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Xue D, Lu S, Zhang H, Zhang L, Dai Z, Kaufman DS, Zhang J. Induced pluripotent stem cell-derived engineered T cells, natural killer cells, macrophages, and dendritic cells in immunotherapy. Trends Biotechnol 2023; 41:907-922. [PMID: 36858941 DOI: 10.1016/j.tibtech.2023.02.003] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 01/31/2023] [Accepted: 02/03/2023] [Indexed: 03/03/2023]
Abstract
T cells, natural killer (NK) cells, macrophages (Macs), and dendritic cells (DCs) are among the most common sources for immune-cell-based therapies for cancer. Antitumor activity can be enhanced in induced pluripotent stem cell (iPSC)-derived immune cells by using iPSCs as a platform for stable genetic modifications that impact immuno-activating or -suppressive signaling pathways, such as transducing a chimeric antigen receptor (CAR) or deletion of immunosuppressive checkpoint molecules. This review outlines the utility of four iPSC-derived immune-cell-based therapies, highlight the latest progress and future trends in the genome-editing strategies designed to improve efficacy, safety, and universality, and provides perspectives that compare different contexts in which each of these iPSC-derived immune cell types can be most effectively used.
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Affiliation(s)
- Dixuan Xue
- Center for Stem Cell and Regenerative Medicine, Department of Basic Medical Sciences, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Zhejiang Laboratory for Systems and Precision Medicine, Zhejiang University Medical Center, 1369 West Wen Yi Road, Hangzhou 311121, China
| | - Shan Lu
- Center for Stem Cell and Regenerative Medicine, Department of Basic Medical Sciences, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Zhejiang Laboratory for Systems and Precision Medicine, Zhejiang University Medical Center, 1369 West Wen Yi Road, Hangzhou 311121, China
| | - Hailing Zhang
- Center for Stem Cell and Regenerative Medicine, Department of Basic Medical Sciences, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Zhejiang Laboratory for Systems and Precision Medicine, Zhejiang University Medical Center, 1369 West Wen Yi Road, Hangzhou 311121, China
| | - Li Zhang
- Center for Stem Cell and Regenerative Medicine, Department of Basic Medical Sciences, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Zhejiang Laboratory for Systems and Precision Medicine, Zhejiang University Medical Center, 1369 West Wen Yi Road, Hangzhou 311121, China
| | - Zhijun Dai
- Department of Breast Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, China
| | - Dan S Kaufman
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Jin Zhang
- Center for Stem Cell and Regenerative Medicine, Department of Basic Medical Sciences, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Zhejiang Laboratory for Systems and Precision Medicine, Zhejiang University Medical Center, 1369 West Wen Yi Road, Hangzhou 311121, China; Institute of Hematology, Zhejiang University, Hangzhou 310058, China; Center of Gene/Cell Engineering and Genome Medicine, Hangzhou, 310058, Zhejiang, China.
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Verheye E, Bravo Melgar J, Deschoemaeker S, Raes G, Maes A, De Bruyne E, Menu E, Vanderkerken K, Laoui D, De Veirman K. Dendritic Cell-Based Immunotherapy in Multiple Myeloma: Challenges, Opportunities, and Future Directions. Int J Mol Sci 2022; 23:904. [PMID: 35055096 PMCID: PMC8778019 DOI: 10.3390/ijms23020904] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 01/11/2022] [Indexed: 12/12/2022] Open
Abstract
Immunotherapeutic approaches, including adoptive cell therapy, revolutionized treatment in multiple myeloma (MM). As dendritic cells (DCs) are professional antigen-presenting cells and key initiators of tumor-specific immune responses, DC-based immunotherapy represents an attractive therapeutic approach in cancer. The past years, various DC-based approaches, using particularly ex-vivo-generated monocyte-derived DCs, have been tested in preclinical and clinical MM studies. However, long-term and durable responses in MM patients were limited, potentially attributed to the source of monocyte-derived DCs and the immunosuppressive bone marrow microenvironment. In this review, we briefly summarize the DC development in the bone marrow niche and the phenotypical and functional characteristics of the major DC subsets. We address the known DC deficiencies in MM and give an overview of the DC-based vaccination protocols that were tested in MM patients. Lastly, we also provide strategies to improve the efficacy of DC vaccines using new, improved DC-based approaches and combination therapies for MM patients.
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Affiliation(s)
- Emma Verheye
- Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, 1090 Brussel, Belgium; (E.V.); (A.M.); (E.D.B.); (E.M.); (K.V.)
- Laboratory of Myeloid Cell Immunology, VIB Center for Inflammation Research, 1050 Brussels, Belgium; (J.B.M.); (S.D.); (G.R.)
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, 1050 Brussels, Belgium
| | - Jesús Bravo Melgar
- Laboratory of Myeloid Cell Immunology, VIB Center for Inflammation Research, 1050 Brussels, Belgium; (J.B.M.); (S.D.); (G.R.)
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, 1050 Brussels, Belgium
| | - Sofie Deschoemaeker
- Laboratory of Myeloid Cell Immunology, VIB Center for Inflammation Research, 1050 Brussels, Belgium; (J.B.M.); (S.D.); (G.R.)
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, 1050 Brussels, Belgium
| | - Geert Raes
- Laboratory of Myeloid Cell Immunology, VIB Center for Inflammation Research, 1050 Brussels, Belgium; (J.B.M.); (S.D.); (G.R.)
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, 1050 Brussels, Belgium
| | - Anke Maes
- Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, 1090 Brussel, Belgium; (E.V.); (A.M.); (E.D.B.); (E.M.); (K.V.)
| | - Elke De Bruyne
- Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, 1090 Brussel, Belgium; (E.V.); (A.M.); (E.D.B.); (E.M.); (K.V.)
| | - Eline Menu
- Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, 1090 Brussel, Belgium; (E.V.); (A.M.); (E.D.B.); (E.M.); (K.V.)
| | - Karin Vanderkerken
- Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, 1090 Brussel, Belgium; (E.V.); (A.M.); (E.D.B.); (E.M.); (K.V.)
| | - Damya Laoui
- Laboratory of Myeloid Cell Immunology, VIB Center for Inflammation Research, 1050 Brussels, Belgium; (J.B.M.); (S.D.); (G.R.)
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, 1050 Brussels, Belgium
| | - Kim De Veirman
- Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, 1090 Brussel, Belgium; (E.V.); (A.M.); (E.D.B.); (E.M.); (K.V.)
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Que W, Guo WZ, Li XK. Manipulation of Regulatory Dendritic Cells for Induction Transplantation Tolerance. Front Immunol 2020; 11:582658. [PMID: 33162996 PMCID: PMC7591396 DOI: 10.3389/fimmu.2020.582658] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 08/31/2020] [Indexed: 12/13/2022] Open
Abstract
Current organ transplantation therapy is life-saving but accompanied by well-recognized side effects due to post-transplantation systematic immunosuppressive treatment. Dendritic cells (DCs) are central instigators and regulators of transplantation immunity and are responsible for balancing allograft rejection and tolerance. They are derived from monocyte-macrophage DC progenitors originating in the bone marrow and are classified into different subsets based on their developmental, phenotypical, and functional criteria. Functionally, DCs instigate allograft immunity by presenting donor antigens to alloreactive T cells via direct, indirect, and semidirect recognition pathways and provide essential signaling for alloreactive T cell activation via costimulatory molecules and pro-inflammatory cytokines. Regulatory DCs (DCregs) are characterized by a relatively low expression of major histocompatibility complex, costimulatory molecules, and altered cytokine production and exert their regulatory function through T cell anergy, T cell deletion, and regulatory T cell induction. In rodent transplantation studies, DCreg-based therapy, by in situ targeting or infusion of ex vivo generated DCregs, exhibits promising potential as a natural, well-tolerated, organ-specific therapeutic strategy for promoting lasting organ-specific transplantation tolerance. Recent early-phase studies of DCregs have begun to examine the safety and efficacy of DCreg-induced allograft tolerance in living-donor renal or liver transplantations. The present review summarizes the basic characteristics, function, and translation of DCregs in transplantation tolerance induction.
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Affiliation(s)
- Weitao Que
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Wen-Zhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiao-Kang Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
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Hashemi V, Farhadi S, Ghasemi Chaleshtari M, Seashore-Ludlow B, Masjedi A, Hojjat-Farsangi M, Namdar A, Ajjoolabady A, Mohammadi H, Ghalamfarsa G, Jadidi-Niaragh F. Nanomedicine for improvement of dendritic cell-based cancer immunotherapy. Int Immunopharmacol 2020; 83:106446. [PMID: 32244048 DOI: 10.1016/j.intimp.2020.106446] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 03/24/2020] [Accepted: 03/24/2020] [Indexed: 02/08/2023]
Abstract
Dendritic cell (DC)-based cancer immunotherapy has shown impressive outcomes, including the development of the first FDA-approved anti-cancer vaccine. However, the clinical application of DC-based cancer immunotherapy is associated with various challenges. Promising novel tools for the administration of cancer vaccines has emerged from recent developments in nanoscale biomaterials. One current strategy to enhance targeted drug delivery, while minimizing drug-related toxicities, is the use of nanoparticles (NPs). These can be utilized for antigen delivery into DCs, which have been shown to provide potent T cell-stimulating effects. Therefore, NP delivery represents one promising approach for creating an effective and stable immune response without toxic side effects. The current review surveys cancer immunotherapy with particular attention toward NP-based delivery methods that target DCs.
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Affiliation(s)
- Vida Hashemi
- Department of Basic Science, Faculty of Medicine, Maragheh University of Medical Sciences, Maragheh, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shohreh Farhadi
- Student Research Committee, Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Brinton Seashore-Ludlow
- Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden
| | - Ali Masjedi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Hojjat-Farsangi
- Bioclinicum, Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden; The Persian Gulf Marine Biotechnology Medicine Research Center, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Afshin Namdar
- Department of Oncology, Cross Cancer Institute, The University of Alberta, Edmonton, Alberta, Canada
| | - Amir Ajjoolabady
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamed Mohammadi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Ghasem Ghalamfarsa
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.
| | - Farhad Jadidi-Niaragh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Bernasconi P, Borsani O. Immune Escape after Hematopoietic Stem Cell Transplantation (HSCT): From Mechanisms to Novel Therapies. Cancers (Basel) 2019; 12:cancers12010069. [PMID: 31881776 PMCID: PMC7016529 DOI: 10.3390/cancers12010069] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Revised: 12/21/2019] [Accepted: 12/24/2019] [Indexed: 12/21/2022] Open
Abstract
Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Recent advances in understanding its molecular basis have opened the way to new therapeutic strategies, including targeted therapies. However, despite an improvement in prognosis it has been documented in recent years (especially in younger patients) that allogenic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative treatment in AML and the first therapeutic option for high-risk patients. After allo-HSCT, relapse is still a major complication, and is observed in about 50% of patients. Current evidence suggests that relapse is not due to clonal evolution, but instead to the ability of the AML cell population to escape immune control by a variety of mechanisms including the altered expression of HLA-molecules, production of anti-inflammatory cytokines, relevant metabolic changes and expression of immune checkpoint (ICP) inhibitors capable of “switching-off” the immune response against leukemic cells. Here, we review the main mechanisms of immune escape and identify potential strategies to overcome these mechanisms.
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Affiliation(s)
- Paolo Bernasconi
- Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
- Hematology Department, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Oscar Borsani
- Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
- Correspondence: ; Tel.: +39-340-656-3988
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Sau S, Alzhrani R, Bhise K, Alsaab HO, Kashaw SK, Iyer AK. Nanomaterials for tumor immunomodulation and overcoming current clinical challenges. Nanomedicine (Lond) 2019; 14:1515-1519. [DOI: 10.2217/nnm-2019-0109] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Affiliation(s)
- Samaresh Sau
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy & Health Sciences, Wayne State University, Detroit, MI 48201, USA
| | - Rami Alzhrani
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy & Health Sciences, Wayne State University, Detroit, MI 48201, USA
- Department of Pharmaceutics & Pharmaceutical Technology, College of Pharmacy, Taif University, Taif, 25671, Saudi Arabia
| | - Ketki Bhise
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy & Health Sciences, Wayne State University, Detroit, MI 48201, USA
| | - Hashem O Alsaab
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy & Health Sciences, Wayne State University, Detroit, MI 48201, USA
- Department of Pharmaceutics & Pharmaceutical Technology, College of Pharmacy, Taif University, Taif, 25671, Saudi Arabia
| | - Sushil K Kashaw
- Department of Pharmaceutical Sciences, Dr Harisingh Gour University (A Central University), Sagar, MP, India
| | - Arun K Iyer
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy & Health Sciences, Wayne State University, Detroit, MI 48201, USA
- Molecular Imaging Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI 48201, USA
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Zeng J, Tang SY, Wang S. Derivation of mimetic γδ T cells endowed with cancer recognition receptors from reprogrammed γδ T cell. PLoS One 2019; 14:e0216815. [PMID: 31071196 PMCID: PMC6508724 DOI: 10.1371/journal.pone.0216815] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 04/23/2019] [Indexed: 01/13/2023] Open
Abstract
Using induced pluripotent stem cells (iPSCs) to derive chimeric antigen receptor-modified T (CAR-T) cells has great industrial potential. A previous study used αβ T cell-derived CAR-modified iPSCs to produce CAR-T cells. However, these αβ T cells are restricted to autologous use and only recognize single cancer antigen. To make CAR-T alternative for allogeneic use, we reprogrammed γδ T cell into iPSCs (γδ T-iPSCs) to circumvent the risk of graft-versus-host disease. To target multiple cancer-associated antigens, we used an "NK cell-promoting" protocol to differentiate γδ T-iPSCs and to induce expression of natural killer receptors (NKRs). Through such two-step strategy, mimetic γδ T cells endowed with an array of NKRs and thus designated as "γδ natural killer T (γδ NKT) cells" were derived. With no/low-level expression of inhibitory killer cell immunoglobulin-like receptors (KIRs) and immune checkpoint receptors, γδ NKT cells may provide a potent "off-the-shelf" cytotoxic cell source to recognize multiple ubiquitous antigens in a broad spectrum of cancers.
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MESH Headings
- Antigens, Neoplasm/genetics
- Antigens, Neoplasm/immunology
- HCT116 Cells
- Hep G2 Cells
- Humans
- Induced Pluripotent Stem Cells/immunology
- Induced Pluripotent Stem Cells/pathology
- K562 Cells
- MCF-7 Cells
- Natural Killer T-Cells/immunology
- Natural Killer T-Cells/pathology
- Neoplasms/genetics
- Neoplasms/immunology
- Receptors, Antigen, T-Cell, alpha-beta/genetics
- Receptors, Antigen, T-Cell, alpha-beta/immunology
- Receptors, Antigen, T-Cell, gamma-delta/immunology
- Receptors, Chimeric Antigen/genetics
- Receptors, Chimeric Antigen/immunology
- THP-1 Cells
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Affiliation(s)
- Jieming Zeng
- Institute of Bioengineering and Nanotechnology, Singapore
- * E-mail: , (JZ); (SW)
| | - Shin Yi Tang
- Institute of Bioengineering and Nanotechnology, Singapore
- Department of Biological Sciences, National University of Singapore, Singapore
| | - Shu Wang
- Institute of Bioengineering and Nanotechnology, Singapore
- Department of Biological Sciences, National University of Singapore, Singapore
- * E-mail: , (JZ); (SW)
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Liu G, Fan X, Cai Y, Fu Z, Gao F, Dong J, Li K, Cai J. Efficacy of dendritic cell-based immunotherapy produced from cord blood in vitro and in a humanized NSG mouse cancer model. Immunotherapy 2019; 11:599-616. [PMID: 30943862 DOI: 10.2217/imt-2018-0103] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 02/18/2019] [Indexed: 02/08/2023] Open
Abstract
AIM To produce dendritic cells (DCs) from CD34+ stem cells from cord blood and explore their prophylactic and curative effect against tumors by vaccinating humanized NSG mice. MATERIALS & METHODS Separated CD34+ stem cells from cord blood were cultured for 30 days, and the resultant DCs (CD34-DCs) were collected. The basic function of the CD34-DCs and the cytotoxicity of CD34-cytotoxic-T lymphocytes (CTLs) were tested in vitro, and tumor inhibition in a humanized NSG mouse tumor model was observed. RESULTS The number of CD34-DCs reached approximately 9 log. These cells performed functions similar to those of DCs derived from monocytes from peripheral blood (PBMC-DCs). The CTLs of the CD34-DCs (CD34-CTLs) presented a better antitumor effect in vitro. The obvious prophylactic and therapeutic antitumor effects of the CD34-DC vaccine were observed in the humanized NSG mouse models. CONCLUSION CD34-DCs from cord blood were sufficient in quantity and quality as a vaccine agent against tumors in vitro and in vivo.
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Affiliation(s)
- Gang Liu
- Department of Surgery, Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang 050017, China
- Department of Surgery, Hebei General Hospital, 348 Heping West Road, Shijiazhuang 050051, China
| | - Xiaoyan Fan
- Department of Oncology, Hebei General Hospital, 348 Heping West Road, Shijiazhuang 050051, China
| | - Ying Cai
- Department of Research and Development, Hebei Engineering Technology Research Center for Cell Therapy, Hebei HOFOY Biotech Corporation Ltd, 238 Changjiang Aveneu, Shijiazhuang 500350, China
| | - Zexian Fu
- Department of Surgery, Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang 050017, China
| | - Fei Gao
- Department of Surgery, Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang 050017, China
| | - Jiantao Dong
- Department of Surgery, Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang 050017, China
- Department of Surgery, Hebei General Hospital, 348 Heping West Road, Shijiazhuang 050051, China
| | - Kang Li
- Department of Surgery, Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang 050017, China
| | - Jianhui Cai
- Department of Surgery, Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang 050017, China
- Department of Surgery, Hebei General Hospital, 348 Heping West Road, Shijiazhuang 050051, China
- Department of Oncology, Hebei General Hospital, 348 Heping West Road, Shijiazhuang 050051, China
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Saxena M, Bhardwaj N. Re-Emergence of Dendritic Cell Vaccines for Cancer Treatment. Trends Cancer 2018; 4:119-137. [PMID: 29458962 DOI: 10.1016/j.trecan.2017.12.007] [Citation(s) in RCA: 215] [Impact Index Per Article: 30.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 12/19/2017] [Accepted: 12/21/2017] [Indexed: 02/07/2023]
Abstract
Dendritic cells (DCs) are essential in immunity owing to their role in activating T cells, thereby promoting antitumor responses. Tumor cells, however, hijack the immune system, causing T cell exhaustion and DC dysfunction. Tumor-induced T cell exhaustion may be reversed through immune checkpoint blockade (ICB); however, this treatment fails to show clinical benefit in many patients. While ICB serves to reverse T cell exhaustion, DCs are still necessary to prime, activate, and direct the T cells to target tumor cells. In this review we provide a brief overview of DC function, describe mechanisms by which DC functions are disrupted by the tumor microenvironment, and highlight recent developments in DC cancer vaccines.
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Affiliation(s)
- Mansi Saxena
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, NY 10029, USA
| | - Nina Bhardwaj
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, NY 10029, USA; Parker Institute of Cancer Immunotherapy, San Francisco, CA 94129, USA.
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Zeng J, Tang SY, Toh LL, Wang S. Generation of "Off-the-Shelf" Natural Killer Cells from Peripheral Blood Cell-Derived Induced Pluripotent Stem Cells. Stem Cell Reports 2017; 9:1796-1812. [PMID: 29173894 PMCID: PMC5785702 DOI: 10.1016/j.stemcr.2017.10.020] [Citation(s) in RCA: 102] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Revised: 10/25/2017] [Accepted: 10/25/2017] [Indexed: 01/09/2023] Open
Abstract
Current donor cell-dependent strategies can only produce limited “made-to-order” therapeutic natural killer (NK) cells for limited patients. To provide unlimited “off-the-shelf” NK cells that serve many recipients, we designed and demonstrated a holistic manufacturing scheme to mass-produce NK cells from induced pluripotent stem cells (iPSCs). Starting with a highly accessible human cell source, peripheral blood cells (PBCs), we derived a good manufacturing practice-compatible iPSC source, PBC-derived iPSCs (PBC-iPSCs) for this purpose. Through our original protocol that excludes CD34+ cell enrichment and spin embryoid body formation, high-purity functional and expandable NK cells were generated from PBC-iPSCs. Above all, most of these NK cells expressed no killer cell immunoglobulin-like receptors (KIRs), which renders them unrestricted by recipients' human leukocyte antigen genotypes. Hence, we have established a practical “from blood cell to stem cells and back with less (less KIRs)” strategy to generate abundant “universal” NK cells from PBC-iPSCs for a wide range of patients.
A GMP-compatible iPSC source has been generated from peripheral blood cells An industry-friendly protocol has been developed to produce NK cells from iPSCs These iPSC-derived NK cells are high-purity, functional, and KIR negative These iPSC-derived NK cells recognize and kill a wide variety of cancer cells
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Affiliation(s)
- Jieming Zeng
- Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, #09-01, Singapore 138669, Singapore.
| | - Shin Yi Tang
- Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, #09-01, Singapore 138669, Singapore; Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore
| | - Lai Ling Toh
- Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, #09-01, Singapore 138669, Singapore
| | - Shu Wang
- Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, #09-01, Singapore 138669, Singapore; Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.
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Galati D, Zanotta S. Hematologic neoplasms: Dendritic cells vaccines in motion. Clin Immunol 2017; 183:181-190. [PMID: 28870867 DOI: 10.1016/j.clim.2017.08.016] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 07/28/2017] [Accepted: 08/29/2017] [Indexed: 12/17/2022]
Abstract
Dendritic cells (DCs) are bone-marrow-derived immune cells accounted for a key role in cancer vaccination as potent antigen-presenting cells within the immune system. Cancer microenvironment can modulate DCs maturation resulting in their accumulation into functional states associated with a reduced antitumor immune response. In this regard, a successful cancer vaccine needs to mount a potent antitumor immune response able to overcome the immunosuppressive tumor milieu. As a consequence, DCs-based approaches are a safe and promising strategy for improving the therapeutic efficacy in hematological malignancies, particularly in combinations with additional treatments. This review summarizes the most significant evidence about the immunotherapeutic strategies performed to target hematologic neoplasms including the tumoral associated antigens (TAA) pulsed on DCs, whole tumor cell vaccines or leukemia-derived DCs.
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Affiliation(s)
- Domenico Galati
- Hematology-Oncology and Stem-Cell Transplantation Unit, Department of Hematology, National Cancer Institute, Fondazione 'G. Pascale', IRCCS, Via Mariano Semmola 49, 80131 Naples, Italy.
| | - Serena Zanotta
- Hematology-Oncology and Stem-Cell Transplantation Unit, Department of Hematology, National Cancer Institute, Fondazione 'G. Pascale', IRCCS, Via Mariano Semmola 49, 80131 Naples, Italy
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Balan S, Finnigan J, Bhardwaj N. Dendritic Cell Strategies for Eliciting Mutation-Derived Tumor Antigen Responses in Patients. Cancer J 2017; 23:131-137. [PMID: 28410301 PMCID: PMC5520811 DOI: 10.1097/ppo.0000000000000251] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Dendritic cells (DCs) are equipped for sensing danger signals and capturing, processing, and presenting antigens to naive or effector cells and are critical in inducing humoral and adaptive immunity. Successful vaccinations are those that activate DCs to elicit both cellular and humoral responses, as well as long-lasting memory response against the target of interest. Recently, it has become apparent that tumor cells can provide new sources of antigens through nonsynonymous mutations or frame-shift mutations, leading to potentially hundreds of mutation-derived tumor antigens (MTAs) or neoantigens. T cells recognizing MTA have been detected in cancer patients and can even lead to tumor regression. Designing MTA-specific vaccination strategies will have to take into account the adjuvant activity of DC subsets and the best formulation to elicit an effective immune response. We discuss the potential of human DCs to prime MTA-specific responses.
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Affiliation(s)
- Sreekumar Balan
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, NY NY
| | - John Finnigan
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, NY NY
| | - Nina Bhardwaj
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, NY NY
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Ishikawa T. Next-generation sequencing traces human induced pluripotent stem cell lines clonally generated from heterogeneous cancer tissue. World J Stem Cells 2017; 9:77-88. [PMID: 28596815 PMCID: PMC5440771 DOI: 10.4252/wjsc.v9.i5.77] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 04/03/2017] [Accepted: 05/05/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate genotype variation among induced pluripotent stem cell (iPSC) lines that were clonally generated from heterogeneous colon cancer tissues using next-generation sequencing.
METHODS Human iPSC lines were clonally established by selecting independent single colonies expanded from heterogeneous primary cells of S-shaped colon cancer tissues by retroviral gene transfer (OCT3/4, SOX2, and KLF4). The ten iPSC lines, their starting cancer tissues, and the matched adjacent non-cancerous tissues were analyzed using next-generation sequencing and bioinformatics analysis using the human reference genome hg19. Non-synonymous single-nucleotide variants (SNVs) (missense, nonsense, and read-through) were identified within the target region of 612 genes related to cancer and the human kinome. All SNVs were annotated using dbSNP135, CCDS, RefSeq, GENCODE, and 1000 Genomes. The SNVs of the iPSC lines were compared with the genotypes of the cancerous and non-cancerous tissues. The putative genotypes were validated using allelic depth and genotype quality. For final confirmation, mutated genotypes were manually curated using the Integrative Genomics Viewer.
RESULTS In eight of the ten iPSC lines, one or two non-synonymous SNVs in EIF2AK2, TTN, ULK4, TSSK1B, FLT4, STK19, STK31, TRRAP, WNK1, PLK1 or PIK3R5 were identified as novel SNVs and were not identical to the genotypes found in the cancer and non-cancerous tissues. This result suggests that the SNVs were de novo or pre-existing mutations that originated from minor populations, such as multifocal pre-cancer (stem) cells or pre-metastatic cancer cells from multiple, different clonal evolutions, present within the heterogeneous cancer tissue. The genotypes of all ten iPSC lines were different from the mutated ERBB2 and MKNK2 genotypes of the cancer tissues and were identical to those of the non-cancerous tissues and that found in the human reference genome hg19. Furthermore, two of the ten iPSC lines did not have any confirmed mutated genotypes, despite being derived from cancerous tissue. These results suggest that the traceability and preference of the starting single cells being derived from pre-cancer (stem) cells, stroma cells such as cancer-associated fibroblasts, and immune cells that co-existed in the tissues along with the mature cancer cells.
CONCLUSION The genotypes of iPSC lines derived from heterogeneous cancer tissues can provide information on the type of starting cell that the iPSC line was generated from.
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Abstract
Immunotherapy using dendritic cell (DC)-based vaccination is an approved approach for harnessing the potential of a patient's own immune system to eliminate tumor cells in metastatic hormone-refractory cancer. Overall, although many DC vaccines have been tested in the clinic and proven to be immunogenic, and in some cases associated with clinical outcome, there remains no consensus on how to manufacture DC vaccines. In this review we will discuss what has been learned thus far about human DC biology from clinical studies, and how current approaches to apply DC vaccines in the clinic could be improved to enhance anti-tumor immunity.
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Elster JD, Krishnadas DK, Lucas KG. Dendritic cell vaccines: A review of recent developments and their potential pediatric application. Hum Vaccin Immunother 2016; 12:2232-9. [PMID: 27245943 DOI: 10.1080/21645515.2016.1179844] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
For many cancers the use of conventional chemotherapy has been maximized, and further intensification of chemotherapy generally results in excess toxicity with little long-term benefit for cure. Many tumors become resistant to chemotherapy, making the investigation of novel approaches such as immunotherapy of interest. Because the tumor microenvironment is known to promote immune tolerance and down regulate the body's natural defense mechanisms, modulating the immune system with the use of dendritic cell (DC) therapy is an attractive approach. Thousands of patients with diverse tumor types have been treated with DC vaccines. While antigen specific immune responses have been reported, the duration and magnitude of these responses are typically weak, and objective clinical responses have been limited. DC vaccine generation and administration is a multi-step process with opportunities for improvement in source of DC for vaccine, selection of target antigen, and boosting effector cell response via administration of vaccine adjuvant or concomitant pharmacologic immunomodulation. In this review we will discuss recent developments in each of these areas and highlight elements that could be moved into pediatric clinical trials.
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Affiliation(s)
- Jennifer D Elster
- a Department of Pediatrics , Hematology/Oncology, University of Louisville , Louisville , KY , USA
| | - Deepa K Krishnadas
- a Department of Pediatrics , Hematology/Oncology, University of Louisville , Louisville , KY , USA
| | - Kenneth G Lucas
- a Department of Pediatrics , Hematology/Oncology, University of Louisville , Louisville , KY , USA
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