tumor cells induce efficient antigen-specific cytotoxic T lymphocytes. A major limitation to the use of this strategy is the availability of adequate amounts of autologous tumor cells. Moreover, MoDCs from cancer patients are often defective in their antigen-processing and presentation machinery. In this study, two types of allogeneic cells, a leukemia plasmacytoid dendritic cell (pDC) line (PMDC05) and pancreatic cancer cell lines (PANC-1 or MIA PaCa-2), were fused instead of autologous MoDCs and tumor cells. We created four types of pDC/tumor fusion cells by alternating fusion partners and treating with lipopolysaccharide (LPS): i) PMDC05 fused with PANC-1 (pDC/PANC-1), ii) PMDC05 fused with MIA PaCa-2 (pDC/MIA PaCa-2), iii) LPS-stimulated pDC/PANC-1 (LPS-pDC/PANC-1) and iv) LPS-stimulated pDC/MIA PaCa-2 (LPS-pDC/MIA PaCa-2) and examined their antitumor immune responses. The LPS-pDC/tumor cell fusions were the most active, as demonstrated by their: i) upregulated expression of HLA-DR and CD86 on a per-fusion-cell basis, ii) increased production of IL-12p70, iii) generation of a higher percentage of IFN-γ-producing CD4⁺ and CD8⁺ T cells and iv) augmented induction of MUC1-specific CD8⁺ T cells that lyse target tumor cells. This study provides the first evidence for an in vitro induction of antigen-specific cytotoxic T lymphocytes by LPS-stimulated fusion cells generated from leukemia plasmacytoid DCs and tumor cells and suggests that this strategy has potential applicability to the field of adoptive immunotherapy.
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Affiliation(s)
- Shigeo Koido
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Chiba 277-8564, Japan
| | - Sadamu Homma
- Department of Oncology, Jikei University School of Medicine, Tokyo 105-8461, Japan
| | - Shin Kan
- Department of Oncology, Jikei University School of Medicine, Tokyo 105-8461, Japan
| | - Kazuki Takakura
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Chiba 277-8564, Japan
| | - Yoshihisa Namiki
- Institute of Clinical Medicine and Research, Jikei University School of Medicine, Chiba 277-8564, Japan
| | - Hiroko Kobayashi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Chiba 277-8564, Japan
| | - Zensho Ito
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Chiba 277-8564, Japan
| | - Kan Uchiyama
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Chiba 277-8564, Japan
| | - Mikio Kajihara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Chiba 277-8564, Japan
| | - Seiji Arihiro
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Chiba 277-8564, Japan
| | - Hiroshi Arakawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Chiba 277-8564, Japan
| | - Masato Okamoto
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Toshifumi Ohkusa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Chiba 277-8564, Japan
| | - Jianlin Gong
- Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA
| | - Hisao Tajiri
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Chiba 277-8564, Japan
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Amedei A, Niccolai E, Prisco D. Pancreatic cancer: role of the immune system in cancer progression and vaccine-based immunotherapy. Hum Vaccin Immunother 2014; 10:3354-3368. [PMID: 25483688 PMCID: PMC4514060 DOI: 10.4161/hv.34392] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2014] [Revised: 07/25/2014] [Accepted: 08/08/2014] [Indexed: 12/18/2022] Open
Abstract
Pancreatic cancer (PC) is the 5th leading cause of cancer related death in the developed world with more than 260,000 deaths annually worldwide and with a dismal 5-year survival. Surgery is the only potential hope of cure for PC, but, unfortunately, only 20% PC patients is resectable at the time of diagnosis. Therapeutic research efforts have mainly focused on improvements in radio/ chemo treatments and to date, there are only a few chemotherapeutic agents that have shown to be effective against PC, including gemcitabine with or without abraxane as well as a combination of 5-FU, leucovorin, oxaliplatin and irinotecan (the so-called FOLFIRINOX regimen). The survival of patients treated with these regimens is marginal and hence we are in urgent need of novel therapeutic approaches to treat pancreatic cancer. The success of immunotherapeutic strategies in other cancers and various evidences that pancreatic adenocarcinoma elicits antitumor immune responses, suggest that immunotherapies can be a promising alternative treatment modality for this deadly disease. PC immunotherapy treatments include passive immunotherapeutic approaches, such as the use of effector cells generated in vitro, and active immunotherapeutic strategies, which goal is to stimulate an antitumor response in vivo, by means of vaccination. In this review, we describe the immune suppressive mechanisms of pancreatic cancer and discuss recent preclinical and clinical efforts toward PC immunotherapy, including passive approaches, such as the use of antibodies and active strategies (vaccination), with a special mention of most recent treatment with CRS-207 and GVAX.
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Key Words
- APC, Antigen Presenting Cells
- CEA, carcinoembryonic antigen
- CTL, Cytotoxic CD8 T cells
- DCs, Dendritic Cells
- ENO1, a-Enolasi
- IDO, Indoleamine 2,3-dioxygenase
- MUC1, Mucin-1
- NK, Natural Killer
- PC, pancreatic cancer
- Th, T helper
- Tregs, Regulatory T cells
- clinical trials
- immune response
- immunotherapy
- mAbs, monoclonal antibodies
- pancreatic cancer
- vaccine
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Affiliation(s)
- Amedeo Amedei
- Department of Experimental and Clinical Internal Medicine; University of Florence; Florence, Italy
- Department of Biomedicine; Azienda Ospedaliera Universitaria Careggi (AOUC); Florence, Italy
| | - Elena Niccolai
- Department of Experimental and Clinical Internal Medicine; University of Florence; Florence, Italy
| | - Domenico Prisco
- Department of Experimental and Clinical Internal Medicine; University of Florence; Florence, Italy
- Department of Biomedicine; Azienda Ospedaliera Universitaria Careggi (AOUC); Florence, Italy
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Koido S, Ohkusa T, Homma S, Namiki Y, Takakura K, Saito K, Ito Z, Kobayashi H, Kajihara M, Uchiyama K, Arihiro S, Arakawa H, Okamoto M, Gong J, Tajiri H. Immunotherapy for colorectal cancer. World J Gastroenterol 2013; 19:8531-8542. [PMID: 24379570 PMCID: PMC3870498 DOI: 10.3748/wjg.v19.i46.8531] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2013] [Revised: 10/22/2013] [Accepted: 11/19/2013] [Indexed: 02/06/2023] Open
Abstract
The incidence of colorectal cancer (CRC) is on the rise, and the prognosis for patients with recurrent or metastatic disease is extremely poor. Although chemotherapy and radiation therapy can improve survival rates, it is imperative to integrate alternative strategies such as immunotherapy to improve outcomes for patients with advanced CRC. In this review, we will discuss the effect of immunotherapy for inducing cytotoxic T lymphocytes and the major immunotherapeutic approaches for CRC that are currently in clinical trials, including peptide vaccines, dendritic cell-based cancer vaccines, whole tumor cell vaccines, viral vector-based cancer vaccines, adoptive cell transfer therapy, antibody-based cancer immunotherapy, and cytokine therapy. The possibility of combination therapies will also be discussed along with the challenges presented by tumor escape mechanisms.
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Koido S, Homma S, Okamoto M, Namiki Y, Takakura K, Takahara A, Odahara S, Tsukinaga S, Yukawa T, Mitobe J, Matsudaira H, Nagatsuma K, Kajihara M, Uchiyama K, Arihiro S, Imazu H, Arakawa H, Kan S, Hayashi K, Komita H, Kamata Y, Ito M, Hara E, Ohkusa T, Gong J, Tajiri H. Augmentation of antitumor immunity by fusions of ethanol-treated tumor cells and dendritic cells stimulated via dual TLRs through TGF-β1 blockade and IL-12p70 production. PLoS One 2013; 8:e63498. [PMID: 23717436 PMCID: PMC3663747 DOI: 10.1371/journal.pone.0063498] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2013] [Accepted: 04/02/2013] [Indexed: 12/13/2022] Open
Abstract
The therapeutic efficacy of fusion cell (FC)-based cancer vaccine generated with whole tumor cells and dendritic cells (DCs) requires the improved immunogenicity of both cells. Treatment of whole tumor cells with ethanol resulted in blockade of immune-suppressive soluble factors such as transforming growth factor (TGF)-β1, vascular endothelial growth factor, and IL-10 without decreased expression of major histocompatibility complex (MHC) class I and the MUC1 tumor-associated antigen. Moreover, the ethanol-treated tumor cells expressed “eat-me” signals such as calreticulin (CRT) on the cell surface and released immunostimulatory factors such as heat shock protein (HSP)90α and high-mobility group box 1 (HMGB1). A dual stimulation of protein-bound polysaccharides isolated from Coriolus versicolor (TLR2 agonist) and penicillin-inactivated Streptococcus pyogenes (TLR4 agonist) led human monocyte-derived DCs to produce HSP90α and multiple cytokines such as IL-12p70 and IL-10. Interestingly, incorporating ethanol-treated tumor cells and TLRs-stimulated DCs during the fusion process promoted fusion efficiency and up-regulated MHC class II molecules on a per fusion basis. Moreover, fusions of ethanol-treated tumor cells and dual TLRs-stimulated DCs (E-tumor/FCs) inhibited the production of multiple immune-suppressive soluble factors including TGF-β1 and up-regulated the production of IL-12p70 and HSP90α. Most importantly, E-tumor/FCs activated T cells capable of producing high levels of IFN-γ, resulting in augmented MUC1-specific CTL induction. Collectively, our results illustrate the synergy between ethanol-treated whole tumor cells and dual TLRs-stimulated DCs in inducing augmented CTL responses in vitro by FC preparations. The alternative system is simple and may provide a platform for adoptive immunotherapy.
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Affiliation(s)
- Shigeo Koido
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
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Koido S, Homma S, Okamoto M, Namiki Y, Takakura K, Takahara A, Odahara S, Tsukinaga S, Yukawa T, Mitobe J, Matsudaira H, Nagatsuma K, Uchiyama K, Kajihara M, Arihiro S, Imazu H, Arakawa H, Kan S, Komita H, Ito M, Ohkusa T, Gong J, Tajiri H. Combined TLR2/4-activated dendritic/tumor cell fusions induce augmented cytotoxic T lymphocytes. PLoS One 2013; 8:e59280. [PMID: 23555011 PMCID: PMC3598755 DOI: 10.1371/journal.pone.0059280] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2013] [Accepted: 02/13/2013] [Indexed: 12/01/2022] Open
Abstract
Induction of antitumor immunity by dendritic cell (DC)-tumor fusion cells (DC/tumor) can be modulated by their activation status. In this study, to address optimal status of DC/tumor to induce efficient antigen-specific cytotoxic T lymphocytes (CTLs), we have created various types of DC/tumor: 1) un-activated DC/tumor; 2) penicillin-killed Streptococcus pyogenes (OK-432; TLR4 agonist)-activated DC/tumor; 3) protein-bound polysaccharides isolated from Coriolus versicolor (PSK; TLR2 agonist)-activated DC/tumor; and 4) Combined OK-432- and PSK-activated DC/tumor. Moreover, we assessed the effects of TGF-β1 derived from DC/tumor on the induction of MUC1-specific CTLs. Combined TLR2- and TLR4-activated DC/tumor overcame immune-suppressive effect of TGF-β1 in comparison to those single activated or un-activated DC/tumor as demonstrated by: 1) up-regulation of MHC class II and CD86 expression on DC/tumor; 2) increased fusion efficiency; 3) increased production of fusions derived IL-12p70; 4) activation of CD4+ and CD8+ T cells that produce high levels of IFN-γ; 5) augmented induction of CTL activity specific for MUC1; and 6) superior efficacy in inhibiting CD4+CD25+Foxp3+ T cell generation. However, DC/tumor-derived TGF-β1 reduced the efficacy of DC/tumor vaccine in vitro. Incorporating combined TLRs-activation and TGF-β1-blockade of DC/tumor may enhance the effectiveness of DC/tumor-based cancer vaccines and have the potential applicability to the field of adoptive immunotherapy.
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Affiliation(s)
- Shigeo Koido
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
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Niccolai E, Prisco D, D'Elios MM, Amedei A. What is recent in pancreatic cancer immunotherapy? BIOMED RESEARCH INTERNATIONAL 2012; 2013:492372. [PMID: 23509731 PMCID: PMC3591222 DOI: 10.1155/2013/492372] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/21/2012] [Accepted: 07/06/2012] [Indexed: 12/13/2022]
Abstract
Pancreatic cancer (PC) represents an unresolved therapeutic challenge, due to the poor prognosis and the reduced response to currently available treatments. Pancreatic cancer is the most lethal type of digestive cancers, with a median survival of 4-6 months. Only a small proportion of PC patients is curative by surgical resection, whilst standard chemotherapy for patients in advanced disease generates only modest effects with considerable toxic damages. Thus, new therapeutic approaches, specially specific treatments such as immunotherapy, are needed. In this paper we analyze recent preclinical and clinical efforts towards immunotherapy of pancreatic cancer, including passive and active immunotherapy approaches, designed to target pancreatic-cancer-associated antigens and to elicit an antitumor response in vivo.
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Affiliation(s)
- Elena Niccolai
- Department of Internal Medicine, University of Florence and Patologia Medica Unit Department of Biomedicine, Azienda Ospedaliero-Universitaria Careggi, 50134 Florence, Italy
| | - Domenico Prisco
- Department of Medical and Surgical Critical Care, University of Florence and Patologia Medica Unit Department of Biomedicine, Azienda Ospedaliero Universitaria Careggi, 50134 Florence, Italy
| | - Mario Milco D'Elios
- Department of Internal Medicine, University of Florence and Patologia Medica Unit Department of Biomedicine, Azienda Ospedaliero-Universitaria Careggi, 50134 Florence, Italy
- Center of Oncologic Minimally Invasive Surgery, University of Florence, Largo Brambilla 3, 50134 Florence, Italy
| | - Amedeo Amedei
- Department of Internal Medicine, University of Florence and Patologia Medica Unit Department of Biomedicine, Azienda Ospedaliero-Universitaria Careggi, 50134 Florence, Italy
- Center of Oncologic Minimally Invasive Surgery, University of Florence, Largo Brambilla 3, 50134 Florence, Italy
- Division of Immunology, Department of Internal Medicine, University of Florence, Viale Pieraccini, 6, 50134 Florence, Italy
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Current immunotherapeutic approaches in pancreatic cancer. Clin Dev Immunol 2011; 2011:267539. [PMID: 21922022 PMCID: PMC3172984 DOI: 10.1155/2011/267539] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2011] [Accepted: 06/26/2011] [Indexed: 12/13/2022]
Abstract
Pancreatic cancer is a highly aggressive and notoriously difficult to treat. As the vast majority of patients are diagnosed at advanced stage of the disease, only a small population is curative by surgical resection. Although gemcitabine-based chemotherapy is typically offered as standard of care, most patients do not survive longer than 6 months. Thus, new therapeutic approaches are needed. Pancreatic cancer cells that develop gemcitabine resistance would still be suitable targets for immunotherapy. Therefore, one promising treatment approach may be immunotherapy that is designed to target pancreatic-cancer-associated antigens. In this paper, we detail recent work in immunotherapy and the advances in concept of combination therapy of immunotherapy and chemotherapy. We offer our perspective on how to increase the clinical efficacy of immunotherapies for pancreatic cancer.
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Immunologic monitoring of cellular responses by dendritic/tumor cell fusion vaccines. J Biomed Biotechnol 2011; 2011:910836. [PMID: 21541197 PMCID: PMC3085507 DOI: 10.1155/2011/910836] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2010] [Revised: 11/11/2010] [Accepted: 02/27/2011] [Indexed: 12/22/2022] Open
Abstract
Although dendritic cell (DC)- based cancer vaccines induce effective antitumor activities in murine models, only limited therapeutic results have been obtained in clinical trials. As cancer vaccines induce antitumor activities by eliciting or modifying immune responses in patients with cancer, the Response Evaluation Criteria in Solid Tumors (RECIST) and WHO criteria, designed to detect early effects of cytotoxic chemotherapy in solid tumors, may not provide a complete assessment of cancer vaccines. The problem may, in part, be resolved by carrying out immunologic cellular monitoring, which is one prerequisite for rational development of cancer vaccines. In this review, we will discuss immunologic monitoring of cellular responses for the evaluation of cancer vaccines including fusions of DC and whole tumor cell.
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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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15
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Regulation of tumor immunity by tumor/dendritic cell fusions. Clin Dev Immunol 2010; 2010:516768. [PMID: 21048993 PMCID: PMC2964897 DOI: 10.1155/2010/516768] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2010] [Accepted: 09/22/2010] [Indexed: 02/07/2023]
Abstract
The goal of cancer vaccines is to induce antitumor immunity that ultimately will reduce tumor burden in tumor environment. Several strategies involving dendritic cells- (DCs)- based vaccine incorporating different tumor-associated antigens to induce antitumor immune responses against tumors have been tested in clinical trials worldwide. Although DCs-based vaccine such as fusions of whole tumor cells and DCs has been proven to be clinically safe and is efficient to enhance antitumor immune responses for inducing effective immune response and for breaking T-cell tolerance to tumor-associated antigens (TAAs), only a limited success has occurred in clinical trials. This paper reviews tumor immune escape and current strategies employed in the field of tumor/DC fusions vaccine aimed at enhancing activation of TAAs-specific cytotoxic T cells in tumor microenvironment.
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