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1
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Fines C, McCarthy H, Buckley N. The search for a TNBC vaccine: the guardian vaccine. Cancer Biol Ther 2025; 26:2472432. [PMID: 40089851 PMCID: PMC11913391 DOI: 10.1080/15384047.2025.2472432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 02/18/2025] [Accepted: 02/19/2025] [Indexed: 03/17/2025] Open
Abstract
Nearly 20 million people are diagnosed with cancer each year with breast cancer being the most common among women. Triple negative breast cancer (TNBC), defined by its no/low expression of ER and PR and lack of amplification of HER2, makes up 15-20% of all breast cancer cases. While patients overall have a higher response to chemotherapy, this subgroup is associated with the lowest survival rate indicating significant clinical and molecular heterogeneity demanding alternate treatment options. Therefore, new therapies have been explored, with a large focus on utilizing the immune system. A whole host of immunotherapies have been studied including immune checkpoint inhibitors, now standard of care for eligible patients, and possibly the most exciting and promising is that of a TNBC vaccine. While currently there are no approved TNBC vaccines, this review highlights many promising studies and points to an antigen, p53, which we believe is highly relevant for TNBC.
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Affiliation(s)
- Cory Fines
- School of Pharmacy, Queen’s University Belfast, Belfast, UK
| | - Helen McCarthy
- School of Pharmacy, Queen’s University Belfast, Belfast, UK
| | - Niamh Buckley
- School of Pharmacy, Queen’s University Belfast, Belfast, UK
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2
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Zhu T, Li Y, Wang Y, Li D. The Application of Dendritic Cells Vaccines in Tumor Therapy and Their Combination with Biomimetic Nanoparticles. Vaccines (Basel) 2025; 13:337. [PMID: 40333202 PMCID: PMC12031636 DOI: 10.3390/vaccines13040337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Revised: 03/14/2025] [Accepted: 03/19/2025] [Indexed: 05/09/2025] Open
Abstract
Dendritic cells (DCs) act as a bridge between innate and adaptive immunity by presenting antigens to effector immune cells and have shown broad application potential in tumor immunotherapy. However, the clinical translation of DC vaccines encounters significant challenges, such as the immunosuppressive tumor microenvironment (TME) and the sub-optimal DC function and vaccine efficacy in vivo. In this review, our investigation has uncovered the latest developments in DC vaccines and their potential in cancer immunotherapy, with a special emphasis on the integration of nanotechnology. Several types of nanomaterials, including protein cage nanoparticles (NPs), biomimetic NPs, and targeted multifunctional NPs, have been developed to enhance the antigen presentation ability of DCs and their stimulatory effects on T cells. In addition, we have also summarized the synergistic anti-cancer effects of DC vaccines with immune checkpoint inhibitors, chemotherapy, and radiotherapy. In addition, recent advances in nanotechnology have made it possible to develop novel biomarkers that can enhance the antigen presentation capacity of DCs and stimulate T cells. These biomarkers not only improve the accuracy and precision of DC vaccine design but also provide new insights into understanding the mechanisms of the DC-mediated immune response. Despite challenges pertaining to technical complexities and individual adaptation in the design and production of DC vaccines, personalized immunotherapy based on DCs is expected to become an important part of cancer treatment with rapid developments in biotechnology and immunology. This review provides new perspectives and potential solutions for the optimal design and application of DC vaccines in cancer therapy.
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Affiliation(s)
- Tong Zhu
- Panjin Central Hospital, Panjin 124010, China;
| | - Yuexin Li
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin 150081, China;
| | - Yutao Wang
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng, Beijing 100000, China
| | - Danyang Li
- Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China
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3
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Tao HY, Zhao CY, Wang Y, Sheng WJ, Zhen YS. Targeting Telomere Dynamics as an Effective Approach for the Development of Cancer Therapeutics. Int J Nanomedicine 2024; 19:3805-3825. [PMID: 38708177 PMCID: PMC11069074 DOI: 10.2147/ijn.s448556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 03/14/2024] [Indexed: 05/07/2024] Open
Abstract
Telomere is a protective structure located at the end of chromosomes of eukaryotes, involved in maintaining the integrity and stability of the genome. Telomeres play an essential role in cancer progression; accordingly, targeting telomere dynamics emerges as an effective approach for the development of cancer therapeutics. Targeting telomere dynamics may work through multifaceted molecular mechanisms; those include the activation of anti-telomerase immune responses, shortening of telomere lengths, induction of telomere dysfunction and constitution of telomerase-responsive drug release systems. In this review, we summarize a wide variety of telomere dynamics-targeted agents in preclinical studies and clinical trials, and reveal their promising therapeutic potential in cancer therapy. As shown, telomere dynamics-active agents are effective as anti-cancer chemotherapeutics and immunotherapeutics. Notably, these agents may display efficacy against cancer stem cells, reducing cancer stem levels. Furthermore, these agents can be integrated with the capability of tumor-specific drug delivery by the constitution of related nanoparticles, antibody drug conjugates and HSA-based drugs.
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Affiliation(s)
- Hong-yu Tao
- Laboratory of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Chun-yan Zhao
- Laboratory of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Ying Wang
- Laboratory of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Wei-jin Sheng
- Laboratory of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
| | - Yong-su Zhen
- Laboratory of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
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4
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Zhao L, Zhang S, Kepp O, Kroemer G, Liu P. Dendritic cell transfer for cancer immunotherapy. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2022; 370:33-64. [PMID: 35798506 DOI: 10.1016/bs.ircmb.2022.03.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Dendritic cells (DCs) play a major role in cancer immunosurveillance as they bridge innate and adaptive immunity by detecting tumor-associated antigens and presenting them to T lymphocytes. The adoptive transfer of antigen loaded DCs has been proposed as an immunotherapeutic approach for the treatment of various types of cancer. Nevertheless, despite promising preclinical data, the therapeutic efficacy of DC transfer is still deceptive in cancer patients. Here we summarize recent findings in DC biology with a special focus on the development of actionable therapeutic strategies and discuss experimental and clinical approaches that aim at improving the efficacy of DC-based immunotherapies, including, but not limited to, optimized DC production and antigen loading, stimulated maturation, the co-treatment with additional immunotherapies, as well as the inhibition of DC checkpoints.
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Affiliation(s)
- Liwei Zhao
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France; Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France
| | - Shuai Zhang
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France; Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France
| | - Oliver Kepp
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France; Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France.
| | - Guido Kroemer
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France; Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France; Institut du Cancer Paris Carpem, Department of Biology, Hôpital Européen Georges Pompidou, APHP, Paris, France.
| | - Peng Liu
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France; Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France.
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5
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Zhou S, Fan C, Zeng Z, Young KH, Li Y. Clinical and Immunological Effects of p53-Targeting Vaccines. Front Cell Dev Biol 2021; 9:762796. [PMID: 34805170 PMCID: PMC8595300 DOI: 10.3389/fcell.2021.762796] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 10/18/2021] [Indexed: 12/11/2022] Open
Abstract
Immunotherapy, including immune checkpoint blockade and chimeric antigen receptor T cells, is one of the most promising approaches to treat cancer. Vaccines have been effective in preventing cancers like liver cancer and cervical cancer with a viral etiology. Instead of preventing disease, therapeutic cancer vaccines mobilize the immune system to attack existing cancer. p53 is dysregulated in the majority of human cancers and is a highly promising target for cancer vaccines. Over twenty clinical trials have targeted p53 in malignant diseases using vaccines. In this work, we review the progress of vaccinations with p53 or its peptides as the antigens and summarize the clinical and immunological effects of p53-targeting vaccines from clinical trials. The delivery platforms include p53 peptides, viral vectors, and dendritic cells pulsed with short peptides or transduced by p53-encoding viruses. These studies shed light on the feasibility, safety, and clinical benefit of p53 vaccination in select groups of patients, implicating that p53-targeting vaccines warrant further investigations in experimental animals and human studies.
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Affiliation(s)
- Shan Zhou
- Section of Epidemiology and Population Science, Department of Medicine, Baylor College of Medicine, Houston, TX, United States
| | - Chunmei Fan
- Section of Epidemiology and Population Science, Department of Medicine, Baylor College of Medicine, Houston, TX, United States
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine, Central South University, Changsha, China
| | - Zhaoyang Zeng
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine, Central South University, Changsha, China
| | - Ken H. Young
- Hematopathology Division, Department of Pathology, Duke University Medical Center, Durham, NC, United States
| | - Yong Li
- Section of Epidemiology and Population Science, Department of Medicine, Baylor College of Medicine, Houston, TX, United States
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6
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Milowska K, Rodacka A, Melikishvili S, Buczkowski A, Pałecz B, Waczulikova I, Hianik T, Majoral JP, Ionov M, Bryszewska M. Dendrimeric HIV-peptide delivery nanosystem affects lipid membranes structure. Sci Rep 2021; 11:16810. [PMID: 34413368 PMCID: PMC8376938 DOI: 10.1038/s41598-021-96194-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 08/03/2021] [Indexed: 11/08/2022] Open
Abstract
The aim of this study was to evaluate the nature and mechanisms of interaction between HIV peptide/dendrimer complexes (dendriplex) and artificial lipid membranes, such as large unilayered vesicles (LUV) and lipid monolayers in the air-water interface. Dendriplexes were combined as one of three HIV-derived peptides (Gp160, P24 and Nef) and one of two cationic phosphorus dendrimers (CPD-G3 and CPD-G4). LUVs were formed of 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC) or of a mixture of DMPC and dipalmitoyl-phosphatidylglycerol (DPPG). Interactions between dendriplexes and vesicles were characterized by dynamic light scattering (DLS), fluorescence anisotropy, differential scanning calorimetry (DSC) and Langmuir-Blodgett methods. The morphology of formed systems was examined by transmission electron microscopy (TEM). The results suggest that dendriplexes interact with both hydrophobic and hydrophilic regions of lipid bilayers. The interactions between dendriplexes and negatively charged lipids (DMPC-DPPG) were stronger than those between dendriplexes and liposomes composed of zwitterionic lipids (DMPC). The former were primarily of electrostatic nature due to the positive charge of dendriplexes and the negative charge of the membrane, whereas the latter can be attributed to disturbances in the hydrophobic domain of the membrane. Obtained results provide new information about mechanisms of interaction between lipid membranes and nanocomplexes formed with HIV-derived peptides and phosphorus dendrimers. These data could be important for the choosing the appropriate antigen delivery vehicle in the new vaccines against HIV infection.
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Affiliation(s)
- Katarzyna Milowska
- Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236, Lodz, Poland
| | - Aleksandra Rodacka
- Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236, Lodz, Poland
| | - Sophie Melikishvili
- Faculty of Mathematics, Physics and Informatics, Comenius University, Mlynska dolina, 842 48, Bratislava, Slovakia
| | - Adam Buczkowski
- Unit of Biophysical Chemistry, Department of Physical Chemistry, Faculty of Chemistry, 165 Pomorska St., 90-236, University of Lodz, Lodz, Poland
| | - Bartlomiej Pałecz
- Unit of Biophysical Chemistry, Department of Physical Chemistry, Faculty of Chemistry, 165 Pomorska St., 90-236, University of Lodz, Lodz, Poland
| | - Iveta Waczulikova
- Faculty of Mathematics, Physics and Informatics, Comenius University, Mlynska dolina, 842 48, Bratislava, Slovakia
| | - Tibor Hianik
- Faculty of Mathematics, Physics and Informatics, Comenius University, Mlynska dolina, 842 48, Bratislava, Slovakia
| | - Jean Pierre Majoral
- Laboratoire de Chimie de Coordination du CNRS (LCC), 205 Route de Narbonne, 31077, Toulouse Cedex 4, France
| | - Maksim Ionov
- Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236, Lodz, Poland.
| | - Maria Bryszewska
- Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236, Lodz, Poland
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7
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Li Y, Lu W, Yang J, Edwards M, Jiang S. Survivin as a biological biomarker for diagnosis and therapy. Expert Opin Biol Ther 2021; 21:1429-1441. [PMID: 33877952 DOI: 10.1080/14712598.2021.1918672] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Introduction: Survivin (SVN) is a member of the inhibitor of apoptosis (IAP) protein family that promotes cellular proliferation and inhibits apoptosis. Overexpression of SVN is associated with autoimmune disease, hyperplasia, and tumors and can be used as a biomarker in these diseases. SVN is widely recognized as a tumor-associated antigen (TAA) and has become an important target for cancer diagnosis and treatment.Areas covered: We reviewed SVN research progress from the PubMed and clinical trials focused on SVN from https://clinicaltrials.gov since 2000 and anticipate future developments in the field. The trials reviewed cover various modalities including diagnostics for early detection and disease progression, small molecule inhibitors of the SVN pathway and immunotherapy targeting SVN epitopes.Expert opinion: The most promising developments involve anti-SVN immunotherapy, with several therapeutic SVN vaccines under evaluation in phase I/II trials. SVN is an important new immune-oncology target that expands the repertoire of individualized combination treatments for cancer.
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Affiliation(s)
- Yuming Li
- Department of Oncology, University of Oxford, Oxford, UK.,School of Life Sciences, Tsinghua University, Beijing, China
| | - Wenshu Lu
- Department of Oncology, University of Oxford, Oxford, UK
| | - Jiarun Yang
- Department of Oncology, University of Oxford, Oxford, UK
| | - Mark Edwards
- Department of Research and Development, Oxford Vacmedix UK Ltd, Oxford, UK
| | - Shisong Jiang
- Department of Oncology, University of Oxford, Oxford, UK.,Department of Research and Development, Oxford Vacmedix UK Ltd, Oxford, UK
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8
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Tanyi JL, Chiang CLL, Chiffelle J, Thierry AC, Baumgartener P, Huber F, Goepfert C, Tarussio D, Tissot S, Torigian DA, Nisenbaum HL, Stevenson BJ, Guiren HF, Ahmed R, Huguenin-Bergenat AL, Zsiros E, Bassani-Sternberg M, Mick R, Powell DJ, Coukos G, Harari A, Kandalaft LE. Personalized cancer vaccine strategy elicits polyfunctional T cells and demonstrates clinical benefits in ovarian cancer. NPJ Vaccines 2021; 6:36. [PMID: 33723260 PMCID: PMC7960755 DOI: 10.1038/s41541-021-00297-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 02/17/2021] [Indexed: 01/31/2023] Open
Abstract
T cells are important for controlling ovarian cancer (OC). We previously demonstrated that combinatorial use of a personalized whole-tumor lysate-pulsed dendritic cell vaccine (OCDC), bevacizumab (Bev), and cyclophosphamide (Cy) elicited neoantigen-specific T cells and prolonged OC survival. Here, we hypothesize that adding acetylsalicylic acid (ASA) and low-dose interleukin (IL)-2 would increase the vaccine efficacy in a recurrent advanced OC phase I trial (NCT01132014). By adding ASA and low-dose IL-2 to the OCDC-Bev-Cy combinatorial regimen, we elicited vaccine-specific T-cell responses that positively correlated with patients' prolonged time-to-progression and overall survival. In the ID8 ovarian model, animals receiving the same regimen showed prolonged survival, increased tumor-infiltrating perforin-producing T cells, increased neoantigen-specific CD8+ T cells, and reduced endothelial Fas ligand expression and tumor-infiltrating T-regulatory cells. This combinatorial strategy was efficacious and also highlighted the predictive value of the ID8 model for future ovarian trial development.
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Affiliation(s)
- Janos L. Tanyi
- grid.25879.310000 0004 1936 8972Ovarian Cancer Research Center, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA
| | - Cheryl L.-L. Chiang
- grid.9851.50000 0001 2165 4204Department of Oncology, Lausanne University Hospital (CHUV), Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland
| | - Johanna Chiffelle
- grid.9851.50000 0001 2165 4204Department of Oncology, Lausanne University Hospital (CHUV), Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland
| | - Anne-Christine Thierry
- grid.8515.90000 0001 0423 4662Center of Experimental Therapeutics, Department of Oncology, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Petra Baumgartener
- grid.8515.90000 0001 0423 4662Center of Experimental Therapeutics, Department of Oncology, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Florian Huber
- grid.9851.50000 0001 2165 4204Department of Oncology, Lausanne University Hospital (CHUV), Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland
| | - Christine Goepfert
- grid.5734.50000 0001 0726 5157Institute of Animal Pathology, COMPATH, Vetsuisse Faculty, University of Bern, Bern, Switzerland ,grid.5333.60000000121839049School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - David Tarussio
- grid.8515.90000 0001 0423 4662Center of Experimental Therapeutics, Department of Oncology, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Stephanie Tissot
- grid.8515.90000 0001 0423 4662Center of Experimental Therapeutics, Department of Oncology, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Drew A. Torigian
- grid.411115.10000 0004 0435 0884Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA USA
| | - Harvey L. Nisenbaum
- grid.411115.10000 0004 0435 0884Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA USA
| | - Brian J. Stevenson
- grid.9851.50000 0001 2165 4204Department of Oncology, Lausanne University Hospital (CHUV), Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland
| | - Hajer Fritah Guiren
- grid.9851.50000 0001 2165 4204Department of Oncology, Lausanne University Hospital (CHUV), Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland
| | - Ritaparna Ahmed
- grid.9851.50000 0001 2165 4204Department of Oncology, Lausanne University Hospital (CHUV), Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland
| | - Anne-Laure Huguenin-Bergenat
- grid.9851.50000 0001 2165 4204Department of Oncology, Lausanne University Hospital (CHUV), Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland
| | - Emese Zsiros
- grid.25879.310000 0004 1936 8972Ovarian Cancer Research Center, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA
| | - Michal Bassani-Sternberg
- grid.9851.50000 0001 2165 4204Department of Oncology, Lausanne University Hospital (CHUV), Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland
| | - Rosemarie Mick
- grid.25879.310000 0004 1936 8972Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA
| | - Daniel J. Powell
- grid.25879.310000 0004 1936 8972Ovarian Cancer Research Center, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA
| | - George Coukos
- grid.9851.50000 0001 2165 4204Department of Oncology, Lausanne University Hospital (CHUV), Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland
| | - Alexandre Harari
- grid.9851.50000 0001 2165 4204Department of Oncology, Lausanne University Hospital (CHUV), Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland ,grid.8515.90000 0001 0423 4662Center of Experimental Therapeutics, Department of Oncology, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Lana E. Kandalaft
- grid.9851.50000 0001 2165 4204Department of Oncology, Lausanne University Hospital (CHUV), Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland ,grid.8515.90000 0001 0423 4662Center of Experimental Therapeutics, Department of Oncology, Lausanne University Hospital (CHUV), Lausanne, Switzerland
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9
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Anti-cancer Immunotherapies Targeting Telomerase. Cancers (Basel) 2020; 12:cancers12082260. [PMID: 32806719 PMCID: PMC7465444 DOI: 10.3390/cancers12082260] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 08/05/2020] [Accepted: 08/07/2020] [Indexed: 02/06/2023] Open
Abstract
Telomerase is a reverse transcriptase that maintains telomeres length, compensating for the attrition of chromosomal ends that occurs during each replication cycle. Telomerase is expressed in germ cells and stem cells, whereas it is virtually undetectable in adult somatic cells. On the other hand, telomerase is broadly expressed in the majority of human tumors playing a crucial role in the replicative behavior and immortality of cancer cells. Several studies have demonstrated that telomerase-derived peptides are able to bind to HLA (human leukocyte antigen) class I and class II molecules and effectively activate both CD8+ and CD4+ T cells subsets. Due to its broad and selective expression in cancer cells and its significant immunogenicity, telomerase is considered an ideal universal tumor-associated antigen, and consequently, a very attractive target for anti-cancer immunotherapy. To date, different telomerase targeting immunotherapies have been studied in pre-clinical and clinical settings, these approaches include peptide vaccination and cell-based vaccination. The objective of this review paper is to discuss the role of human telomerase in cancer immunotherapy analyzing recent developments and future perspectives in this field.
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10
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Harari A, Graciotti M, Bassani-Sternberg M, Kandalaft LE. Antitumour dendritic cell vaccination in a priming and boosting approach. Nat Rev Drug Discov 2020; 19:635-652. [PMID: 32764681 DOI: 10.1038/s41573-020-0074-8] [Citation(s) in RCA: 190] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/19/2020] [Indexed: 02/06/2023]
Abstract
Mobilizing antitumour immunity through vaccination potentially constitutes a powerful anticancer strategy but has not yet provided robust clinical benefits in large patient populations. Although major hurdles still exist, we believe that currently available strategies for vaccines that target dendritic cells or use them to present antitumour antigens could be integrated into existing clinical practice using prime-boost approaches. In the priming phase, these approaches capitalize on either standard treatment modalities to trigger in situ vaccination and release tumour antigens or vaccination with dendritic cells loaded with tumour lysates or patient-specific neoantigens. In a second boost phase, personalized synthetic vaccines specifically boost T cells that were triggered during the priming phase. This immunotherapy approach has been enabled by the substantial recent improvements in dendritic cell vaccines. In this Perspective, we discuss these improvements, highlight how the prime-boost approach can be translated into clinical practice and provide solutions for various anticipated hurdles.
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Affiliation(s)
- Alexandre Harari
- Center of Experimental Therapeutics, Department of Oncology, University Hospital of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland
| | - Michele Graciotti
- Center of Experimental Therapeutics, Department of Oncology, University Hospital of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland
| | - Michal Bassani-Sternberg
- Center of Experimental Therapeutics, Department of Oncology, University Hospital of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland
| | - Lana E Kandalaft
- Center of Experimental Therapeutics, Department of Oncology, University Hospital of Lausanne, Lausanne, Switzerland. .,Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland.
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11
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Hanif A, Lee S, Gupta M, Chander A, Kannisto ED, Punnanitinont A, Fenstermaker R, Ciesielski M, Attwood K, Qiu J, Yendamuri S, Iyer R. Exploring the role of survivin in neuroendocrine neoplasms. Oncotarget 2020; 11:2246-2258. [PMID: 32577168 PMCID: PMC7289533 DOI: 10.18632/oncotarget.27631] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 05/14/2020] [Indexed: 12/21/2022] Open
Abstract
Neuroendocrine tumors (NETs) are a heterogenous group of tumors. While most NETs have excellent prognosis, certain subsets have aggressive biology and have limited treatment options. We explored the role of survivin in NET as a prognostic and potentially therapeutic marker. Tissue microarrays of 132 patients were stained for survivin using immunohistochemistry (IHC) and correlated with outcomes. Using genomic database, we then correlated survivin (BIRC5) mRNA expression with radiosensitivity index (RSI) in 52 samples of NET. Finally, we studied the effect of radiation on survivin expression in human cell lines and the impact of knock-down of BIRC5 on cell proliferation and radiation sensitivity. We found that survivin positivity by IHC correlated with a shorter survival (overall survival 8.5 years vs. 18.3 years, p < 0.001). There was a positive correlation between BIRC5 expression and RSI (r = 0.234, p < 0.0001). Radiation exposure increased BIRC5 gene expression in a human carcinoid cell line. Knockout of BIRC5 using siRNA reduced proliferation of neuroendocrine cells but did not increase radiation sensitivity. We conclude that survivin expression in NET correlates with an inferior survival and survivin expression in human carcinoid cell lines increases after exposure to ionizing radiation.
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Affiliation(s)
- Ahmad Hanif
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Sunyoung Lee
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Medhavi Gupta
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Ankush Chander
- Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Eric D Kannisto
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Achamaporn Punnanitinont
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Robert Fenstermaker
- Department of Neurosurgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Michael Ciesielski
- Department of Neurosurgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Kristopher Attwood
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Jingxin Qiu
- Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Sai Yendamuri
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Renuka Iyer
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
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12
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Belderbos RA, Aerts JGJV, Vroman H. Enhancing Dendritic Cell Therapy in Solid Tumors with Immunomodulating Conventional Treatment. MOLECULAR THERAPY-ONCOLYTICS 2019; 13:67-81. [PMID: 31020037 PMCID: PMC6475716 DOI: 10.1016/j.omto.2019.03.007] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Dendritic cells (DCs) are the most potent antigen-presenting cells and are the key initiator of tumor-specific immune responses. These characteristics are exploited by DC therapy, where DCs are ex vivo loaded with tumor-associated antigens (TAAs) and used to induce tumor-specific immune responses. Unfortunately, clinical responses remain limited to a proportion of the patients. Tumor characteristics and the immunosuppressive tumor microenvironment (TME) of the tumor are likely hampering efficacy of DC therapy. Therefore, reducing the immunosuppressive TME by combining DC therapy with other treatments could be a promising strategy. Initially, conventional cancer therapies, such as chemotherapy and radiotherapy, were thought to specifically target cancerous cells. Recent insights indicate that these therapies additionally augment tumor immunity by targeting immunosuppressive cell subsets in the TME, inducing immunogenic cell death (ICD), or blocking inhibitory molecules. Therefore, combining DC therapy with registered therapies such as chemotherapy, radiotherapy, or checkpoint inhibitors could be a promising treatment strategy to improve the efficacy of DC therapy. In this review, we evaluate various clinical applicable combination strategies to improve the efficacy of DC therapy.
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Affiliation(s)
- Robert A Belderbos
- Department of Pulmonary Medicine, Erasmus MC Rotterdam, the Netherlands.,Erasmus MC Cancer Institute, Erasmus MC Rotterdam, the Netherlands
| | - Joachim G J V Aerts
- Department of Pulmonary Medicine, Erasmus MC Rotterdam, the Netherlands.,Erasmus MC Cancer Institute, Erasmus MC Rotterdam, the Netherlands
| | - Heleen Vroman
- Department of Pulmonary Medicine, Erasmus MC Rotterdam, the Netherlands.,Erasmus MC Cancer Institute, Erasmus MC Rotterdam, the Netherlands
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13
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Empowering dendritic cell cancer vaccination: the role of combinatorial strategies. Cytotherapy 2018; 20:1309-1323. [PMID: 30360963 DOI: 10.1016/j.jcyt.2018.09.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 09/18/2018] [Accepted: 09/19/2018] [Indexed: 01/22/2023]
Abstract
Dendritic cells (DCs) are bone marrow-derived immune cells that play a crucial role in inducing the adaptive immunity and supporting the innate immune response independently from T cells. In the last decade, DCs have become a hopeful instrument for cancer vaccines that aims at re-educating the immune system, leading to a potent anti-cancer immune response able to overcome the immunosuppressive tumor microenvironment (TME). Although several studies have indicated that DC-based vaccines are feasible and safe, the clinical advantages of DC vaccination as monotherapy for most of the neoplasms remain a distant target. Recently, many reports and clinical trials have widely used innovative combinatorial therapeutic strategies to normalize the immune function in the TME and synergistically enhance DC function. This review will describe the most relevant and updated evidence of the anti-cancer combinatorial approaches to boost the clinical potency of DC-based vaccines.
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14
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de Goeje PL, Klaver Y, Kaijen-Lambers MEH, Langerak AW, Vroman H, Kunert A, Lamers CHJ, Aerts JGJV, Debets R, Hendriks RW. Autologous Dendritic Cell Therapy in Mesothelioma Patients Enhances Frequencies of Peripheral CD4 T Cells Expressing HLA-DR, PD-1, or ICOS. Front Immunol 2018; 9:2034. [PMID: 30245692 PMCID: PMC6137618 DOI: 10.3389/fimmu.2018.02034] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 08/17/2018] [Indexed: 01/05/2023] Open
Abstract
Introduction: Malignant pleural mesothelioma (MPM) is a malignancy with a very poor prognosis for which new treatment options are urgently needed. We have previously shown that dendritic cell (DC) immunotherapy provides a clinically feasible treatment option. In the current study, we set out to assess the immunological changes induced by DC immunotherapy in peripheral blood of MPM patients. Methods: Peripheral blood was collected from nine patients enrolled in a phase I dose escalation study, before and after treatment with DCs that were pulsed with an allogeneic tumor lysate preparation consisting of a mixture of five cultured mesothelioma cell lines. We used immune profiling by multiplex flow cytometry to characterize different populations of immune cells. In particular, we determined frequencies of T cell subsets that showed single and combinatorial expression of multiple markers that signify T cell activation, maturation and inhibition. Therapy-induced T cell reactivity was assessed in peptide/MHC multimer stainings using mesothelin as a prototypic target antigen with confirmed expression in the clinical tumor lysate preparation. T cell receptor (TCR) diversity was evaluated by TCRB gene PCR assays. Results: We observed an increase in the numbers of B cells, CD4 and CD8 T cells, but not NK cells at 6 weeks post-treatment. The increases in B and T lymphocytes were not accompanied by major changes in T cell reactivity toward mesothelin nor in TCRB diversity. Notably, we did observe enhanced proportions of CD4 T cells expressing HLA-DR, PD-1 (at 2 weeks after onset of treatment) and ICOS (6 weeks) and a CD8 T cell population expressing LAG3 (2 weeks). Discussion: DC immunotherapy using allogeneic tumor lysate resulted in enhanced frequencies of B cells and T cells in blood. We did not detect a skewed antigen-reactivity of peripheral CD8 T cells. Interestingly, frequencies of CD4 T cells expressing activation markers and PD-1 were increased. These findings indicate a systemic activation of the adaptive immune response and may guide future immune monitoring studies of DC therapies.
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Affiliation(s)
- Pauline L de Goeje
- Department of Pulmonary Medicine, Erasmus MC, Rotterdam, Netherlands.,Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, Netherlands
| | - Yarne Klaver
- Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, Netherlands.,Department of Medical Oncology, Laboratory of Tumor Immunology, Erasmus MC, Rotterdam, Netherlands
| | - Margaretha E H Kaijen-Lambers
- Department of Pulmonary Medicine, Erasmus MC, Rotterdam, Netherlands.,Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, Netherlands
| | - Anton W Langerak
- Department of Immunology, Laboratory Medical Immunology, Erasmus MC, Rotterdam, Netherlands
| | - Heleen Vroman
- Department of Pulmonary Medicine, Erasmus MC, Rotterdam, Netherlands.,Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, Netherlands
| | - André Kunert
- Department of Pulmonary Medicine, Erasmus MC, Rotterdam, Netherlands.,Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, Netherlands.,Department of Medical Oncology, Laboratory of Tumor Immunology, Erasmus MC, Rotterdam, Netherlands
| | - Cor H J Lamers
- Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, Netherlands.,Department of Medical Oncology, Laboratory of Tumor Immunology, Erasmus MC, Rotterdam, Netherlands
| | - Joachim G J V Aerts
- Department of Pulmonary Medicine, Erasmus MC, Rotterdam, Netherlands.,Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, Netherlands
| | - Reno Debets
- Erasmus MC Cancer Institute, Erasmus MC, Rotterdam, Netherlands.,Department of Medical Oncology, Laboratory of Tumor Immunology, Erasmus MC, Rotterdam, Netherlands
| | - Rudi W Hendriks
- Department of Pulmonary Medicine, Erasmus MC, Rotterdam, Netherlands
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15
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Aerts JGJV, de Goeje PL, Cornelissen R, Kaijen-Lambers MEH, Bezemer K, van der Leest CH, Mahaweni NM, Kunert A, Eskens FALM, Waasdorp C, Braakman E, van der Holt B, Vulto AG, Hendriks RW, Hegmans JPJJ, Hoogsteden HC. Autologous Dendritic Cells Pulsed with Allogeneic Tumor Cell Lysate in Mesothelioma: From Mouse to Human. Clin Cancer Res 2017; 24:766-776. [PMID: 29233904 DOI: 10.1158/1078-0432.ccr-17-2522] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Revised: 11/01/2017] [Accepted: 12/04/2017] [Indexed: 11/16/2022]
Abstract
Purpose: Mesothelioma has been regarded as a nonimmunogenic tumor, which is also shown by the low response rates to treatments targeting the PD-1/PD-L1 axis. Previously, we demonstrated that autologous tumor lysate-pulsed dendritic cell (DC) immunotherapy increased T-cell response toward malignant mesothelioma. However, the use of autologous tumor material hampers implementation in large clinical trials, which might be overcome by using allogeneic tumor cell lines as tumor antigen source. The purpose of this study was to investigate whether allogeneic lysate-pulsed DC immunotherapy is effective in mice and safe in humans.Experimental Design: First, in two murine mesothelioma models, mice were treated with autologous DCs pulsed with either autologous or allogeneic tumor lysate or injected with PBS (negative control). Survival and tumor-directed T-cell responses of these mice were monitored. Results were taken forward in a first-in-human clinical trial, in which 9 patients were treated with 10, 25, or 50 million DCs per vaccination. DC vaccination consisted of autologous monocyte-derived DCs pulsed with tumor lysate from five mesothelioma cell lines.Results: In mice, allogeneic lysate-pulsed DC immunotherapy induced tumor-specific T cells and led to an increased survival, to a similar extent as DC immunotherapy with autologous tumor lysate. In the first-in-human clinical trial, no dose-limiting toxicities were established and radiographic responses were observed. Median PFS was 8.8 months [95% confidence interval (CI), 4.1-20.3] and median OS not reached (median follow-up = 22.8 months).Conclusions: DC immunotherapy with allogeneic tumor lysate is effective in mice and safe and feasible in humans. Clin Cancer Res; 24(4); 766-76. ©2017 AACR.
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Affiliation(s)
- Joachim G J V Aerts
- Department of Pulmonary Medicine, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
| | - Pauline L de Goeje
- Department of Pulmonary Medicine, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Robin Cornelissen
- Department of Pulmonary Medicine, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | | | - Koen Bezemer
- Department of Pulmonary Medicine, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Cor H van der Leest
- Department of Pulmonary Medicine, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Niken M Mahaweni
- Department of Pulmonary Medicine, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - André Kunert
- Department of Pulmonary Medicine, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.,Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Ferry A L M Eskens
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Cynthia Waasdorp
- Department of Pulmonary Medicine, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Eric Braakman
- Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Bronno van der Holt
- Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Arnold G Vulto
- Hospital Pharmacy, Erasmus MC, Rotterdam, the Netherlands
| | - Rudi W Hendriks
- Department of Pulmonary Medicine, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Joost P J J Hegmans
- Department of Pulmonary Medicine, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Henk C Hoogsteden
- Department of Pulmonary Medicine, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
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16
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Buschow SI, Ramazzotti M, Reinieren-Beeren IMJ, Heinzerling LM, Westdorp H, Stefanini I, Beltrame L, Hato SV, Ellebaek E, Gross S, Nguyen VA, Weinlich G, Ragoussis J, Baban D, Schuler-Thurner B, Svane IM, Romani N, Austyn JM, De Vries IJM, Schuler G, Cavalieri D, Figdor CG. Survival of metastatic melanoma patients after dendritic cell vaccination correlates with expression of leukocyte phosphatidylethanolamine-binding protein 1/Raf kinase inhibitory protein. Oncotarget 2017; 8:67439-67456. [PMID: 28978044 PMCID: PMC5620184 DOI: 10.18632/oncotarget.18698] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 05/22/2017] [Indexed: 02/07/2023] Open
Abstract
Immunotherapy for metastatic melanoma offers great promise but, to date, only a subset of patients have responded. There is an urgent need to identify ways of allocating patients to the most beneficial therapy, to increase survival and decrease therapy-associated morbidity and costs. Blood-based biomarkers are of particular interest because of their straightforward implementation in routine clinical care. We sought to identify markers for dendritic cell (DC) vaccine-based immunotherapy against metastatic melanoma through gene expression analysis of peripheral blood mononuclear cells. A large-scale microarray analysis of 74 samples from two treatment centers, taken directly after the first round of DC vaccination, was performed. We found that phosphatidylethanolamine binding protein 1 (PEBP1)/Raf Kinase inhibitory protein (RKIP) expression can be used to identify a significant proportion of patients who performed poorly after DC vaccination. This result was validated by q-PCR analysis on blood samples from a second cohort of 95 patients treated with DC vaccination in four different centers. We conclude that low PEBP1 expression correlates with poor overall survival after DC vaccination. Intriguingly, this was only the case for expression of PEBP1 after, but not prior to, DC vaccination. Moreover, the change in PEBP1 expression upon vaccination correlated well with survival. Further analyses revealed that PEBP1 expression positively correlated with genes involved in T cell responses but inversely correlated with genes associated with myeloid cells and aberrant inflammation including STAT3, NOTCH1, and MAPK1. Concordantly, PEBP1 inversely correlated with the myeloid/lymphoid-ratio and was suppressed in patients suffering from chronic inflammatory disease.
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Affiliation(s)
- Sonja I Buschow
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.,Department of Gastroenterology and Hepatology, Erasmus University Medical Center (Erasmus MC), Rotterdam, The Netherlands
| | - Matteo Ramazzotti
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Inge M J Reinieren-Beeren
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Lucie M Heinzerling
- Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg (FAU), Erlangen, Germany
| | - Harm Westdorp
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Irene Stefanini
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Luca Beltrame
- Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
| | - Stanleyson V Hato
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Eva Ellebaek
- CCIT, Center for Cancer Immune Therapy, Department of Hematology and Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Stefanie Gross
- Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg (FAU), Erlangen, Germany
| | - Van Anh Nguyen
- Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria
| | - Georg Weinlich
- Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria
| | - Jiannis Ragoussis
- Genomics Group, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.,Current address: McGill University and Genome Quebec Innovation Centre, McGill University, Quebec, Canada
| | - Dilair Baban
- Genomics Group, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Beatrice Schuler-Thurner
- Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg (FAU), Erlangen, Germany
| | - Inge M Svane
- CCIT, Center for Cancer Immune Therapy, Department of Hematology and Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Nikolaus Romani
- Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria
| | - Jonathan M Austyn
- Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - I Jolanda M De Vries
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Gerold Schuler
- Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg (FAU), Erlangen, Germany
| | | | - Carl G Figdor
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
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17
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Tao Z, Li S, Ichim TE, Yang J, Riordan N, Yenugonda V, Babic I, Kesari S. Cellular immunotherapy of cancer: an overview and future directions. Immunotherapy 2017; 9:589-606. [DOI: 10.2217/imt-2016-0086] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The clinical success of checkpoint inhibitors has led to a renaissance of interest in cancer immunotherapies. In particular, the possibility of ex vivo expanding autologous lymphocytes that specifically recognize tumor cells has attracted much research and clinical trial interest. In this review, we discuss the historical background of tumor immunotherapy using cell-based approaches, and provide some rationale for overcoming current barriers to success of autologous immunotherapy. An overview of adoptive transfer of lymphocytes, tumor infiltrating lymphocytes and dendritic cell therapies is provided. We conclude with discussing the possibility of gene-manipulating immune cells in order to augment therapeutic activity, including silencing of the immune-suppressive zinc finger orphan nuclear receptor, NR2F6, as an attractive means of overcoming tumor-associated immune suppression.
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Affiliation(s)
- Ziqi Tao
- The Affiliated XuZhou Center Hospital of Nanjing University of Chinese Medicine, The Affiliated XuZhou Hospital of Medical College of Southeast University, Jiangsu, China
| | - Shuang Li
- Department of Endocrinology, the Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | | | - Junbao Yang
- Department of Translational Neurosciences and Neurotherapeutics, Pacific Neuroscience Institute, John Wayne Cancer Institute, Providence Saint John’s Health Center, Santa Monica, CA 90404, USA
| | - Neil Riordan
- Medistem Panama, Inc., City of Knowledge, Clayton, Republic of Panama
| | - Venkata Yenugonda
- Department of Translational Neurosciences and Neurotherapeutics, Pacific Neuroscience Institute, John Wayne Cancer Institute, Providence Saint John’s Health Center, Santa Monica, CA 90404, USA
| | - Ivan Babic
- Department of Translational Neurosciences and Neurotherapeutics, Pacific Neuroscience Institute, John Wayne Cancer Institute, Providence Saint John’s Health Center, Santa Monica, CA 90404, USA
| | - Santosh Kesari
- Department of Translational Neurosciences and Neurotherapeutics, Pacific Neuroscience Institute, John Wayne Cancer Institute, Providence Saint John’s Health Center, Santa Monica, CA 90404, USA
- John Wayne Cancer Institute, 2200 Santa Monica Blvd, Santa Monica, CA 90404, USA
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18
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Gross S, Erdmann M, Haendle I, Voland S, Berger T, Schultz E, Strasser E, Dankerl P, Janka R, Schliep S, Heinzerling L, Sotlar K, Coulie P, Schuler G, Schuler-Thurner B. Twelve-year survival and immune correlates in dendritic cell-vaccinated melanoma patients. JCI Insight 2017; 2:91438. [PMID: 28422751 DOI: 10.1172/jci.insight.91438] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Accepted: 03/02/2017] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Reports on long-term (≥10 years) effects of cancer vaccines are missing. Therefore, in 2002, we initiated a phase I/II trial in cutaneous melanoma patients to further explore the immunogenicity of our DC vaccine and to establish its long-term toxicity and clinical benefit after a planned 10-year followup. METHODS Monocyte-derived DCs matured by TNFα, IL-1β, IL-6, and PGE2 and then loaded with 4 HLA class I and 6 class II-restricted tumor peptides were injected intradermally in high doses over 2 years. We performed serial immunomonitoring in all 53 evaluable patients. RESULTS Vaccine-specific immune responses including high-affinity, IFNγ-producing CD4+ and lytic polyfunctional CD8+ T cells were de novo induced or boosted in most patients. Exposure of mature DCs to trimeric soluble CD40 ligand, unexpectedly, did not further enhance such immune responses, while keyhole limpet hemocyanin (KLH) pulsing to provide unspecific CD4+ help promoted CD8+ T cell responses - notably, their longevity. An unexpected 19% of nonresectable metastatic melanoma patients are still alive after 11 years, a survival rate similar to that observed in ipilimumab-treated patients and achieved without any major (>grade 2) toxicity. Survival correlated significantly with the development of intense vaccine injection site reactions, and with blood eosinophilia after the first series of vaccinations, suggesting that prolonged survival was a consequence of DC vaccination. CONCLUSIONS Long-term survival in advanced melanoma patients undergoing DC vaccination is similar to ipilimumab-treated patients and occurs upon induction of tumor-specific T cells, blood eosinophilia, and strong vaccine injection site reactions occurring after the initial vaccinations. TRIAL REGISTRATION ClinicalTrials.gov NCT00053391. FUNDING European Community, Sixth Framework Programme (Cancerimmunotherapy LSHC-CT-2006-518234; DC-THERA LSHB-CT-2004-512074), and German Research Foundation (CRC 643, C1, Z2).
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Affiliation(s)
| | | | | | | | | | | | | | - Peter Dankerl
- Department of Radiology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg (FAU), Erlangen, Germany
| | - Rolf Janka
- Department of Radiology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg (FAU), Erlangen, Germany
| | | | | | - Karl Sotlar
- Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany
| | - Pierre Coulie
- de Duve Institute, Université catholique de Louvain, Brussels, Belgium
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19
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Borch TH, Engell-Noerregaard L, Zeeberg Iversen T, Ellebaek E, Met Ö, Hansen M, Andersen MH, Thor Straten P, Svane IM. mRNA-transfected dendritic cell vaccine in combination with metronomic cyclophosphamide as treatment for patients with advanced malignant melanoma. Oncoimmunology 2016; 5:e1207842. [PMID: 27757300 DOI: 10.1080/2162402x.2016.1207842] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 06/13/2016] [Accepted: 06/25/2016] [Indexed: 01/02/2023] Open
Abstract
INTRODUCTION Vaccination with dendritic cells (DCs) has generally not fulfilled its promise in cancer immunotherapy due to ineffective translation of immune responses into clinical responses. A proposed reason for this is intrinsic immune regulatory mechanisms, such as regulatory T cells (Tregs). A metronomic regimen of cyclophosphamide (mCy) has been shown to selectively deplete Tregs. To test this in a clinical setting, we conducted a phase I trial to evaluate the feasibility and safety of vaccination with DCs transfected with mRNA in combination with mCy in patients with metastatic malignant melanoma (MM). In addition, clinical and immunological effect of the treatment was evaluated. EXPERIMENTAL DESIGN Twenty-two patients were enrolled and treated with six cycles of cyclophosphamide 50 mg orally bi-daily for a week every second week (day 1-7). During the six cycles patients received at least 5 × 106 autologous DCs administered by intradermal (i.d.) injection in the week without chemotherapy. Patients were evaluated 12 and 27 weeks and every 3rd mo thereafter with CT scans according to RECIST 1.0. Blood samples for immune monitoring were collected at baseline, at the time of 4th and 6th vaccines. Immune monitoring consisted of IFNγ ELISpot assay, proliferation assay, and flow cytometry for enumeration of immune cell subsets. RESULTS Toxicity was manageable. Eighteen patients were evaluable after six cycles. Of these, nine patients had progressive disease as best response and nine patients achieved stable disease. In three patients minor tumor regression was observed. By IFNγ ELISpot and proliferation assay immune responses were seen in 6/17 and 4/17 patients, respectively; however, no correlation with clinical response was found. The percentage of Tregs was unchanged during treatment. CONCLUSION Treatment with autologous DCs transfected with mRNA in combination with mCy was feasible and safe. Importantly, mCy did not alter the percentage of Tregs in our patient cohort. There was an indication of clinical benefit; however, more knowledge is needed in order for DCs to be exploited as a therapeutic option.
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Affiliation(s)
- Troels Holz Borch
- Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital, Herlev, Denmark; Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Lotte Engell-Noerregaard
- Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital, Herlev, Denmark; Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Trine Zeeberg Iversen
- Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital, Herlev, Denmark; Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Eva Ellebaek
- Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital, Herlev, Denmark; Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Özcan Met
- Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital, Herlev, Denmark; Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Morten Hansen
- Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital , Herlev, Denmark
| | - Mads Hald Andersen
- Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital , Herlev, Denmark
| | - Per Thor Straten
- Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital , Herlev, Denmark
| | - Inge Marie Svane
- Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital, Herlev, Denmark; Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
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20
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Garg H, Suri P, Gupta JC, Talwar GP, Dubey S. Survivin: a unique target for tumor therapy. Cancer Cell Int 2016; 16:49. [PMID: 27340370 PMCID: PMC4917988 DOI: 10.1186/s12935-016-0326-1] [Citation(s) in RCA: 325] [Impact Index Per Article: 36.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 06/10/2016] [Indexed: 12/13/2022] Open
Abstract
Survivin is the smallest member of the Inhibitor of apoptosis (IAP) family of proteins, involved in inhibition of apoptosis and regulation of cell cycle. These functional attributes make Survivin a unique protein exhibiting divergent functions i.e. regulating cell proliferation and cell death. Expression pattern of Survivin is also distinctive; it is prominently expressed during embryonal development, absent in most normal, terminally differentiated tissues but upregulated in a variety of human cancers. Expression of Survivin in tumours correlates with not only inhibition of apoptosis and a decreased rate of cell death, but also resistance to chemotherapy and aggressiveness of tumours. Therefore, Survivin is an important target for cancer vaccines and therapeutics. Survivin has also been found to be prominently expressed on both human and embryonic stem cells and many somatic stem cell types indicating its yet unexplored role in stem cell generation and maintenance. Overall, Survivin emerges as a molecule with much wider role in cellular homeostasis. This review will discuss various aspects of Survivin biology and its role in regulation of apoptosis, cell division, chemo-resistance and tumour progression. Various molecular and immunotherapeutic approaches targeting Survivin will also be discussed.
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Affiliation(s)
- Himani Garg
- Amity Institute of Virology and Immunology, Amity University Uttar Pradesh, J-3 Block, Room No: LG21, Sector 125, Noida, Uttar Pradesh 201303 India
| | - Prerna Suri
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Sector 125, Noida, India
| | - Jagdish C Gupta
- Talwar Research Foundation, E-8 Neb Valley, Neb Sarai, New Delhi, 110 068 India
| | - G P Talwar
- Talwar Research Foundation, E-8 Neb Valley, Neb Sarai, New Delhi, 110 068 India
| | - Shweta Dubey
- Amity Institute of Virology and Immunology, Amity University Uttar Pradesh, J-3 Block, Room No: LG21, Sector 125, Noida, Uttar Pradesh 201303 India
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Xu Y, Goldkorn A. Telomere and Telomerase Therapeutics in Cancer. Genes (Basel) 2016; 7:genes7060022. [PMID: 27240403 PMCID: PMC4929421 DOI: 10.3390/genes7060022] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Revised: 05/18/2016] [Accepted: 05/20/2016] [Indexed: 12/13/2022] Open
Abstract
Telomerase is a reverse transcriptase capable of utilizing an integrated RNA component as a template to add protective tandem telomeric single strand DNA repeats, TTAGGG, to the ends of chromosomes. Telomere dysfunction and telomerase reactivation are observed in approximately 90% of human cancers; hence, telomerase activation plays a unique role as a nearly universal step on the path to malignancy. In the past two decades, multiple telomerase targeting therapeutic strategies have been pursued, including direct telomerase inhibition, telomerase interference, hTERT or hTERC promoter driven therapy, telomere-based approaches, and telomerase vaccines. Many of these strategies have entered clinical development, and some have now advanced to phase III clinical trials. In the coming years, one or more of these new telomerase-targeting drugs may be expected to enter the pharmacopeia of standard care. Here, we briefly review the molecular functions of telomerase in cancer and provide an update about the preclinical and clinical development of telomerase targeting therapeutics.
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Affiliation(s)
- Yucheng Xu
- Division of Medical Oncology, Department of Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA.
| | - Amir Goldkorn
- Division of Medical Oncology, Department of Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA.
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22
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Hodges TR, Ferguson SD, Caruso HG, Kohanbash G, Zhou S, Cloughesy TF, Berger MS, Poste GH, Khasraw M, Ba S, Jiang T, Mikkelson T, Yung WKA, de Groot JF, Fine H, Cantley LC, Mellinghoff IK, Mitchell DA, Okada H, Heimberger AB. Prioritization schema for immunotherapy clinical trials in glioblastoma. Oncoimmunology 2016; 5:e1145332. [PMID: 27471611 DOI: 10.1080/2162402x.2016.1145332] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Revised: 01/12/2016] [Accepted: 01/16/2016] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Emerging immunotherapeutic strategies for the treatment of glioblastoma (GBM) such as dendritic cell (DC) vaccines, heat shock proteins, peptide vaccines, and adoptive T-cell therapeutics, to name a few, have transitioned from the bench to clinical trials. With upcoming strategies and developing therapeutics, it is challenging to critically evaluate the practical, clinical potential of individual approaches and to advise patients on the most promising clinical trials. METHODS The authors propose a system to prioritize such therapies in an organized and data-driven fashion. This schema is based on four categories of factors: antigenic target robustness, immune-activation and -effector responses, preclinical vetting, and early evidence of clinical response. Each of these categories is subdivided to focus on the most salient elements for developing a successful immunotherapeutic approach for GBM, and a numerical score is generated. RESULTS The Score Card reveals therapeutics that have the most robust data to support their use, provides a reference prioritization score, and can be applied in a reiterative fashion with emerging data. CONCLUSIONS The authors hope that this schema will give physicians an evidence-based and rational framework to make the best referral decisions to better guide and serve this patient population.
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Affiliation(s)
- Tiffany R Hodges
- Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center , Houston, TX, USA
| | - Sherise D Ferguson
- Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center , Houston, TX, USA
| | - Hillary G Caruso
- The Division of Pediatrics, The University of Texas M.D. Anderson Cancer Center , Houston, TX, USA
| | - Gary Kohanbash
- Department of Neurosurgery, the University of California at San Francisco , San Francisco, USA
| | - Shouhao Zhou
- Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center , Houston, TX, USA
| | - Timothy F Cloughesy
- Department of Neuro-Oncology, the University of California at Los Angeles , Los Angeles, CA, USA
| | - Mitchel S Berger
- Department of Neurosurgery, the University of California at San Francisco , San Francisco, USA
| | | | | | - Sujuan Ba
- The National Foundation for Cancer Research, Bethesda, MD, USA, Asian Fund for Cancer Research , Hong Kong, People's Republic of China
| | - Tao Jiang
- Department of Neurosurgery, Tiantan Hospital, Capital Medical University , Beijing, China
| | - Tom Mikkelson
- Department of Neurosurgery, Henry Ford Health System , Detroit, MI, USA
| | - W K Alfred Yung
- Department of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center , Houston, TX, USA
| | - John F de Groot
- Department of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center , Houston, TX, USA
| | - Howard Fine
- Division of Neuro-Oncology, Weill Cornell Medical College , New York, NY, USA
| | - Lewis C Cantley
- Department of Systems Biology, Harvard Medical School , Boston, MA, USA
| | - Ingo K Mellinghoff
- Department of Neurology and Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center , New York, NY, USA
| | - Duane A Mitchell
- Department of Neurosurgery, University of Florida , Gainesville, FL, USA
| | - Hideho Okada
- Department of Neurosurgery, the University of California at San Francisco , San Francisco, USA
| | - Amy B Heimberger
- Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center , Houston, TX, USA
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Type I-polarized BRAF-pulsed dendritic cells induce antigen-specific CD8+ T cells that impact BRAF-mutant murine melanoma. Melanoma Res 2016; 26:1-11. [DOI: 10.1097/cmr.0000000000000203] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Abstract
Immunotherapy has great potential to treat cancer and prevent future relapse by activating the immune system to recognize and kill cancer cells. A variety of strategies are continuing to evolve in the laboratory and in the clinic, including therapeutic noncellular (vector-based or subunit) cancer vaccines, dendritic cell vaccines, engineered T cells, and immune checkpoint blockade. Despite their promise, much more research is needed to understand how and why certain cancers fail to respond to immunotherapy and to predict which therapeutic strategies, or combinations thereof, are most appropriate for each patient. Underlying these challenges are technological needs, including methods to rapidly and thoroughly characterize the immune microenvironment of tumors, predictive tools to screen potential therapies in patient-specific ways, and sensitive, information-rich assays that allow patient monitoring of immune responses, tumor regression, and tumor dissemination during and after therapy. The newly emerging field of immunoengineering is addressing some of these challenges, and there is ample opportunity for engineers to contribute their approaches and tools to further facilitate the clinical translation of immunotherapy. Here we highlight recent technological advances in the diagnosis, therapy, and monitoring of cancer in the context of immunotherapy, as well as ongoing challenges.
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Affiliation(s)
- Laura Jeanbart
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Swiss Institute for Experimental Cancer Research, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Melody A Swartz
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Swiss Institute for Experimental Cancer Research, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Institute for Molecular Engineering and Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637
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25
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Fang RH, Kroll AV, Zhang L. Nanoparticle-Based Manipulation of Antigen-Presenting Cells for Cancer Immunotherapy. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2015; 11:5483-96. [PMID: 26331993 PMCID: PMC4641138 DOI: 10.1002/smll.201501284] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Revised: 06/20/2015] [Indexed: 05/18/2023]
Abstract
Immunotherapeutic approaches for treating cancer overall have been receiving a considerable amount of interest due to the recent approval of several clinical formulations. Among the different modalities, anticancer vaccination acts by training the body to endogenously generate a response against tumor cells. However, despite the large amount of work that has gone into the development of such vaccines, the near absence of clinically approved formulations highlights the many challenges facing those working in the field. The generation of potent endogenous anticancer responses poses unique challenges due to the similarity between cancer cells and normal, healthy cells. As researchers continue to tackle the limited efficacy of vaccine formulations, fresh and novel approaches are being sought after to address many of the underlying problems. Here the application of nanoparticle technology towards the development of anticancer vaccines is discussed. Specifically, there is a focus on the benefits of using such strategies to manipulate antigen presenting cells (APCs), which are essential to the vaccination process, and how nanoparticle-based platforms can be rationally engineered to elicit appropriate downstream immune responses.
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Affiliation(s)
- Ronnie H. Fang
- Department of NanoEngineering and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA
| | - Ashley V. Kroll
- Department of NanoEngineering and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA
| | - Liangfang Zhang
- Department of NanoEngineering and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA
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Vacas-Córdoba E, Climent N, De La Mata FJ, Plana M, Gómez R, Pion M, García F, Muñoz-Fernández MÁ. Dendrimers as nonviral vectors in dendritic cell-based immunotherapies against human immunodeficiency virus: steps toward their clinical evaluation. Nanomedicine (Lond) 2015; 9:2683-702. [PMID: 25529571 DOI: 10.2217/nnm.14.172] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Although the antiretroviral therapy has led to a long-term control of HIV-1, it does not cure the disease. Therefore, several strategies are being explored to develop an effective HIV vaccine, such as the use of dendritic cells (DCs). DC-based immunotherapies bear different limitations, but one of the most critical point is the antigen loading into DCs. Nanotechnology offers new tools to overcome these constraints. Dendrimers have been proposed as carriers for targeted delivery of HIV antigens in DCs. These nanosystems can release the antigens in a controlled manner leading to a more potent specific immune response. This review focuses on the first steps for clinical development of dendrimers to assess their safety and potential use in DC-based immunotherapies against HIV.
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Affiliation(s)
- Enrique Vacas-Córdoba
- Laboratorio InmunoBiología Molecular, Sección Inmunologia, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Instituto de Investigación Sanitaria del Gregorio Marañón, C/Dr. Esquerdo 46, 28007, Madrid, Spain
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27
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Powell KL, Stephens AS, Ralph SJ. Development of a potent melanoma vaccine capable of stimulating CD8(+) T-cells independently of dendritic cells in a mouse model. Cancer Immunol Immunother 2015; 64:861-72. [PMID: 25893808 PMCID: PMC11028525 DOI: 10.1007/s00262-015-1695-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2014] [Accepted: 03/19/2015] [Indexed: 10/23/2022]
Abstract
At present, there are no vaccines approved for the prevention or treatment of malignant melanoma, despite the amount of time and resources that has been invested. In this study, we aimed to develop a self-contained vaccine capable of directly stimulating anticancer CD8(+) T-cell immune responses. To achieve this, three whole-cell melanoma vaccines were developed expressing 4-1BBL or B7.1 T-cell co-stimulatory molecules individually or in combination. The ability of engineered vaccine cell lines to stimulate potent anticancer immune responses in C57BL/6 mice was assessed. Mice vaccinated with cells overexpressing both 4-1BBL and B7.1 (B16-F10-4-1BBL-B7.1-IFNγ/β anticancer vaccine) displayed the greatest increases in CD8(+) T-cell populations (1.9-fold increase versus control within spleens), which were efficiently activated following antigenic stimulation, resulting in a 10.7-fold increase in cancer cell cytotoxicity relative to control. The enhanced immune responses in B16-F10-4-1BBL-B7.1-IFNγ/β-vaccinated mice translated into highly efficient rejection of live tumour burdens and conferred long-term protection against repeated tumour challenges, which were likely due to enhanced effector memory T-cell populations. Similar results were observed when dendritic cell (DC)-deficient LTα(-/-) mice were treated with the B16-F10-4-1BBL-B7.1-IFNγ/β anticancer vaccine, suggesting that the vaccine can directly stimulate CD8(+) T-cell responses in the context of severely reduced DCs. This study shows that the B16-F10-4-1BBL-B7.1-IFNγ/β anticancer vaccine acted as a highly effective antigen-presenting cell and is likely to be able to directly stimulate CD8(+) T-cells, without requiring co-stimulatory signals from either CD4(+) T-cells or DCs, and warrants translation of this technology into the clinical setting.
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Affiliation(s)
- Katie L Powell
- School of Medical Science, Griffith University, Gold Coast, QLD, Australia,
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Bongiovanni L, D'Andrea A, Porcellato I, Ciccarelli A, Malatesta D, Romanucci M, Della Salda L, Mechelli L, Brachelente C. Canine cutaneous melanocytic tumours: significance of β-catenin and survivin immunohistochemical expression. Vet Dermatol 2015; 26:270-e59. [DOI: 10.1111/vde.12211] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/02/2015] [Indexed: 12/13/2022]
Affiliation(s)
- Laura Bongiovanni
- Faculty of Veterinary Medicine; University of Teramo; Piazza A. Moro 45 Teramo 64100 Italy
| | - Alessandra D'Andrea
- Faculty of Veterinary Medicine; University of Teramo; Piazza A. Moro 45 Teramo 64100 Italy
| | - Ilaria Porcellato
- Department of Veterinary Medicine; University of Perugia; Via San Costanzo 4 Perugia 06126 Italy
| | - Andrea Ciccarelli
- Faculty of Political Science; University of Teramo; Campus Coste Sant'Agostino Teramo 64100 Italy
| | - Daniela Malatesta
- Faculty of Veterinary Medicine; University of Teramo; Piazza A. Moro 45 Teramo 64100 Italy
| | - Mariarita Romanucci
- Faculty of Veterinary Medicine; University of Teramo; Piazza A. Moro 45 Teramo 64100 Italy
| | - Leonardo Della Salda
- Faculty of Veterinary Medicine; University of Teramo; Piazza A. Moro 45 Teramo 64100 Italy
| | - Luca Mechelli
- Department of Veterinary Medicine; University of Perugia; Via San Costanzo 4 Perugia 06126 Italy
| | - Chiara Brachelente
- Department of Veterinary Medicine; University of Perugia; Via San Costanzo 4 Perugia 06126 Italy
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29
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Lewis JS, Dolgova NV, Zhang Y, Xia CQ, Wasserfall CH, Atkinson MA, Clare-Salzler MJ, Keselowsky BG. A combination dual-sized microparticle system modulates dendritic cells and prevents type 1 diabetes in prediabetic NOD mice. Clin Immunol 2015; 160:90-102. [PMID: 25842187 DOI: 10.1016/j.clim.2015.03.023] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Revised: 03/16/2015] [Accepted: 03/24/2015] [Indexed: 12/17/2022]
Abstract
We developed a novel poly(lactic-co-glycolic acid)-based, microparticle (MP) system providing concurrent delivery of multiple encapsulated immuno-suppressive factors and antigen, for in vivo conditioning of dendritic cells (DCs) toward a tolerance promoting pathway. Subcutaneous administration prevents onset of type 1 diabetes (T1D) in NOD mice. Two MP sizes were made: phagocytosable MPs were fabricated encapsulating vitamin D3 or insulin B(9-23) peptide, while unphagocytosable MPs were fabricated encapsulating TGF-β1 or GM-CSF. The combination of Vit D3/TGF-β1 MPs confers an immature and LPS activation-resistant phenotype to DCs, and MP-delivered antigen is efficiently and functionally presented. Notably, two subcutaneous injections into 4week old NOD mice using the combination of MPs encapsulating Vit D3, Ins B, TGF-β1 and GM-CSF protected 40% of mice from T1D development, significant in comparison to the control. This work represents one of the first applications of a biomaterial-based, MP vaccine system to successfully prevent autoimmune diabetes.
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Affiliation(s)
- Jamal S Lewis
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA
| | - Natalia V Dolgova
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA
| | - Ying Zhang
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA
| | - Chang Qing Xia
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32611, USA
| | - Clive H Wasserfall
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32611, USA
| | - Mark A Atkinson
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32611, USA
| | - Michael J Clare-Salzler
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32611, USA
| | - Benjamin G Keselowsky
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA; Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32611, USA.
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30
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Gaipl US, Multhoff G, Scheithauer H, Lauber K, Hehlgans S, Frey B, Rödel F. Kill and spread the word: stimulation of antitumor immune responses in the context of radiotherapy. Immunotherapy 2015; 6:597-610. [PMID: 24896628 DOI: 10.2217/imt.14.38] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Besides the direct, targeted effects of ionizing irradiation (x-ray) on cancer cells, namely DNA damage and cell death induction, indirect, nontargeted ones exist, which are mediated in large part by the immune system. Immunogenic forms of tumor cell death induced by x-ray, including immune modulating danger signals like the heat shock protein 70, adenosine triphosphate, and high-mobility group box 1 protein are presented. Further, antitumor effects exerted by cells of the innate (natural killer cells) as well as adaptive immune system (T cells activated by dendritic cells) are outlined. Tumor cell death inhibiting molecules such as survivin are introduced as suitable target for molecularly tailored therapies in combination with x-ray. Finally, reasonable combinations of immune therapies with radiotherapy are discussed.
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Affiliation(s)
- Udo S Gaipl
- Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
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31
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Narita M, Kanda T, Abe T, Uchiyama T, Iwafuchi M, Zheng Z, Liu A, Kaifu T, Kosugi S, Minagawa M, Itoh K, Takahashi M. Immune responses in patients with esophageal cancer treated with SART1 peptide-pulsed dendritic cell vaccine. Int J Oncol 2015; 46:1699-709. [PMID: 25625346 DOI: 10.3892/ijo.2015.2846] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2014] [Accepted: 11/20/2014] [Indexed: 12/27/2022] Open
Abstract
Patients with advanced stage of squamous cell carcinoma of esophagus have a poor prognosis with a lethal outcome. In order to explore the feasibility and effectiveness of dendritic cell (DC)-based immunotherapy for squamous cell carcinoma of esophagus, we performed a phase I/II clinical trial of monocyte-derived dendritic cells (moDCs) pulsed with SART1 peptide in seven patients with advanced stage of this disease. Although the feasibility of this therapy was definite, the effectiveness was not clearly confirmed in advanced stage of squamous cell carcinoma of esophagus. However, in vitro study revealed that moDCs generated for this therapy possessed a potent ability of inducing SART1 peptide-specific cytotoxic T lymphocytes (CTLs). In addition, these moDCs were demonstrated to be able to produce exosomes with an antigen presenting ability for inducing SART1 peptide-specific CTLs. ELISPOT assay using cryopreserved patient's lymphocytes demonstrated that IFN-γ ELISPOTs were increased after four times of SART1 peptide-pulsed moDC vaccinations compared with before the vaccination in a patient. The present study demonstrated that moDCs prepared from advanced stage of squamous cell carcinoma of esophagus possess a good immune function and in vivo immune responses (detected by ELISPOT assay) were evoked by the infusion of these moDCs. These findings suggest that DC-based immunotherapy could be one of the modalities applicable for squamous cell carcinoma of esophagus.
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Affiliation(s)
- Miwako Narita
- Laboratory of Hematology and Oncology, Graduate School of Health Sciences, Niigata University, Niigata 951‑8518, Japan
| | - Tatsuo Kanda
- Department of Surgery, School of Medicine, Niigata University, Niigata 951‑8520, Japan
| | - Takashi Abe
- Department of Hematology, Endocrinology, and Metabolism, School of Medicine, Niigata University, Niigata 951‑8520, Japan
| | - Takayoshi Uchiyama
- Laboratory of Hematology and Oncology, Graduate School of Health Sciences, Niigata University, Niigata 951‑8518, Japan
| | - Minami Iwafuchi
- Laboratory of Hematology and Oncology, Graduate School of Health Sciences, Niigata University, Niigata 951‑8518, Japan
| | - Zhiyin Zheng
- Department of Hematology, Endocrinology, and Metabolism, School of Medicine, Niigata University, Niigata 951‑8520, Japan
| | - Aichun Liu
- Department of Hematology, Endocrinology, and Metabolism, School of Medicine, Niigata University, Niigata 951‑8520, Japan
| | - Tsutomu Kaifu
- Department of Surgery, School of Medicine, Niigata University, Niigata 951‑8520, Japan
| | - Shinichi Kosugi
- Department of Surgery, School of Medicine, Niigata University, Niigata 951‑8520, Japan
| | - Masahiro Minagawa
- Department of Surgery, School of Medicine, Niigata University, Niigata 951‑8520, Japan
| | - Kyogo Itoh
- Cancer Vaccine Development Division, Kurume University Research Center for Innovative Cancer Therapy, Fukuoka 830‑0011, Japan
| | - Masuhiro Takahashi
- Laboratory of Hematology and Oncology, Graduate School of Health Sciences, Niigata University, Niigata 951‑8518, Japan
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Vasaturo A, Verdoes M, de Vries J, Torensma R, Figdor CG. Restoring immunosurveillance by dendritic cell vaccines and manipulation of the tumor microenvironment. Immunobiology 2014; 220:243-8. [PMID: 25466585 DOI: 10.1016/j.imbio.2014.11.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Revised: 11/06/2014] [Accepted: 11/07/2014] [Indexed: 12/19/2022]
Abstract
Cancer cells evolve from normal cells throughout life and are usually recognized by our immune system and destroyed, a process called immunosurveillance. Unfortunately, in some instances cancer cells paralyze our immune system, resulting in outgrowth and spreading of the tumor. Understanding the complexity of immunomodulation by tumors is important for the development of therapeutical strategies. Nowadays, various approaches have been developed to enhance anti-tumor immune responses and abrogate the immune dampening effect of the tumor and its surrounding environment, including dendritic cell-based vaccines, therapies to counteract myeloid derived suppressor cell function within the tumor and antagonists of inhibitory signaling pathways to overcome 'immune checkpoints'. The challenge is now to find the right combination of immune based therapies to fully restore immune function and provide a more efficacious and enduring anti-tumor response.
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Affiliation(s)
- Angela Vasaturo
- Radboud Institute for Molecular Life Sciences, Radboudumc, Department of Tumorimmunology, Geert Grooteplein 26, 6525GA Nijmegen, The Netherlands
| | - Martijn Verdoes
- Radboud Institute for Molecular Life Sciences, Radboudumc, Department of Tumorimmunology, Geert Grooteplein 26, 6525GA Nijmegen, The Netherlands
| | - Jolanda de Vries
- Radboud Institute for Molecular Life Sciences, Radboudumc, Department of Tumorimmunology, Geert Grooteplein 26, 6525GA Nijmegen, The Netherlands
| | - Ruurd Torensma
- Radboud Institute for Molecular Life Sciences, Radboudumc, Department of Tumorimmunology, Geert Grooteplein 26, 6525GA Nijmegen, The Netherlands
| | - Carl G Figdor
- Radboud Institute for Molecular Life Sciences, Radboudumc, Department of Tumorimmunology, Geert Grooteplein 26, 6525GA Nijmegen, The Netherlands.
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Role of type I interferon in inducing a protective immune response: perspectives for clinical applications. Cytokine Growth Factor Rev 2014; 26:195-201. [PMID: 25466627 DOI: 10.1016/j.cytogfr.2014.10.002] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 10/22/2014] [Indexed: 11/24/2022]
Abstract
Type I IFNs (IFN-I) are antiviral cytokines endowed with many biological effects, including antitumor activity. Over the last 15 years, an ensemble of studies has revealed that these cytokines play a crucial role in the induction of a protective antitumor immune response. Early in vivo studies in mouse models have been instrumental for understanding the IFN-I-induced host-mediated mechanisms. IFN-α is currently recognized as a powerful inducer of the differentiation/activation of dendritic cells (DCs) and today IFN-α-conditioned DCs represent promising DC candidates for the development of therapeutic cancer vaccines. Moreover, data from pilot clinical trials support the concept of using IFN-α as an enhancer of the response of patients to cancer vaccines. Notably, endogenous IFN-I production does also play a critical role in the antitumor response to some chemotherapeutic agents. Thus, we can now envisage new strategies of clinical use of IFN-α, based on the injection of IFN-conditioned cells as well as the usage of these cytokines as cancer vaccine adjuvants, alone or in combination with other treatments (including epigenetic drugs) to induce an immunogenic cell death and a long lasting antitumor response.
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GK-1 improves the immune response induced by bone marrow dendritic cells loaded with MAGE-AX in mice with melanoma. J Immunol Res 2014; 2014:158980. [PMID: 25759825 PMCID: PMC4230216 DOI: 10.1155/2014/158980] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Accepted: 09/29/2014] [Indexed: 12/13/2022] Open
Abstract
The aim of dendritic cell (DC) vaccination in cancer is to induce tumor-specific effector T cells that may reduce and control tumor mass. Immunostimulants that could drive a desired immune response are necessary to be found in order to generate a long lasting tumor immune response. GK-1 peptide, derived from Taenia crassiceps, induces not only increase in TNFα, IFNγ, and MCP-1 production in cocultures of DCs and T lymphocytes but also immunological protection against influenza virus. Moreover, the aim of this investigation is the use of GK-1 as a bone marrow DCs (BMDCs) immunostimulant targeted with MAGE antigen; thus, BMDC may be used as immunotherapy against murine melanoma. GK-1 induced in BMDCs a meaningful increment of CD86 and IL-12. In addition, the use of BMDCs TNFα/GK-1/MAGE-AX induced the highest survival and the smallest tumors in mice. Besides, the treatment helped to increase CD8 lymphocytes levels and to produce IFNγ in lymph nodes. Moreover, the histopathological analysis showed that BMDCs treated with GK-1/TNFα and loaded with MAGE-AX induced the apparition of more apoptotic and necrotic areas in tumors than in mice without treatment. These results highlight the properties of GK-1 as an immunostimulant of DCs and suggest as a potential candidate the use of this immunotherapy against cancer disease.
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Galluzzi L, Senovilla L, Vacchelli E, Eggermont A, Fridman WH, Galon J, Sautès-Fridman C, Tartour E, Zitvogel L, Kroemer G. Trial watch: Dendritic cell-based interventions for cancer therapy. Oncoimmunology 2014; 1:1111-1134. [PMID: 23170259 PMCID: PMC3494625 DOI: 10.4161/onci.21494] [Citation(s) in RCA: 140] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Dendritic cells (DCs) occupy a central position in the immune system, orchestrating a wide repertoire of responses that span from the development of self-tolerance to the elicitation of potent cellular and humoral immunity. Accordingly, DCs are involved in the etiology of conditions as diverse as infectious diseases, allergic and autoimmune disorders, graft rejection and cancer. During the last decade, several methods have been developed to load DCs with tumor-associated antigens, ex vivo or in vivo, in the attempt to use them as therapeutic anticancer vaccines that would elicit clinically relevant immune responses. While this has not always been the case, several clinical studies have demonstrated that DC-based anticancer vaccines are capable of activating tumor-specific immune responses that increase overall survival, at least in a subset of patients. In 2010, this branch of clinical research has culminated with the approval by FDA of a DC-based therapeutic vaccine (sipuleucel-T, Provenge®) for use in patients with asymptomatic or minimally symptomatic metastatic hormone-refractory prostate cancer. Intense research efforts are currently dedicated to the identification of the immunological features of patients that best respond to DC-based anticancer vaccines. This knowledge may indeed lead to personalized combination strategies that would extend the benefit of DC-based immunotherapy to a larger patient population. In addition, widespread enthusiasm has been generated by the results of the first clinical trials based on in vivo DC targeting, an approach that holds great promises for the future of DC-based immunotherapy. In this Trial Watch, we will summarize the results of recently completed clinical trials and discuss the progress of ongoing studies that have evaluated/are evaluating DC-based interventions for cancer therapy.
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Affiliation(s)
- Lorenzo Galluzzi
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France ; Institut Gustave Roussy; Villejuif, France
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Van Elssen CH, Oth T, Germeraad WT, Bos GM, Vanderlocht J. Natural Killer Cells: The Secret Weapon in Dendritic Cell Vaccination Strategies. Clin Cancer Res 2014; 20:1095-103. [DOI: 10.1158/1078-0432.ccr-13-2302] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Abstract
Effective antitumor immunity requires the generation and persistence of functional tumor-specific T-cell responses. Among the critical factors that often control these responses is how the antigen is delivered and presented to T cells. The use of peptide-based vaccination has been found to be a promising means to induce antitumor T-cell responses but with limited effects even if the peptide is co-delivered with a potent adjuvant. This limited response could be due to cancer-induced dysfunction in dendritic cells (DC), which play a central role in shaping the quantity and quality of antitumor immunity. Therefore, DC-based peptide delivery of tumor antigen is becoming a potential approach in cancer immunotherapy. In this approach, autologous DC are generated from their precursors in bone marrow or peripheral blood mononuclear cells, loaded with tumor antigen(s) and then infused back to the tumor-bearing host in about 7 days. This DC-based vaccination can act as an antigen delivery vehicle as well as a potent adjuvant, resulting in measurable antitumor immunity in several cancer settings in preclinical and clinical studies. This chapter focuses on DC-based vaccination and how this approach can be more efficacious in cancer immunotherapy.Effective antitumor immunity requires the generation and persistence of functional tumor-specific T-cell responses. Among the critical factors that often control these responses is how the antigen is delivered and presented to T cells. The use of peptide-based vaccination has been found to be a promising means to induce antitumor T-cell responses but with limited effects even if the peptide is co-delivered with a potent adjuvant. This limited response could be due to cancer-induced dysfunction in dendritic cells (DC), which play a central role in shaping the quantity and quality of antitumor immunity. Therefore, DC-based peptide delivery of tumor antigen is becoming a potential approach in cancer immunotherapy. In this approach, autologous DC are generated from their precursors in bone marrow or peripheral blood mononuclear cells, loaded with tumor antigen(s) and then infused back to the tumor-bearing host in about 7 days. This DC-based vaccination can act as an antigen delivery vehicle as well as a potent adjuvant, resulting in measurable antitumor immunity in several cancer settings in preclinical and clinical studies. This chapter focuses on DC-based vaccination and how this approach can be more efficacious in cancer immunotherapy.
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Affiliation(s)
- Mohamed L Salem
- Immunology and Biotechnology Unit, Zoology Department, Faculty of Science, Tanta University, Tanta, Egypt
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Aranda F, Vacchelli E, Eggermont A, Galon J, Sautès-Fridman C, Tartour E, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Peptide vaccines in cancer therapy. Oncoimmunology 2013; 2:e26621. [PMID: 24498550 PMCID: PMC3902120 DOI: 10.4161/onci.26621] [Citation(s) in RCA: 94] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Accepted: 09/26/2013] [Indexed: 02/08/2023] Open
Abstract
Throughout the past 3 decades, along with the recognition that the immune system not only influences oncogenesis and tumor progression, but also determines how established neoplastic lesions respond therapy, renovated enthusiasm has gathered around the possibility of using vaccines as anticancer agents. Such an enthusiasm quickly tempered when it became clear that anticancer vaccines would have to be devised as therapeutic, rather than prophylactic, measures, and that malignant cells often fail to elicit (or actively suppress) innate and adaptive immune responses. Nonetheless, accumulating evidence indicates that a variety of anticancer vaccines, including cell-based, DNA-based, and purified component-based preparations, are capable of circumventing the poorly immunogenic and highly immunosuppressive nature of most tumors and elicit (at least under some circumstances) therapeutically relevant immune responses. Great efforts are currently being devoted to the identification of strategies that may provide anticancer vaccines with the capacity of breaking immunological tolerance and eliciting tumor-associated antigen-specific immunity in a majority of patients. In this sense, promising results have been obtained by combining anticancer vaccines with a relatively varied panels of adjuvants, including multiple immunostimulatory cytokines, Toll-like receptor agonists as well as inhibitors of immune checkpoints. One year ago, in the December issue of OncoImmunology, we discussed the biological mechanisms that underlie the antineoplastic effects of peptide-based vaccines and presented an abundant literature demonstrating the prominent clinical potential of such an approach. Here, we review the latest developments in this exciting area of research, focusing on high-profile studies that have been published during the last 13 mo and clinical trials launched in the same period to evaluate purified peptides or full-length proteins as therapeutic anticancer agents.
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Affiliation(s)
- Fernando Aranda
- Gustave Roussy; Villejuif, France ; INSERM, U848; Villejuif, France ; Université Paris-Sud/Paris XI; Le Kremlin-Bicêtre, France ; Equipe 11 labellisée par la Lique Nationale contre le Cancer; Centre de Recherche des Cordeliers; Paris, France
| | - Erika Vacchelli
- Gustave Roussy; Villejuif, France ; INSERM, U848; Villejuif, France ; Université Paris-Sud/Paris XI; Le Kremlin-Bicêtre, France ; Equipe 11 labellisée par la Lique Nationale contre le Cancer; Centre de Recherche des Cordeliers; Paris, France
| | | | - Jerome Galon
- Université Paris Descartes/Paris V, Sorbonne Paris Cité; Paris, France ; Université Pierre et Marie Curie/Paris VI; Paris, France ; INSERM, U872; Paris, France ; Equipe 15, Centre de Recherche des Cordeliers; Paris, France
| | - Catherine Sautès-Fridman
- Université Pierre et Marie Curie/Paris VI; Paris, France ; INSERM, U872; Paris, France ; Equipe 13, Centre de Recherche des Cordeliers; Paris, France
| | - Eric Tartour
- Pôle de Biologie; Hôpital Européen Georges Pompidou; AP-HP; Paris, France ; INSERM, U970; Paris, France
| | - Laurence Zitvogel
- Gustave Roussy; Villejuif, France ; INSERM, U1015; CICBT507; Villejuif, France
| | - Guido Kroemer
- Pôle de Biologie; Hôpital Européen Georges Pompidou; AP-HP; Paris, France ; INSERM, U848; Villejuif, France ; Equipe 11 labellisée par la Lique Nationale contre le Cancer; Centre de Recherche des Cordeliers; Paris, France ; Université Paris Descartes/Paris V, Sorbonne Paris Cité; Paris, France ; Metabolomics and Cell Biology Platforms; Gustave Roussy; Villejuif, France
| | - Lorenzo Galluzzi
- Gustave Roussy; Villejuif, France ; Equipe 11 labellisée par la Lique Nationale contre le Cancer; Centre de Recherche des Cordeliers; Paris, France ; Université Paris Descartes/Paris V, Sorbonne Paris Cité; Paris, France
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Córdoba EV, Pion M, Rasines B, Filippini D, Komber H, Ionov M, Bryszewska M, Appelhans D, Muñoz-Fernández M. Glycodendrimers as new tools in the search for effective anti-HIV DC-based immunotherapies. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2013; 9:972-84. [DOI: 10.1016/j.nano.2013.03.004] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2012] [Revised: 02/28/2013] [Accepted: 03/08/2013] [Indexed: 11/29/2022]
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Jin H, Sun Y, Wang S, Cheng X. Matrine activates PTEN to induce growth inhibition and apoptosis in V600EBRAF harboring melanoma cells. Int J Mol Sci 2013; 14:16040-57. [PMID: 23912239 PMCID: PMC3759898 DOI: 10.3390/ijms140816040] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2013] [Revised: 07/12/2013] [Accepted: 07/18/2013] [Indexed: 01/06/2023] Open
Abstract
Here, we report a natural chemical Matrine, which exhibits anti-melanoma potential with its PTEN activation mechanism. Matrine effectively inhibited proliferation of several carcinoma cell lines, including melanoma V600EBRAF harboring M21 cells. Flow cytometry analysis showed Matrine induced G0/G1 cell cycle arrest in M21 cells dose-dependently. Apoptosis in M21 cells induced by Matrine was identified by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis and Annexin-V/FITC staining. Molecular mechanistic study suggested that Matrine upregulated both mRNA level and protein expression level of phosphatase and tensin homolog deleted on chromosome ten (PTEN), leading to inhibition of the PI3K/Akt pathway. Downregulation of phosphor-Aktser473 by Matrine activated p21 and Bax, which contributed to G0/G1 cell cycle and apoptosis. Besides, Matrine enhanced the PI3K/Akt inhibition effects to inhibit the cell proliferation with PI3K inhibitor, LY2940002. In summary, our findings suggest Matrine is a promising antitumor drug candidate with its possible PTEN activation mechanisms for treating cancer diseases, such as melanomas.
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Affiliation(s)
- Hui Jin
- School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; E-Mail:
| | - Yu Sun
- Yue-yang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China; E-Mails: (Y.S.); (S.W.)
| | - Shuiying Wang
- Yue-yang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China; E-Mails: (Y.S.); (S.W.)
| | - Xiaodong Cheng
- School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; E-Mail:
- Yue-yang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China; E-Mails: (Y.S.); (S.W.)
- East Hospital, Tongji University, Shanghai 200120, China
- Author to whom correspondence should be addressed; E-Mail: ; Tel./Fax: +86-21-6598-0295
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Dillman RO, Cornforth AN, Nistor G. Cancer stem cell antigen-based vaccines: the preferred strategy for active specific immunotherapy of metastatic melanoma? Expert Opin Biol Ther 2013; 13:643-56. [PMID: 23451922 DOI: 10.1517/14712598.2013.759556] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION There are now two chemotherapy agents, one tyrosine kinase inhibitor and three immunotherapy products approved for the treatment of metastatic melanoma, but an unmet need persists because these options are toxic and of limited therapeutic benefit. Active specific immunotherapy with therapeutic vaccines could be a useful addition to the therapeutic armamentarium, especially in patients whose tumor burden has been reduced by other treatment modalities. AREAS COVERED This article reviews various sources of melanoma antigens, such as peptides, gangliosides, autologous tumor and cancer stem cells including allogeneic and autologous cell lines. The advantages and disadvantages of various antigen sources and allogeneic and autologous approaches are discussed with an emphasis on the theoretical benefits of immunizing against cancer stem cells. The results from published randomized trials testing the benefit of various vaccine approaches are summarized, as well as promising results from three Phase II trials (one randomized) of patient-specific stem cell antigen-based products. EXPERT OPINION Immune responses directed toward the unique neoantigens and stem cell antigens expressed on continuously proliferating, self-renewing, autologous tumor cells could potentially overcome the limitations inherent in these other antigen-based approaches, that to date, have yielded disappointing results in randomized trials.
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Affiliation(s)
- Robert O Dillman
- Hoag Institute for Research and Education, Hoag Hospital, One Hoag Dr, Bldg 44 Suite 210, Newport Beach, California 92663, USA.
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Perez-Campos E, Perez JA, Mayoral LPC, Velasco IG, Cruz PH, Olivera PG. Why not change classical treatments for glioblastoma in elderly patients? World J Exp Med 2013; 3:50. [DOI: 10.5493/wjem.v3.i4.50] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Revised: 09/06/2013] [Accepted: 11/08/2013] [Indexed: 02/06/2023] Open
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Interaction of tumor cells with the immune system: implications for dendritic cell therapy and cancer progression. Drug Discov Today 2013; 18:35-42. [DOI: 10.1016/j.drudis.2012.07.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2012] [Revised: 06/30/2012] [Accepted: 07/18/2012] [Indexed: 01/21/2023]
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Engell-Noerregaard L, Hendel HW, Johannesen HH, Alslev L, Svane IM. FDG PET scans as evaluation of clinical response to dendritic cell vaccination in patients with malignant melanoma. Cancer Immunol Immunother 2013; 62:17-25. [PMID: 22722450 PMCID: PMC11029132 DOI: 10.1007/s00262-012-1306-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2011] [Accepted: 06/02/2012] [Indexed: 10/28/2022]
Abstract
BACKGROUND Measurements of tumour metabolism by [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) have been successfully applied to monitor tumour response after chemo- and chemo-radiotherapy and may not have the same limitations as other morphological imaging techniques. In this study it is investigated whether FDG-PET might add information on the efficacy of immune therapy. MATERIALS AND METHODS In a retrospective analysis data from patients with advanced progressive melanoma, treated with DC vaccinations and evaluated by PET/CT scans at baseline as well as after 6 vaccinations were analysed. If a patient achieved stable disease according to RECIST, additional vaccinations were given. The PET scans were evaluated according to EORTC guidelines. RESULTS PET/CT scans from 13 patients were evaluated. According to RECIST 3 patients achieved stable disease and 10 patients progressed. Interestingly, when evaluated by PET scans 2 patients had partial metabolic response and 1 patient had complete metabolic response of the 2 index lesions even though a new lesion appeared simultaneously. Ten patients were seen to have stable or progressive metabolic disease. CONCLUSION By adding PET scans to the CT evaluation of patients treated with DC vaccines, a more detailed picture of the single lesions was found. This seems to improve the clinical evaluation of the treatment. The lack of correlation between the PET and CT scans suggests that some of the increases in target lesions seen in CT scans might be due to oedema or immune-infiltrates and not progression of the disease. Thus, further investigation into the contribution of PET scans to the evaluation of cancer immunotherapy is needed.
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Affiliation(s)
- Lotte Engell-Noerregaard
- Department of Haematology, Center for Cancer ImmuneTherapy (CCIT), University Hospital Herlev, Herlev, Denmark.
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Zhang H, Wang Y, Liu C, Zhang L, Xia Q, Zhang Y, Wu J, Jiang C, Chen Y, Wu Y, Zha X, Yu X, Kong W. DNA and adenovirus tumor vaccine expressing truncated survivin generates specific immune responses and anti-tumor effects in a murine melanoma model. Cancer Immunol Immunother 2012; 61:1857-67. [PMID: 22706381 PMCID: PMC11028718 DOI: 10.1007/s00262-012-1296-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2012] [Accepted: 05/29/2012] [Indexed: 12/20/2022]
Abstract
Survivin is overexpressed in major types of cancer and is considered an ideal "universal" tumor-associated antigen that can be targeted by immunotherapeutic vaccines. However, its anti-apoptosis function raises certain safety concerns. Here, a new truncated human survivin, devoid of the anti-apoptosis function, was generated as a candidate tumor vaccine. Interleukin 2 (IL-2) has been widely used as an adjuvant for vaccination against various diseases. Meanwhile, the DNA prime and recombinant adenovirus (rAd) boost heterologous immunization strategy has been proven to be highly effective in enhancing immune responses. Therefore, the efficacy of a new cancer vaccine based on a truncated form of survivin, combined with IL-2, DNA prime, and rAd boost, was tested. As prophylaxis, immunization with the DNA vaccine alone resulted in a weak immune response and modest anti-tumor effect, whereas the tumor inhibition ratio with the DNA vaccine administered with IL-2 increased to 89 % and was further increased to nearly 100 % by rAd boosting. Moreover, complete tumor rejection was observed in 5 of 15 mice. Efficacy of the vaccine administered therapeutically was enhanced by nearly 300 % when combined with carboplatin. These results indicated that vaccination with a truncated survivin vaccine using DNA prime-rAd boost combined with IL-2 adjuvant and carboplatin represents an attractive strategy to overcoming immune tolerance to tumors and has potential therapeutic benefits in melanoma cancer.
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MESH Headings
- Adenoviridae/genetics
- Adjuvants, Immunologic/therapeutic use
- Animals
- Antigens, Neoplasm/genetics
- Antigens, Neoplasm/immunology
- Antineoplastic Agents/therapeutic use
- Cancer Vaccines/genetics
- Cancer Vaccines/immunology
- Cancer Vaccines/therapeutic use
- Carboplatin/therapeutic use
- Cell Line, Tumor
- Combined Modality Therapy
- Female
- Humans
- Inhibitor of Apoptosis Proteins/genetics
- Inhibitor of Apoptosis Proteins/immunology
- Interleukin-2/therapeutic use
- Melanoma, Experimental/drug therapy
- Melanoma, Experimental/immunology
- Melanoma, Experimental/therapy
- Mice
- Mice, Inbred C57BL
- Mutation
- Skin Neoplasms/drug therapy
- Skin Neoplasms/immunology
- Skin Neoplasms/therapy
- Survivin
- Treatment Outcome
- Vaccines, DNA/genetics
- Vaccines, DNA/immunology
- Vaccines, DNA/therapeutic use
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Affiliation(s)
- Haihong Zhang
- National Engineering Laboratory for AIDS Vaccine, College of Life Science, Jilin University, No. 2699, Qianjin Street, Changchun, 130012 China
- Key Laboratory for Molecular Enzymology and Engineering, College of Life Science, Jilin University, No. 2699, Qianjin Street, Changchun, 130012 China
| | - Yuqian Wang
- National Engineering Laboratory for AIDS Vaccine, College of Life Science, Jilin University, No. 2699, Qianjin Street, Changchun, 130012 China
| | - Chenlu Liu
- National Engineering Laboratory for AIDS Vaccine, College of Life Science, Jilin University, No. 2699, Qianjin Street, Changchun, 130012 China
| | - Lixing Zhang
- National Engineering Laboratory for AIDS Vaccine, College of Life Science, Jilin University, No. 2699, Qianjin Street, Changchun, 130012 China
| | - Qiu Xia
- National Engineering Laboratory for AIDS Vaccine, College of Life Science, Jilin University, No. 2699, Qianjin Street, Changchun, 130012 China
| | - Yong Zhang
- National Engineering Laboratory for AIDS Vaccine, College of Life Science, Jilin University, No. 2699, Qianjin Street, Changchun, 130012 China
- Key Laboratory for Molecular Enzymology and Engineering, College of Life Science, Jilin University, No. 2699, Qianjin Street, Changchun, 130012 China
| | - Jiaxin Wu
- National Engineering Laboratory for AIDS Vaccine, College of Life Science, Jilin University, No. 2699, Qianjin Street, Changchun, 130012 China
- Key Laboratory for Molecular Enzymology and Engineering, College of Life Science, Jilin University, No. 2699, Qianjin Street, Changchun, 130012 China
| | - Chunlai Jiang
- National Engineering Laboratory for AIDS Vaccine, College of Life Science, Jilin University, No. 2699, Qianjin Street, Changchun, 130012 China
- Key Laboratory for Molecular Enzymology and Engineering, College of Life Science, Jilin University, No. 2699, Qianjin Street, Changchun, 130012 China
| | - Yan Chen
- National Engineering Laboratory for AIDS Vaccine, College of Life Science, Jilin University, No. 2699, Qianjin Street, Changchun, 130012 China
- Key Laboratory for Molecular Enzymology and Engineering, College of Life Science, Jilin University, No. 2699, Qianjin Street, Changchun, 130012 China
| | - Yongge Wu
- National Engineering Laboratory for AIDS Vaccine, College of Life Science, Jilin University, No. 2699, Qianjin Street, Changchun, 130012 China
- Key Laboratory for Molecular Enzymology and Engineering, College of Life Science, Jilin University, No. 2699, Qianjin Street, Changchun, 130012 China
| | - Xiao Zha
- Sichuan Tumor Hospital and Institute, Chengdu, 610041 China
| | - Xianghui Yu
- National Engineering Laboratory for AIDS Vaccine, College of Life Science, Jilin University, No. 2699, Qianjin Street, Changchun, 130012 China
- Key Laboratory for Molecular Enzymology and Engineering, College of Life Science, Jilin University, No. 2699, Qianjin Street, Changchun, 130012 China
| | - Wei Kong
- National Engineering Laboratory for AIDS Vaccine, College of Life Science, Jilin University, No. 2699, Qianjin Street, Changchun, 130012 China
- Key Laboratory for Molecular Enzymology and Engineering, College of Life Science, Jilin University, No. 2699, Qianjin Street, Changchun, 130012 China
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Ellebaek E, Engell-Noerregaard L, Iversen TZ, Froesig TM, Munir S, Hadrup SR, Andersen MH, Svane IM. Metastatic melanoma patients treated with dendritic cell vaccination, Interleukin-2 and metronomic cyclophosphamide: results from a phase II trial. Cancer Immunol Immunother 2012; 61:1791-804. [PMID: 22426890 PMCID: PMC11029126 DOI: 10.1007/s00262-012-1242-4] [Citation(s) in RCA: 97] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2011] [Accepted: 03/04/2012] [Indexed: 02/07/2023]
Abstract
Dendritic cells (DC) are the most potent antigen presenting cells and have proven effective in stimulation of specific immune responses in vivo. Competing immune inhibition could limit the clinical efficacy of DC vaccination. In this phase II trial, metronomic Cyclophosphamide and a Cox-2 inhibitor have been added to a DC vaccine with the intend to dampen immunosuppressive mechanisms. Twenty-eight patients with progressive metastatic melanoma were treated with autologous DCs pulsed with survivin, hTERT, and p53-derived peptides (HLA-A2(+)) or tumor lysate (HLA-A2(-)). Concomitantly the patients were treated with IL-2, Cyclophosphamide, and Celecoxib. The treatment was safe and tolerable. Sixteen patients (57 %) achieved stable disease (SD) at 1st evaluation and 8 patients had prolonged SD (7-13.7 months). The median OS was 9.4 months. Patients with SD had an OS of 10.5 months while patients with progressive disease (PD) had an OS of 6.0 months (p = 0.048) even though there were no differences in prognostic factors between the two groups. Despite the use of metronomic Cyclophosphamide, regulatory T cells did not decrease during treatment. Indirect IFN-γ ELISPOT assays showed a general increase in immune responses from baseline to the time of 4th vaccination. Induction of antigen-specific immune responses was seen in 9 out of 15 screened HLA-A2(+) patients. In conclusion, the number of patients obtaining SD more than doubled and 6-month survival significantly increased compared to a previous trial without Cyclophosphamide and Celecoxib. A general increase in immune responses against the tested peptides was observed.
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Affiliation(s)
- Eva Ellebaek
- Department of Haematology, Center for Cancer Immune Therapy (CCIT), Copenhagen University Hospital, Herlev, Herlev Ringvej 75, 2730 Herlev, Denmark
- Department of Oncology, Copenhagen University Hospital, Herlev, Herlev, Denmark
| | - Lotte Engell-Noerregaard
- Department of Haematology, Center for Cancer Immune Therapy (CCIT), Copenhagen University Hospital, Herlev, Herlev Ringvej 75, 2730 Herlev, Denmark
- Department of Oncology, Copenhagen University Hospital, Herlev, Herlev, Denmark
| | - Trine Zeeberg Iversen
- Department of Haematology, Center for Cancer Immune Therapy (CCIT), Copenhagen University Hospital, Herlev, Herlev Ringvej 75, 2730 Herlev, Denmark
- Department of Oncology, Copenhagen University Hospital, Herlev, Herlev, Denmark
| | - Thomas Moerch Froesig
- Department of Haematology, Center for Cancer Immune Therapy (CCIT), Copenhagen University Hospital, Herlev, Herlev Ringvej 75, 2730 Herlev, Denmark
- Department of Pharmacology and Pharmacotherapy, Pharmaceutical Faculty, University of Copenhagen, Copenhagen, Denmark
| | - Shamaila Munir
- Department of Haematology, Center for Cancer Immune Therapy (CCIT), Copenhagen University Hospital, Herlev, Herlev Ringvej 75, 2730 Herlev, Denmark
| | - Sine Reker Hadrup
- Department of Haematology, Center for Cancer Immune Therapy (CCIT), Copenhagen University Hospital, Herlev, Herlev Ringvej 75, 2730 Herlev, Denmark
| | - Mads Hald Andersen
- Department of Haematology, Center for Cancer Immune Therapy (CCIT), Copenhagen University Hospital, Herlev, Herlev Ringvej 75, 2730 Herlev, Denmark
| | - Inge Marie Svane
- Department of Haematology, Center for Cancer Immune Therapy (CCIT), Copenhagen University Hospital, Herlev, Herlev Ringvej 75, 2730 Herlev, Denmark
- Department of Oncology, Copenhagen University Hospital, Herlev, Herlev, Denmark
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Samarasinghe RM, Gibbons J, Kanwar RK, Kanwar JR. Nanotechnology based platforms for survivin targeted drug discovery. Expert Opin Drug Discov 2012; 7:1083-92. [PMID: 22950742 DOI: 10.1517/17460441.2012.719869] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
INTRODUCTION Development of an effective, safe and targeted drug delivery system to fight cancer and other diseases is a prime focus in the area of drug discovery. The emerging field of nanotechnology has revolutionised the way cancer therapy and diagnosis is achieved primarily due to the recent advances in material engineering and drug availability. Further, the recognition of the crucial role played by anti-apoptotic proteins such as survivin, has initiated the development of therapeutics that can target this protein as an attempt to develop alternative cancer therapies. However, a key challenge faced in drug development is the efficient delivery of survivin-targeted molecules to specific areas in the body. AREAS COVERED This review primarily focuses on the different strategies employing nanotechnology for targeting survivin expressed in human cancers. Different nanomaterials incorporating nucleic molecules or drugs targeted at survivin are discussed and the results obtained from studies are highlighted. EXPERT OPINION There are extensive studies reporting different treatment regimens for cancer, however, they still result in systemic toxicity, reduced bioavailability and ineffective delivery. Novel approaches involve the use of biocompatible nanomaterials together with gene or drug molecules to target proteins such as survivin, which is overexpressed in cancerous cells. These nanoformulations allow the benefits of protecting easily degradable molecules, allow controlled release, and enhance targeted delivery and effectiveness. Hence, nanotherapy utilizing survivin targeting can be considered to play a key role in the development of personalized nanomedicine for cancer.
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Affiliation(s)
- Rasika M Samarasinghe
- Deakin University, Institute for Frontier Materials (IFM), Nanomedicine-Laboratory of Immunology and Molecular Biomedical Research (LIMBR), Waurn Ponds, Australia
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Bobadilla S, Sunseri N, Landau NR. Efficient transduction of myeloid cells by an HIV-1-derived lentiviral vector that packages the Vpx accessory protein. Gene Ther 2012; 20:514-20. [PMID: 22895508 DOI: 10.1038/gt.2012.61] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Lentiviral vectors are widely used for the stable expression of genes and small hairpin RNA (shRNA)-mediated knockdown and are currently under development for clinical use in gene therapy. Pseudotyping of the vectors with VSV-G allows them to infect a wide range of cell types. However, myeloid cells, such as dendritic cells and macrophages, are relatively refractory to lentiviral vector transduction as a result of the myeloid-specific restriction factor, SAMHD1. SIVmac/HIV-2 and related viruses relieve the SAMHD1-mediated restriction by encoding Vpx, a virion-packaged accessory protein that induces the degradation of SAMHD1 upon infection. HIV-1 does not encode Vpx and cannot package the protein. We report the development of an HIV-1-based lentiviral vector in which the Vpx packaging motif has been placed in the p6 region of the Gag/Pol expression vector that is used to generate the lentiviral vector virions. The virions package Vpx in high copy number and infect myeloid cells with a two-log increase in titer. Transduction of dendritic cells with an shRNA against transportin-3 resulted in >90% knockdown of the encoding mRNA. The system can be applied to any HIV-based lentiviral vector and is useful for laboratory and clinical applications where the efficient transduction of myeloid cells is required.
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Affiliation(s)
- S Bobadilla
- Department of Microbiology, New York University School of Medicine, New York, NY, USA
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Brimnes MK, Gang AO, Donia M, thor Straten P, Svane IM, Hadrup SR. Generation of autologous tumor-specific T cells for adoptive transfer based on vaccination, in vitro restimulation and CD3/CD28 dynabead-induced T cell expansion. Cancer Immunol Immunother 2012; 61:1221-31. [PMID: 22237888 PMCID: PMC11029656 DOI: 10.1007/s00262-011-1199-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2011] [Accepted: 12/25/2011] [Indexed: 10/14/2022]
Abstract
Adoptive cell transfer (ACT) of in vitro expanded autologous tumor-infiltrating lymphocytes (TIL) has been shown to exert therapeutic efficacy in melanoma patients. We aimed to develop an ACT protocol based on tumor-specific T cells isolated from peripheral blood and in vitro expanded by Dynabeads® ClinExVivo™CD3/CD28. We show here that the addition of an in vitro restimulation step with relevant peptides prior to bead expansion dramatically increased the proportion of tumor-specific T cells in PBMC-cultures. Importantly, peptide-pulsed dendritic cells (DCs) as well as allogeneic tumor lysate-pulsed DCs from the DC vaccine preparation could be used with comparable efficiency to peptides for in vitro restimulation, to increase the tumor-specific T-cell response. Furthermore, we tested the use of different ratios and different types of Dynabeads® CD3/CD28 and CD3/CD28/CD137 T-cell expander, for optimized expansion of tumor-specific T cells. A ratio of 1:3 of Dynabeads® CD3/CD28 T-cell expander to T cells resulted in the maximum number of tumor-specific T cells. The addition of CD137 did not improve functionality or fold expansion. Both T-cell expansion systems could generate tumor-specific T cells that were both cytotoxic and effective cytokine producers upon antigen recognition. Dynabeads®-expanded T-cell cultures shows phenotypical characteristics of memory T cells with potential to migrate and expand in vivo. In addition, they possess longer telomeres compared to TIL cultures. Taken together, we demonstrate that in vitro restimulation of tumor-specific T cells prior to bead expansion is necessary to achieve high numbers of tumor-specific T cells. This is effective and easily applicable in combination with DC vaccination, by use of vaccine-generated DCs, either pulsed with peptide or tumor-lysate.
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Affiliation(s)
- Marie Klinge Brimnes
- Department of Hematology 54P4, Center for Cancer Immune Therapy (CCIT), University Hospital Herlev, 2730 Herlev, Denmark
| | - Anne Ortved Gang
- Department of Hematology 54P4, Center for Cancer Immune Therapy (CCIT), University Hospital Herlev, 2730 Herlev, Denmark
| | - Marco Donia
- Department of Hematology 54P4, Center for Cancer Immune Therapy (CCIT), University Hospital Herlev, 2730 Herlev, Denmark
- Department of Biomedical Sciences, University of Catania, Catania, Italy
| | - Per thor Straten
- Department of Hematology 54P4, Center for Cancer Immune Therapy (CCIT), University Hospital Herlev, 2730 Herlev, Denmark
| | - Inge Marie Svane
- Department of Hematology 54P4, Center for Cancer Immune Therapy (CCIT), University Hospital Herlev, 2730 Herlev, Denmark
- Department of Oncology, University Hospital Herlev, Herlev, Denmark
| | - Sine Reker Hadrup
- Department of Hematology 54P4, Center for Cancer Immune Therapy (CCIT), University Hospital Herlev, 2730 Herlev, Denmark
- Institute for International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
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Bhargava A, Mishra D, Banerjee S, Mishra PK. Dendritic cell engineering for tumor immunotherapy: from biology to clinical translation. Immunotherapy 2012; 4:703-718. [PMID: 22853757 DOI: 10.2217/imt.12.40] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Dendritic cells (DCs) are the most potent APCs, with the ability to orchestrate a repertoire of immune responses. DCs play a pivotal role in the initiation, programming and regulation of tumor-specific immune responses, as they are poised to take up, process and present tumor antigens to naive or effector T lymphocytes. Although, to an extent, DC-based immunotherapeutic strategies have successfully induced specific anti-tumor responses in animal models, their clinical efficacy has rarely been translated into the clinic. This article attempts to present a complete picture of recent developments of DC-based therapeutic strategies addressing multiple components of tumor immunoenvironment. It also showcases certain practical intricacies in order to explore novel strategies for providing new impetus to DC-based cancer vaccination.
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Affiliation(s)
- Arpit Bhargava
- Division of Translational Research, Tata Memorial Centre, ACTREC, India
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