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Lin Y, Xiao Z, Hu F, Zheng X, Zhang C, Wang Y, Liu Y, Huang D, Wang Z, Xia C, Weng Q, Zhang L, Zhao Y, Qi H, Shen Y, Chen Y, Zhang F, Wu J, Liu P, Xu J, Liu L, Zhu Y, Zhang J, Qian W, Liang A, Zhu X, Wang T, Zhang M, Wang J. Engineered CRO-CD7 CAR-NK cells derived from pluripotent stem cells avoid fratricide and efficiently suppress human T-cell malignancies. J Hematol Oncol 2025; 18:57. [PMID: 40390054 PMCID: PMC12090657 DOI: 10.1186/s13045-025-01712-3] [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: 01/23/2025] [Accepted: 05/09/2025] [Indexed: 05/21/2025] Open
Abstract
BACKGROUND T-cell malignancies are highly aggressive hematological tumors with limited effective treatment options. CAR-NK cell therapy targeting CD7 has emerged as a promising approach for treating T-cell malignancies. However, conventional CAR-NK cell therapy faces the challenges of cell fratricide due to CD7 expression on both malignant cells and normal NK cells. Additionally, engineering CARs into human tissue-derived NK cells demonstrates heterogeneity, low transduction efficiency, and high manufacturing costs. METHODS The human pluripotent stem cells (hPSCs) were genetically modified by knocking out the CD7 gene and introducing the CD7 CAR expression cassette to generate CD7 KO-CD7 CAR-hPSCs. These modified hPSCs were subsequently differentiated into CD7 KO-CD7 CAR-iNK cells using an efficient organoid induction method. The cytotoxicity of CD7 KO-CD7 CAR-iNK cells against CD7+ tumor cells was evaluated. Furthermore, we overexpressed the CXCR4 gene in CD7 KO-CD7 CAR-hPSCs and derived CXCR4-expressing CD7 KO-CD7 CAR-iNK (CRO-CD7 CAR-iNK) cells. The dynamics of CRO-CD7 CAR-iNK cells in vivo were tracked, and their therapeutic efficacy was assessed using human T-cell acute lymphoblastic leukemia (T-ALL) xenograft models. RESULTS The CD7 KO-CD7 CAR-iNK cells derived from CD7 KO-CD7 CAR-hPSCs effectively avoided fratricide, demonstrated normal expansion, and exhibited potent and specific anti-tumor activity against CD7+ T-cell tumor cell lines and primary T-ALL cells. CXCR4 overexpression in CRO-CD7 CAR-iNK cells improved their homing capacity and extended their persistence in vivo. The CRO-CD7 CAR-iNK cells significantly suppressed tumor growth and prolonged the survival of T-ALL tumor-bearing mice. CONCLUSIONS Our study provides a reliable strategy for the large-scale generation of fratricide-resistant CD7 CAR-iNK cells with robust anti-tumor effects from hPSCs, offering a promising cell product to treat T-cell malignancies.
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MESH Headings
- Humans
- Animals
- Receptors, Chimeric Antigen/genetics
- Receptors, Chimeric Antigen/immunology
- Mice
- Antigens, CD7/genetics
- Antigens, CD7/immunology
- Immunotherapy, Adoptive/methods
- Pluripotent Stem Cells/cytology
- Pluripotent Stem Cells/immunology
- Killer Cells, Natural/immunology
- Killer Cells, Natural/transplantation
- Xenograft Model Antitumor Assays
- Mice, Inbred NOD
- Mice, SCID
- Receptors, CXCR4/genetics
- Cell Line, Tumor
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Affiliation(s)
- Yunqing Lin
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Ziyun Xiao
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Fangxiao Hu
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Xiujuan Zheng
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Chenyuan Zhang
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yao Wang
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yanhong Liu
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Dehao Huang
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Zhiqian Wang
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Chengxiang Xia
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Qitong Weng
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Leqiang Zhang
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yaoqin Zhao
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Hanmeng Qi
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Yiyuan Shen
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Yi Chen
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Fan Zhang
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jiaxin Wu
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Pengcheng Liu
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jiacheng Xu
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Lijuan Liu
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yanping Zhu
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jingliao Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Wenbin Qian
- Department of Hematology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China
| | - Aibin Liang
- Department of Hematology, Tongji Hospital of Tongji University, Shanghai, 200065, China
| | - Xiaofan Zhu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Tongjie Wang
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Mengyun Zhang
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Jinyong Wang
- State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
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2
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Balkhi S, Zuccolotto G, Di Spirito A, Rosato A, Mortara L. CAR-NK cell therapy: promise and challenges in solid tumors. Front Immunol 2025; 16:1574742. [PMID: 40260240 PMCID: PMC12009813 DOI: 10.3389/fimmu.2025.1574742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Accepted: 03/17/2025] [Indexed: 04/23/2025] Open
Abstract
Over the past few years, cellular immunotherapy has emerged as a promising treatment for certain hematologic cancers, with various CAR-T therapies now widely used in clinical settings. However, challenges related to the production of autologous cell products and the management of CAR-T cell toxicity highlight the need for new cell therapy options that are universal, safe, and effective. Natural killer (NK) cells, which are part of the innate immune system, offer unique advantages, including the potential for off-the-shelf therapy. A recent first-in-human trial of CD19-CAR-NK infusion in patients with relapsed/refractory lymphoid malignancies demonstrated safety and promising clinical activity. Building on these positive clinical outcomes, current research focuses on enhancing CAR-NK cell potency by increasing their in vivo persistence and addressing functional exhaustion. There is also growing interest in applying the successes seen in hematologic malignancies to solid tumors. This review discusses current trends and emerging concepts in the engineering of next-generation CAR- NK therapies. It will cover the process of constructing CAR-NK cells, potential targets for their manufacturing, and their role in various solid tumors. Additionally, it will examine the mechanisms of action and the research status of CAR-NK therapies in the treatment of solid tumors, along with their advantages, limitations, and future challenges. The insights provided may guide future investigations aimed at optimizing CAR-NK therapy for a broader range of malignancies.
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Affiliation(s)
- Sahar Balkhi
- Immunology and General Pathology Laboratory, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
| | - Gaia Zuccolotto
- Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padova, Italy
| | - Anna Di Spirito
- Immunology and General Pathology Laboratory, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
| | - Antonio Rosato
- Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padova, Italy
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Lorenzo Mortara
- Immunology and General Pathology Laboratory, Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
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3
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Poorva P, Mast J, Cao B, Shah MV, Pollok KE, Shen J. Killing the killers: Natural killer cell therapy targeting glioma stem cells in high-grade glioma. Mol Ther 2025:S1525-0016(25)00168-6. [PMID: 40040281 DOI: 10.1016/j.ymthe.2025.02.043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 01/22/2025] [Accepted: 02/26/2025] [Indexed: 03/06/2025] Open
Abstract
High-grade gliomas (HGGs), including glioblastoma (GBM) in adults and diffuse intrinsic pontine glioma (DIPG) in children, are among the most aggressive and deadly brain tumors. A key factor in their resilience is the presence of glioma stem cells (GSCs), which drive tumor initiation, progression, and resistance to treatment. Targeting and eradicating GSCs holds potential for curing both GBM and DIPG. Natural killer (NK) cells, as part of the innate immune system, naturally recognize and destroy malignant cells. Recent advances in NK cell-based therapies, such as chimeric antigen receptor (CAR)-NK cells, NK cell engagers, and NK cell-derived exosomes, offer promising approaches for treating GBM and DIPG, particularly by addressing the persistence of GSCs. This review highlights these advancements, explores challenges such as the blood-brain barrier and the immunosuppressive tumor microenvironment, and proposes future directions for improving and clinically advancing these NK cell-based therapies for HGGs.
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Affiliation(s)
- Poorva Poorva
- Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN 47405, USA
| | - Jensen Mast
- Biochemistry Graduate Program, Indiana University, Bloomington, IN 47405, USA
| | - Bihui Cao
- Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN 47405, USA
| | - Mitesh V Shah
- Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Karen E Pollok
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA
| | - Jia Shen
- Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN 47405, USA; Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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4
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Gordon KS, Perez CR, Garmilla A, Lam MSY, Aw JJY, Datta A, Lauffenburger DA, Pavesi A, Birnbaum ME. Pooled screening for CAR function identifies novel IL-13Rα2-targeted CARs for treatment of glioblastoma. J Immunother Cancer 2025; 13:e009574. [PMID: 39933837 PMCID: PMC11815465 DOI: 10.1136/jitc-2024-009574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 01/20/2025] [Indexed: 02/13/2025] Open
Abstract
BACKGROUND Chimeric antigen receptor (CAR) therapies have demonstrated potent efficacy in treating B-cell malignancies, but have yet to meaningfully translate to solid tumors. Nonetheless, they are of particular interest for the treatment of glioblastoma, which is an aggressive form of brain cancer with few effective therapeutic options, due to their ability to cross the highly selective blood-brain barrier. METHODS Here, we use our pooled screening platform, CARPOOL, to expedite the discovery of CARs with antitumor functions necessary for solid tumor efficacy. We performed selections in primary human T cells expressing a library of 1.3×106 third generation CARs targeting IL-13Rα2, a cancer testis antigen commonly expressed in glioblastoma. Selections were performed for cytotoxicity, proliferation, memory formation, and persistence on repeated antigen challenge. RESULTS Each enriched CAR robustly produced the phenotype for which it was selected, and one enriched CAR triggered potent cytotoxicity and long-term proliferation on in vitro tumor rechallenge. It also showed significantly improved persistence and comparable tumor control in a microphysiological human in vitro model and a xenograft model of human glioblastoma, but also demonstrated increased off-target recognition of IL-13Rα1. CONCLUSION Taken together, this work demonstrates the utility of extending CARPOOL to diseases beyond hematological malignancies and represents the largest exploration of signaling combinations in human primary cells to date.
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Affiliation(s)
- Khloe S Gordon
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Singapore-MIT Alliance for Research and Technology Centre, Singapore
| | - Caleb R Perez
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Singapore-MIT Alliance for Research and Technology Centre, Singapore
| | - Andrea Garmilla
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Program in Immunology, Harvard Medical School, Boston, Massachusetts, USA
| | - Maxine S Y Lam
- Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore
| | - Joey J Y Aw
- Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore
| | - Anisha Datta
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Douglas A Lauffenburger
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Andrea Pavesi
- Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Michael E Birnbaum
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Singapore-MIT Alliance for Research and Technology Centre, Singapore
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5
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Dehghan F, Metanat Y, Askarizadeh M, Ahmadi E, Moradi V. Novel gene manipulation approaches to unlock the existing bottlenecks of CAR-NK cell therapy. Front Cell Dev Biol 2025; 12:1511931. [PMID: 40007761 PMCID: PMC11850336 DOI: 10.3389/fcell.2024.1511931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 12/10/2024] [Indexed: 02/27/2025] Open
Abstract
Currently, CAR-T cell therapy is known as an efficacious treatment for patients with relapsed/refractory hematologic malignancies. Nonetheless, this method faces several bottlenecks, including low efficacy for solid tumors, lethal adverse effects, high cost of autologous products, and the risk of GvHD in allogeneic settings. As a potential alternative, CAR-NK cell therapy can overcome most of the limitations of CAR-T cell therapy and provide an off-the-shelf, safer, and more affordable product. Although published results from preclinical and clinical studies with CAR-NK cells are promising, several bottlenecks must be unlocked to maximize the effectiveness of CAR-NK cell therapy. These bottlenecks include low in vivo persistence, low trafficking into tumor sites, modest efficacy in solid tumors, and sensitivity to immunosuppressive tumor microenvironment. In recent years, advances in gene manipulation tools and strategies have laid the groundwork to overcome the current bottlenecks of CAR-NK cell therapy. This review will introduce the existing gene manipulation tools and discuss their advantages and disadvantages. We will also explore how these tools can enhance CAR-NK cell therapy's safety and efficacy.
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Affiliation(s)
- Fatemeh Dehghan
- Department of Anatomy and Molecular Biology, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Yekta Metanat
- Faculty of Medicine, Zahedan University of Medical Sciences, Zahedan, Sistan and Baluchestan Province, Iran
| | - Mandana Askarizadeh
- School of Biology and Ecology, University of Maine, Orono, ME, United States
| | - Ehsan Ahmadi
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Vahid Moradi
- Department of Hematology and Blood Transfusion Sciences, School of Allied Medicine, Tehran University of Medical Sciences, Tehran, Iran
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6
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Shi Y, Li X, Dong Y, Yuan H, Wang Y, Yang R. Exploring the potential of CAR-macrophage therapy. Life Sci 2025; 361:123300. [PMID: 39643037 DOI: 10.1016/j.lfs.2024.123300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 11/28/2024] [Accepted: 12/03/2024] [Indexed: 12/09/2024]
Abstract
Chimeric antigen receptor T cell (CAR-T) cell therapy has achieved significant success in treating hematologic malignancies, but its efficacy in solid tumor treatment is relatively limited. Therefore, researchers are exploring other genetically modified immune cells as potential treatment strategies to address the challenges in solid tumor therapy. Chimeric antigen receptor macrophage (CAR-M) involves the genetic engineering of macrophages to express chimeric antigen receptors, enabling them to recognize and attack tumor cells. In contrast to CAR-T cells, CAR-M cells offer distinct advantages such as enhanced infiltration and survival capabilities, along with a diverse array of anti-tumor mechanisms, making them a promising immunotherapy approach that may yield better results in solid tumor treatment. This article provides an overview of the research advancements in CAR-M-mediated tumor immunotherapy, encompassing topics such as the design and transduction of CAR, cell sources, anti-tumor mechanisms and clinical applications. The future research direction in this field will involve leveraging innovative biological technologies to augment the anti-tumor efficacy of CAR-M, understand the underlying mechanisms, and enhance the safety and efficacy of CAR-M therapy.
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Affiliation(s)
- Yongyu Shi
- Department of Immunology and Shandong Key Laboratory of Infection and Immunity, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, China.
| | - Xia Li
- Department of Internal Medicine, Jinan No. 1 People's Hospital, China
| | - Yanlei Dong
- Department of Immunology and Shandong Key Laboratory of Infection and Immunity, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, China
| | - Hong Yuan
- Department of Immunology and Shandong Key Laboratory of Infection and Immunity, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, China
| | - Yingyue Wang
- Department of Immunology and Shandong Key Laboratory of Infection and Immunity, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, China
| | - Ruoxuan Yang
- Department of Immunology and Shandong Key Laboratory of Infection and Immunity, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, China
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Rao ZY, Kuang J, Pan T, Qin YT, Huang QX, Sun YL, Zhao K, Jin XK, Yang CH, Zhang SM, Yan Y, Zhang XZ. Cationic Magnetic Nanoparticles Activate Natural Killer Cells for the Treatment of Glioblastoma. ACS NANO 2025; 19:649-661. [PMID: 39711185 DOI: 10.1021/acsnano.4c11250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2024]
Abstract
The blood-brain barrier (BBB) and the immunosuppressive microenvironment of glioblastoma (GBM) severely hinder the infiltration and activity of natural killer (NK) cells, thereby reducing their clinical efficacy in GBM treatment. To address this challenge, we introduced an engineered living material, HEFDS-NK cells, designed to enhance the penetration of NK cells across the BBB and improve their cytotoxicity against GBM. HEFDS comprises magnetic nanoparticles modified using cationic polyethylenimine (PEI), selenocysteine (Sec), and sodium hyaluronate (HA) and cocultured with NK cells to form HEFDS-NK cells. With the assistance of HA and magnet targeting, HEFDS-NK cells can effectively cross the BBB and localize at the GBM site. Moreover, PEI enhances the expression of C-X-C chemokine receptor type 4 (CXCR4) and C-C chemokine receptor type 4 (CCR4) on NK cells, thereby improving their recognition and cytotoxicity against GBM. Additionally, Sec boosts the immune activity of NK cells against GBM. Upon recognizing GBM, the activated HEFDS-NK cells produce Granzyme B, Perforin, and IFN-γ, ultimately achieving effective therapy for GBM. This study demonstrates an effective treatment of GBM while enhancing NK cell activity and their ability to penetrate the BBB, providing an innovative and high-precision therapeutic approach for GBM.
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Affiliation(s)
- Zhi-Yong Rao
- Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China
| | - Jing Kuang
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China
| | - Ting Pan
- Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China
| | - You-Teng Qin
- Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China
| | - Qian-Xiao Huang
- Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China
| | - Yu-Liang Sun
- Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China
| | - Kai Zhao
- Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China
| | - Xiao-Kang Jin
- Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China
| | - Chi-Hui Yang
- Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China
| | - Shi-Man Zhang
- Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China
| | - Yu Yan
- Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China
| | - Xian-Zheng Zhang
- Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China
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8
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Kong Y, Li J, Zhao X, Wu Y, Chen L. CAR-T cell therapy: developments, challenges and expanded applications from cancer to autoimmunity. Front Immunol 2025; 15:1519671. [PMID: 39850899 PMCID: PMC11754230 DOI: 10.3389/fimmu.2024.1519671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 12/17/2024] [Indexed: 01/25/2025] Open
Abstract
Chimeric Antigen Receptor (CAR)-T cell therapy has rapidly emerged as a groundbreaking approach in cancer treatment, particularly for hematologic malignancies. However, the application of CAR-T cell therapy in solid tumors remains challenging. This review summarized the development of CAR-T technologies, emphasized the challenges and solutions in CAR-T cell therapy for solid tumors. Also, key innovations were discussed including specialized CAR-T, combination therapies and the novel use of CAR-Treg, CAR-NK and CAR-M cells. Besides, CAR-based cell therapy have extended its reach beyond oncology to autoimmune disorders. We reviewed preclinical experiments and clinical trials involving CAR-T, Car-Treg and CAAR-T cell therapies in various autoimmune diseases. By highlighting these cutting-edge developments, this review underscores the transformative potential of CAR technologies in clinical practice.
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Affiliation(s)
| | | | | | - Yanwei Wu
- School of Medicine, Shanghai University, Shanghai, China
| | - Liang Chen
- School of Medicine, Shanghai University, Shanghai, China
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9
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Liu Y, Xiao L, Yang M, Chen X, Liu H, Wang Q, Guo M, Luo J. CAR-armored-cell therapy in solid tumor treatment. J Transl Med 2024; 22:1076. [PMID: 39609705 PMCID: PMC11603843 DOI: 10.1186/s12967-024-05903-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 11/18/2024] [Indexed: 11/30/2024] Open
Abstract
Over the past decade, chimeric antigen receptor (CAR)-T cell therapy has emerged as a revolutionary immunotherapeutic approach to combat cancer. This therapy constructs a CAR on the surface of T cells through genetic engineering techniques. The CAR is formed from a combination of antibody-derived or ligand-derived domains and T-cell receptor (TCR) domains. This enables T cells to specifically bind to and activate against tumor cells. However, the efficacy of CAR-T cells in solid tumors remains inconclusive due to several challenges such as poor tumor trafficking, infiltration, and the immunosuppressive tumor microenvironment (TME). In response, CAR natural killer (CAR-NK) and CAR macrophages (CAR-M) have been developed as complementary strategies for solid tumors. CAR-NK cells do not require HLA compatibility, demonstrate reduced toxicity, and are thus seen as potential substitutes for CAR-T cells. Furthermore, CAR-M immunotherapy is also being researched and has shown phagocytic capabilities and tumor-antigen presentation. This study discusses the features, advantages, and limitations of CAR-T, CAR-NK, and CAR-M cells in the treatment of solid tumors and suggests prospective solutions for enhancing the efficacy of CAR host-cell-based immunotherapy.
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Affiliation(s)
- Yan Liu
- Navy Medical University, Shanghai, 200433, China
| | - Lin Xiao
- Navy Medical University, Shanghai, 200433, China
| | | | - Xuemei Chen
- Linyi People's Hospital, Linyi, Shandong, 276000, China
| | - Hongyue Liu
- Navy Medical University, Shanghai, 200433, China
| | - Quanxing Wang
- Navy Medical University, Shanghai, 200433, China
- National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai, China
| | - Meng Guo
- Navy Medical University, Shanghai, 200433, China.
- National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai, China.
| | - Jianhua Luo
- Navy Medical University, Shanghai, 200433, China.
- National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, Shanghai, China.
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10
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Chen S, Zhu H, Jounaidi Y. Comprehensive snapshots of natural killer cells functions, signaling, molecular mechanisms and clinical utilization. Signal Transduct Target Ther 2024; 9:302. [PMID: 39511139 PMCID: PMC11544004 DOI: 10.1038/s41392-024-02005-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Revised: 08/25/2024] [Accepted: 09/17/2024] [Indexed: 11/15/2024] Open
Abstract
Natural killer (NK) cells, initially identified for their rapid virus-infected and leukemia cell killing and tumor destruction, are pivotal in immunity. They exhibit multifaceted roles in cancer, viral infections, autoimmunity, pregnancy, wound healing, and more. Derived from a common lymphoid progenitor, they lack CD3, B-cell, or T-cell receptors but wield high cytotoxicity via perforin and granzymes. NK cells orchestrate immune responses, secreting inflammatory IFNγ or immunosuppressive TGFβ and IL-10. CD56dim and CD56bright NK cells execute cytotoxicity, while CD56bright cells also regulate immunity. However, beyond the CD56 dichotomy, detailed phenotypic diversity reveals many functional subsets that may not be optimal for cancer immunotherapy. In this review, we provide comprehensive and detailed snapshots of NK cells' functions and states of activation and inhibitions in cancer, autoimmunity, angiogenesis, wound healing, pregnancy and fertility, aging, and senescence mediated by complex signaling and ligand-receptor interactions, including the impact of the environment. As the use of engineered NK cells for cancer immunotherapy accelerates, often in the footsteps of T-cell-derived engineering, we examine the interactions of NK cells with other immune effectors and relevant signaling and the limitations in the tumor microenvironment, intending to understand how to enhance their cytolytic activities specifically for cancer immunotherapy.
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Affiliation(s)
- Sumei Chen
- Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, China.
| | - Haitao Zhu
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Youssef Jounaidi
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
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11
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Corsaro A, Tremonti B, Bajetto A, Barbieri F, Thellung S, Florio T. Chemokine signaling in tumors: potential role of CXC chemokines and their receptors as glioblastoma therapeutic targets. Expert Opin Ther Targets 2024; 28:937-952. [PMID: 39582130 DOI: 10.1080/14728222.2024.2433130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 11/19/2024] [Indexed: 11/26/2024]
Abstract
INTRODUCTION Glioblastoma is the most aggressive brain tumor, typically associated with poor prognosis. Its treatment is challenging due to the peculiar glioblastoma cell biology and its microenvironment complexity. Specifically, a small fraction of glioma stem cells within the tumor mass drives tumor growth and invasiveness by hijacking brain resident and immune cells. This process also involves modification of extracellular matrix components, such as collagen and glycoproteins, where the secretion of soluble mediators, particularly CXC chemokines, plays a significant role. AREAS COVERED We analyze the critical role of chemokines in glioblastoma tumorigenesis, proliferation, angiogenesis, tumor progression, and brain parenchyma invasiveness. Recent evidence highlights how chemokines and their receptors impact glioblastoma biology and represent potential therapeutic targets. Several studies show that chemokines modulate glioblastoma development by acting on glioma stem cell proliferation and self-renewal, promoting vasculogenic mimicry, and altering the extracellular matrix to facilitate tumor invasiveness. EXPERT OPINION There is clear evidence supporting CXC receptors (such as CXCR1, 2, 3, 4, and ACKR3/CXCR7) and their signaling pathways as promising pharmacological targets. This in-depth review of chemokine roles in glioblastoma development provides a critical evaluation of the possible clinical translation of innovative compounds targeting these ligand/receptor systems, leading to improved therapeutic outcomes for glioblastoma patients.
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Affiliation(s)
- Alessandro Corsaro
- Sezione di Farmacologia, Dipartimento di Medicina Interna, Università di Genova, Genova, Italy
| | - Beatrice Tremonti
- Sezione di Farmacologia, Dipartimento di Medicina Interna, Università di Genova, Genova, Italy
| | - Adriana Bajetto
- Sezione di Farmacologia, Dipartimento di Medicina Interna, Università di Genova, Genova, Italy
| | - Federica Barbieri
- Sezione di Farmacologia, Dipartimento di Medicina Interna, Università di Genova, Genova, Italy
- IRCCS Policlinico San Martino, Genova, Italy
| | - Stefano Thellung
- Sezione di Farmacologia, Dipartimento di Medicina Interna, Università di Genova, Genova, Italy
- IRCCS Policlinico San Martino, Genova, Italy
| | - Tullio Florio
- Sezione di Farmacologia, Dipartimento di Medicina Interna, Università di Genova, Genova, Italy
- IRCCS Policlinico San Martino, Genova, Italy
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12
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Sarantopoulos A, Ene C, Aquilanti E. Therapeutic approaches to modulate the immune microenvironment in gliomas. NPJ Precis Oncol 2024; 8:241. [PMID: 39443641 PMCID: PMC11500177 DOI: 10.1038/s41698-024-00717-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 09/18/2024] [Indexed: 10/25/2024] Open
Abstract
Immunomodulatory therapies, including immune checkpoint inhibitors, have drastically changed outcomes for certain cancer types over the last decade. Gliomas are among the cancers that have seem limited benefit from these agents, with most trials yielding negative results. The unique composition of the glioma immune microenvironment is among the culprits for this lack of efficacy. In recent years, several efforts have been made to improve understanding of the glioma immune microenvironment, aiming to pave the way for novel therapeutic interventions. In this review, we discuss some of the main components of the glioma immune microenvironment, including macrophages, myeloid-derived suppressor cells, neutrophils and microglial cells, as well as lymphocytes. We then provide a comprehensive overview of novel immunomodulatory agents that are currently in clinical development, namely oncolytic viruses, vaccines, cell-based therapies such as CAR-T cells and CAR-NK cells as well as antibodies and peptides.
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Affiliation(s)
| | - Chibawanye Ene
- Department of Neurosurgery, The University of Texas M D Anderson Cancer Center, Houston, TX, USA
| | - Elisa Aquilanti
- Center for Neuro-Oncology, Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
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13
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Tachi T, Kijima N, Kuroda H, Ikeda S, Murakami K, Nakagawa T, Yaga M, Nakagawa K, Utsugi R, Hirayama R, Okita Y, Kagawa N, Kishima H, Imai C, Hosen N. Antitumor effects of intracranial injection of B7-H3-targeted Car-T and Car-Nk cells in a patient-derived glioblastoma xenograft model. Cancer Immunol Immunother 2024; 73:256. [PMID: 39367952 PMCID: PMC11456075 DOI: 10.1007/s00262-024-03808-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Accepted: 08/12/2024] [Indexed: 10/07/2024]
Abstract
BACKGROUND Glioblastoma multiforme (GBM) is the most lethal primary brain tumor for which novel therapies are needed. Recently, chimeric antigen receptor (CAR) T cell therapy has been shown to be effective against GBM, but it is a personalized medicine and requires high cost and long time for the cell production. CAR-transduced natural killer (NK) cells can be used for "off-the-shelf" cellular immunotherapy because they do not induce graft-versus-host disease. Therefore, we aimed to analyze the anti-GBM effect of CAR-T or NK cells targeting B7-H3, which is known to be highly expressed in GBM. METHODS CAR-T cells targeting B7-H3 were generated using previously reported anti-B7-H3 scFv sequences. Cord blood (CB)-derived NK cells transduced with the B7-H3 CAR were also generated. Their anti-GBM effect was analyzed in vitro. The antitumor effect of intracranial injection of the B7-H3 CAR-T or NK cells was investigated in an in vivo xenograft model with patient-derived GBM cells. RESULTS Both B7-H3 CAR-T cells and CAR-NK cells exhibited marked cytotoxicity against patient-derived GBM cells in vitro. Furthermore, intracranial injection of CAR-T cells and CAR-NK cells targeting B7-H3 resulted in a significant antitumor effect against patient-derived GBM xenografts. CONCLUSION Not only CAR-T cells but also CB-derived CAR-NK cells targeting B7-H3 may have the potential to eliminate GBM cells.
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Affiliation(s)
- Tetsuro Tachi
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 5650871, Japan
| | - Noriyuki Kijima
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 5650871, Japan.
| | - Hideki Kuroda
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 5650871, Japan
| | - Syunya Ikeda
- World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan
| | - Koki Murakami
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 5650871, Japan
| | - Tomoyoshi Nakagawa
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 5650871, Japan
| | - Moto Yaga
- Department of Respiratory Medicine, Osaka General Hospital, Osaka, Japan
| | - Kanji Nakagawa
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 5650871, Japan
| | - Reina Utsugi
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 5650871, Japan
| | - Ryuichi Hirayama
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 5650871, Japan
| | - Yoshiko Okita
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 5650871, Japan
| | - Naoki Kagawa
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 5650871, Japan
| | - Haruhiko Kishima
- Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 5650871, Japan
| | - Chihaya Imai
- Department of Pediatrics, Faculty of Medicine, University of Toyama, Toyama, Japan
| | - Naoki Hosen
- World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
- Department of Hematology and Oncology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 5650871, Japan.
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14
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Wang K, Wang L, Wang Y, Xiao L, Wei J, Hu Y, Wang D, Huang H. Reprogramming natural killer cells for cancer therapy. Mol Ther 2024; 32:2835-2855. [PMID: 38273655 PMCID: PMC11403237 DOI: 10.1016/j.ymthe.2024.01.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 01/05/2024] [Accepted: 01/19/2024] [Indexed: 01/27/2024] Open
Abstract
The last decade has seen rapid development in the field of cellular immunotherapy, particularly in regard to chimeric antigen receptor (CAR)-modified T cells. However, challenges, such as severe treatment-related toxicities and inconsistent quality of autologous products, have hindered the broader use of CAR-T cell therapy, highlighting the need to explore alternative immune cells for cancer targeting. In this regard, natural killer (NK) cells have been extensively studied in cellular immunotherapy and were found to exert cytotoxic effects without being restricted by human leukocyte antigen and have a lower risk of causing graft-versus-host disease; making them favorable for the development of readily available "off-the-shelf" products. Clinical trials utilizing unedited NK cells or reprogrammed NK cells have shown early signs of their effectiveness against tumors. However, limitations, including limited in vivo persistence and expansion potential, remained. To enhance the antitumor function of NK cells, advanced gene-editing technologies and combination approaches have been explored. In this review, we summarize current clinical trials of antitumor NK cell therapy, provide an overview of innovative strategies for reprogramming NK cells, which include improvements in persistence, cytotoxicity, trafficking and the ability to counteract the immunosuppressive tumor microenvironment, and also discuss some potential combination therapies.
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Affiliation(s)
- Kexin Wang
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China; Liangzhu Laboratory, Hangzhou, Zhejiang Province, China; Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang Province, China; Zhejiang Province Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou, Zhejiang Province, China
| | - Linqin Wang
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China; Liangzhu Laboratory, Hangzhou, Zhejiang Province, China; Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang Province, China; Zhejiang Province Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou, Zhejiang Province, China
| | - Yiyun Wang
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China; Liangzhu Laboratory, Hangzhou, Zhejiang Province, China; Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang Province, China; Zhejiang Province Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou, Zhejiang Province, China
| | - Lu Xiao
- Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Jieping Wei
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China; Liangzhu Laboratory, Hangzhou, Zhejiang Province, China; Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang Province, China; Zhejiang Province Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou, Zhejiang Province, China
| | - Yongxian Hu
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China; Liangzhu Laboratory, Hangzhou, Zhejiang Province, China; Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang Province, China; Zhejiang Province Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou, Zhejiang Province, China.
| | - Dongrui Wang
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China; Liangzhu Laboratory, Hangzhou, Zhejiang Province, China; Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang Province, China; Zhejiang Province Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou, Zhejiang Province, China.
| | - He Huang
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China; Liangzhu Laboratory, Hangzhou, Zhejiang Province, China; Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang Province, China; Zhejiang Province Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou, Zhejiang Province, China.
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15
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Fang M, Allen A, Luo C, Finn JD. Unlocking the potential of iPSC-derived immune cells: engineering iNK and iT cells for cutting-edge immunotherapy. Front Immunol 2024; 15:1457629. [PMID: 39281684 PMCID: PMC11392856 DOI: 10.3389/fimmu.2024.1457629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 08/14/2024] [Indexed: 09/18/2024] Open
Abstract
Induced pluripotent stem cells (iPSCs) have emerged as a revolutionary tool in cell therapies due to their ability to differentiate into various cell types, unlimited supply, and potential as off-the-shelf cell products. New advances in iPSC-derived immune cells have generated potent iNK and iT cells which showed robust killing of cancer cells in animal models and clinical trials. With the advent of advanced genome editing technologies that enable the development of highly engineered cells, here we outline 12 strategies to engineer iPSCs to overcome limitations and challenges of current cell-based immunotherapies, including safety switches, stealth edits, avoiding graft-versus-host disease (GvHD), targeting, reduced lymphodepletion, efficient differentiation, increased in vivo persistence, stemness, metabolic fitness, homing/trafficking, and overcoming suppressive tumor microenvironment and stromal cell barrier. With the development of advanced genome editing techniques, it is now possible to insert large DNA sequences into precise genomic locations without the need for DNA double strand breaks, enabling the potential for multiplexed knock out and insertion. These technological breakthroughs have made it possible to engineer complex cell therapy products at unprecedented speed and efficiency. The combination of iPSC derived iNK, iT and advanced gene editing techniques provides new opportunities and could lead to a new era for next generation of cell immunotherapies.
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Affiliation(s)
- Minggang Fang
- Cell Therapy, Tome Biosciences, Watertown, MA, United States
| | - Alexander Allen
- Cell Therapy, Tome Biosciences, Watertown, MA, United States
| | - Chong Luo
- Cell Therapy, Tome Biosciences, Watertown, MA, United States
| | - Jonathan D Finn
- Cell Therapy, Tome Biosciences, Watertown, MA, United States
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16
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Douka S, Papamoschou V, Raimo M, Mastrobattista E, Caiazzo M. Harnessing the Power of NK Cell Receptor Engineering as a New Prospect in Cancer Immunotherapy. Pharmaceutics 2024; 16:1143. [PMID: 39339180 PMCID: PMC11434712 DOI: 10.3390/pharmaceutics16091143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 08/26/2024] [Accepted: 08/27/2024] [Indexed: 09/30/2024] Open
Abstract
Natural killer (NK) cells have recently gained popularity as an alternative for cancer immunotherapy. Adoptive cell transfer employing NK cells offers a safer therapeutic option compared to T-cell-based therapies, due to their significantly lower toxicity and the availability of diverse autologous and allogeneic NK cell sources. However, several challenges are associated with NK cell therapies, including limited in vivo persistence, the immunosuppressive and hostile tumor microenvironment (TME), and the lack of effective treatments for solid tumors. To address these limitations, the modification of NK cells to stably produce cytokines has been proposed as a strategy to enhance their persistence and proliferation. Additionally, the overexpression of activating receptors and the blockade of inhibitory receptors can restore the NK cell functions hindered by the TME. To further improve tumor infiltration and the elimination of solid tumors, innovative approaches focusing on the enhancement of NK cell chemotaxis through the overexpression of chemotactic receptors have been introduced. This review highlights the latest advancements in preclinical and clinical studies investigating the engineering of activating, inhibitory, and chemotactic NK cell receptors; discusses recent progress in cytokine manipulation; and explores the potential of combining the chimeric antigen receptor (CAR) technology with NK cell receptors engineering.
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Affiliation(s)
- Stefania Douka
- Pharmaceutics Division, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands
| | - Vasilis Papamoschou
- Pharmaceutics Division, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands
| | - Monica Raimo
- Glycostem Therapeutics B.V., Kloosterstraat 9, 5349 AB Oss, The Netherlands;
| | - Enrico Mastrobattista
- Pharmaceutics Division, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands
| | - Massimiliano Caiazzo
- Pharmaceutics Division, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands
- Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, Via Pansini 5, 80131 Naples, Italy
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17
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Tsiverioti CA, Gottschlich A, Trefny M, Theurich S, Anders HJ, Kroiss M, Kobold S. Beyond CAR T cells: exploring alternative cell sources for CAR-like cellular therapies. Biol Chem 2024; 405:485-515. [PMID: 38766710 DOI: 10.1515/hsz-2023-0317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 04/18/2024] [Indexed: 05/22/2024]
Abstract
Chimeric antigen receptor (CAR)-T cell therapy has led to remarkable clinical outcomes in the treatment of hematological malignancies. However, challenges remain, such as limited infiltration into solid tumors, inadequate persistence, systemic toxicities, and manufacturing insufficiencies. The use of alternative cell sources for CAR-based therapies, such as natural killer cells (NK), macrophages (MΦ), invariant Natural Killer T (iNKT) cells, γδT cells, neutrophils, and induced pluripotent stem cells (iPSC), has emerged as a promising avenue. By harnessing these cells' inherent cytotoxic mechanisms and incorporating CAR technology, common CAR-T cell-related limitations can be effectively mitigated. We herein present an overview of the tumoricidal mechanisms, CAR designs, and manufacturing processes of CAR-NK cells, CAR-MΦ, CAR-iNKT cells, CAR-γδT cells, CAR-neutrophils, and iPSC-derived CAR-cells, outlining the advantages, limitations, and potential solutions of these therapeutic strategies.
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Affiliation(s)
| | - Adrian Gottschlich
- Division of Clinical Pharmacology, University Hospital, LMU Munich, Lindwurmstr. 2a, 80337 Munich, Germany
- Department of Medicine III, University Hospital, LMU Munich, Marchioninstr. 15, 81377 Munich, Germany
- Bavarian Cancer Research Center (BZKF), LMU Munich, Pettenkoferstr. 8a, 80336 Munich, Germany
| | - Marcel Trefny
- Division of Clinical Pharmacology, University Hospital, LMU Munich, Lindwurmstr. 2a, 80337 Munich, Germany
| | - Sebastian Theurich
- Department of Medicine III, University Hospital, LMU Munich, Marchioninstr. 15, 81377 Munich, Germany
- Bavarian Cancer Research Center (BZKF), LMU Munich, Pettenkoferstr. 8a, 80336 Munich, Germany
- 74939 German Cancer Consortium (DKTK), Partner Site Munich, A Partnership Between DKFZ and University Hospital of the LMU , Marchioninstr. 15, 81377 Munich, Germany
- Cancer and Immunometabolism Research Group, 74939 Gene Center LMU , Feodor-Lynen Str. 25, 81377 Munich, Germany
| | - Hans-Joachim Anders
- Department of Medicine IV, University Hospital, LMU Munich, Ziemssenstr. 5, 80336 Munich, Germany
| | - Matthias Kroiss
- Department of Medicine IV, University Hospital, LMU Munich, Ziemssenstr. 5, 80336 Munich, Germany
- Division of Endocrinology and Diabetes, Department of Medicine, University Hospital, University of Würzburg, Josef-Schneider-Str, 9780 Würzburg, Germany
- Comprehensive Cancer Center Mainfranken, University of Würzburg, Josef-Schneider-Str. 6, 9780 Würzburg, Germany
| | - Sebastian Kobold
- Division of Clinical Pharmacology, University Hospital, LMU Munich, Lindwurmstr. 2a, 80337 Munich, Germany
- 74939 German Cancer Consortium (DKTK), Partner Site Munich, A Partnership Between DKFZ and University Hospital of the LMU , Marchioninstr. 15, 81377 Munich, Germany
- Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München - German Research Center for Environmental Health, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany
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18
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Nguyen NTT, Müller R, Briukhovetska D, Weber J, Feucht J, Künkele A, Hudecek M, Kobold S. The Spectrum of CAR Cellular Effectors: Modes of Action in Anti-Tumor Immunity. Cancers (Basel) 2024; 16:2608. [PMID: 39061247 PMCID: PMC11274444 DOI: 10.3390/cancers16142608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Revised: 07/13/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024] Open
Abstract
Chimeric antigen receptor-T cells have spearheaded the field of adoptive cell therapy and have shown remarkable results in treating hematological neoplasia. Because of the different biology of solid tumors compared to hematological tumors, response rates of CAR-T cells could not be transferred to solid entities yet. CAR engineering has added co-stimulatory domains, transgenic cytokines and switch receptors to improve performance and persistence in a hostile tumor microenvironment, but because of the inherent cell type limitations of CAR-T cells, including HLA incompatibility, toxicities (cytokine release syndrome, neurotoxicity) and high costs due to the logistically challenging preparation process for autologous cells, the use of alternative immune cells is gaining traction. NK cells and γδ T cells that do not need HLA compatibility or macrophages and dendritic cells with additional properties such as phagocytosis or antigen presentation are increasingly seen as cellular vehicles with potential for application. As these cells possess distinct properties, clinicians and researchers need a thorough understanding of their peculiarities and commonalities. This review will compare these different cell types and their specific modes of action seen upon CAR activation.
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Affiliation(s)
- Ngoc Thien Thu Nguyen
- Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, LMU Munich, 80336 Munich, Germany; (N.T.T.N.); (R.M.); (D.B.)
- German Cancer Consortium (DKTK), Partner Site Munich, a Partnership between the DKFZ Heidelberg and the University Hospital of the LMU, 80336 Munich, Germany
| | - Rasmus Müller
- Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, LMU Munich, 80336 Munich, Germany; (N.T.T.N.); (R.M.); (D.B.)
| | - Daria Briukhovetska
- Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, LMU Munich, 80336 Munich, Germany; (N.T.T.N.); (R.M.); (D.B.)
| | - Justus Weber
- Department of Medicine II, Chair in Cellular Immunotherapy, University Hospital Würzburg, 97080 Würzburg, Germany; (J.W.); (M.H.)
| | - Judith Feucht
- Cluster of Excellence iFIT “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, 72076 Tuebingen, Germany;
- Department of Hematology and Oncology, University Children’s Hospital Tuebingen, University of Tübingen, 72076 Tuebingen, Germany
| | - Annette Künkele
- Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, Germany;
- German Cancer Consortium (DKTK), Partner Site Berlin, 10117 Berlin, Germany
| | - Michael Hudecek
- Department of Medicine II, Chair in Cellular Immunotherapy, University Hospital Würzburg, 97080 Würzburg, Germany; (J.W.); (M.H.)
- Fraunhofer Institute for Cell Therapy and Immunology, Cellular Immunotherapy Branch Site Würzburg, 97080 Würzburg, Germany
| | - Sebastian Kobold
- Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, LMU Munich, 80336 Munich, Germany; (N.T.T.N.); (R.M.); (D.B.)
- German Cancer Consortium (DKTK), Partner Site Munich, a Partnership between the DKFZ Heidelberg and the University Hospital of the LMU, 80336 Munich, Germany
- Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München—German Research Center for Environmental Health Neuherberg, 85764 Oberschleißheim, Germany
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19
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Wu J. Emerging Innate Immune Cells in Cancer Immunotherapy: Promises and Challenges. BioDrugs 2024; 38:499-509. [PMID: 38700835 PMCID: PMC11246812 DOI: 10.1007/s40259-024-00657-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/30/2024] [Indexed: 05/29/2024]
Abstract
Immune checkpoint inhibitor (ICI)-based therapy has made an unprecedented impact on survival benefit for a subset of cancer patients; however, only a subset of cancer patients is benefiting from ICI therapy if all cancer types are considered. With the advanced understanding of interactions of immune effector cell types and tumors, cell-based therapies are emerging as alternatives to patients who could not benefit from ICI therapy. Pioneering work of chimeric antigen receptor T (CAR-T) therapy for hematological malignancies has brought encouragement to a broad range of development for cellular-based cancer immunotherapy, both innate immune cell-based therapies and T-cell-based therapies. Innate immune cells are important cell types due to their rapid response, versatile function, superior safety profiles being demonstrated in early clinical development, and being able to utilize multiple allogeneic cell sources. Efforts on engineering innate immune cells and exploring their therapeutic potential are rapidly emerging. Some of the therapies, such as CD19 CAR natural killer (CAR-NK) cell-based therapy, have demonstrated comparable early efficacy with CD19 CAR-T cells. These studies underscore the significance of developing innate immune cells for cancer therapy. In this review, we focus on the current development of emerging NK cells, γδ T cells, and macrophages. We also present our views on potential challenges and perspectives to overcome these challenges.
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Affiliation(s)
- Jennifer Wu
- Department of Urology, Feinberg School of Medicine, Robert Lurie Comprehensive Cancer Center, Northwestern University, 303 E. Superior St, Chicago, IL, 60611, USA.
- Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
- Robert Lurie Comprehensive Cancer Center, Chicago, IL, USA.
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20
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Moles MW, Erdlei H, Menzel L, Massaro M, Fiori A, Bunse M, Schrimpf M, Gerlach K, Gudipati V, Reiser J, Mathavan K, Goodrich JP, Huppa JB, Krönke J, Valamehr B, Höpken UE, Rehm A. CXCR4 has a dual role in improving the efficacy of BCMA-redirected CAR-NK cells in multiple myeloma. Front Immunol 2024; 15:1383136. [PMID: 38979422 PMCID: PMC11228140 DOI: 10.3389/fimmu.2024.1383136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 06/06/2024] [Indexed: 07/10/2024] Open
Abstract
Multiple myeloma (MM) is a plasma cell disease with a preferential bone marrow (BM) tropism. Enforced expression of tissue-specific chemokine receptors has been shown to successfully guide adoptively-transferred CAR NK cells towards the malignant milieu in solid cancers, but also to BM-resident AML and MM. For redirection towards BM-associated chemokine CXCL12, we armored BCMA CAR-NK-92 as well as primary NK cells with ectopic expression of either wildtype CXCR4 or a gain-of-function mutant CXCR4R334X. Our data showed that BCMA CAR-NK-92 and -primary NK cells equipped with CXCR4 gained an improved ability to migrate towards CXCL12 in vitro. Beyond its classical role coordinating chemotaxis, CXCR4 has been shown to participate in T cell co-stimulation, which prompted us to examine the functionality of CXCR4-cotransduced BCMA-CAR NK cells. Ectopic CXCR4 expression enhanced the cytotoxic capacity of BCMA CAR-NK cells, as evidenced by the ability to eliminate BCMA-expressing target cell lines and primary MM cells in vitro and through accelerated cytolytic granule release. We show that CXCR4 co-modification prolonged BCMA CAR surface deposition, augmented ZAP-70 recruitment following CAR-engagement, and accelerated distal signal transduction kinetics. BCMA CAR sensitivity towards antigen was enhanced by virtue of an enhanced ZAP-70 recruitment to the immunological synapse, revealing an increased propensity of CARs to become triggered upon CXCR4 overexpression. Unexpectedly, co-stimulation via CXCR4 occurred in the absence of CXCL12 ligand-stimulation. Collectively, our findings imply that co-modification of CAR-NK cells with tissue-relevant chemokine receptors affect adoptive NK cell therapy beyond improved trafficking and retention within tumor sites.
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MESH Headings
- Multiple Myeloma/immunology
- Multiple Myeloma/therapy
- Humans
- Receptors, CXCR4/metabolism
- Receptors, CXCR4/genetics
- B-Cell Maturation Antigen/immunology
- B-Cell Maturation Antigen/metabolism
- B-Cell Maturation Antigen/genetics
- Killer Cells, Natural/immunology
- Killer Cells, Natural/metabolism
- Receptors, Chimeric Antigen/immunology
- Receptors, Chimeric Antigen/genetics
- Receptors, Chimeric Antigen/metabolism
- Immunotherapy, Adoptive/methods
- Chemokine CXCL12/metabolism
- Cell Line, Tumor
- Cytotoxicity, Immunologic
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Affiliation(s)
- Michael W Moles
- Translational Tumorimmunology, Max Delbrück Center, Berlin, Germany
| | - Henry Erdlei
- Translational Tumorimmunology, Max Delbrück Center, Berlin, Germany
| | - Lutz Menzel
- Translational Tumorimmunology, Max Delbrück Center, Berlin, Germany
| | - Marialucia Massaro
- Microenvironmental Regulation in Autoimmunity and Cancer, Max Delbrück Center, Berlin, Germany
| | - Agnese Fiori
- Translational Tumorimmunology, Max Delbrück Center, Berlin, Germany
| | - Mario Bunse
- Microenvironmental Regulation in Autoimmunity and Cancer, Max Delbrück Center, Berlin, Germany
| | - Moritz Schrimpf
- Translational Tumorimmunology, Max Delbrück Center, Berlin, Germany
| | - Kerstin Gerlach
- Translational Tumorimmunology, Max Delbrück Center, Berlin, Germany
| | - Venugopal Gudipati
- Center for Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Medical University of Vienna, Vienna, Austria
| | - John Reiser
- Fate Therapeutics, San Diego, CA, United States
| | | | | | - Johannes B Huppa
- Center for Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Medical University of Vienna, Vienna, Austria
| | - Jan Krönke
- Department of Hematology, Oncology and Tumorimmunology, Charité-University Medicine Berlin, Berlin, Germany
| | | | - Uta E Höpken
- Microenvironmental Regulation in Autoimmunity and Cancer, Max Delbrück Center, Berlin, Germany
| | - Armin Rehm
- Translational Tumorimmunology, Max Delbrück Center, Berlin, Germany
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21
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Kuznetsova AV, Glukhova XA, Popova OP, Beletsky IP, Ivanov AA. Contemporary Approaches to Immunotherapy of Solid Tumors. Cancers (Basel) 2024; 16:2270. [PMID: 38927974 PMCID: PMC11201544 DOI: 10.3390/cancers16122270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 06/11/2024] [Accepted: 06/15/2024] [Indexed: 06/28/2024] Open
Abstract
In recent years, the arrival of the immunotherapy industry has introduced the possibility of providing transformative, durable, and potentially curative outcomes for various forms of malignancies. However, further research has shown that there are a number of issues that significantly reduce the effectiveness of immunotherapy, especially in solid tumors. First of all, these problems are related to the protective mechanisms of the tumor and its microenvironment. Currently, major efforts are focused on overcoming protective mechanisms by using different adoptive cell therapy variants and modifications of genetically engineered constructs. In addition, a complex workforce is required to develop and implement these treatments. To overcome these significant challenges, innovative strategies and approaches are necessary to engineer more powerful variations of immunotherapy with improved antitumor activity and decreased toxicity. In this review, we discuss recent innovations in immunotherapy aimed at improving clinical efficacy in solid tumors, as well as strategies to overcome the limitations of various immunotherapies.
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Affiliation(s)
- Alla V. Kuznetsova
- Laboratory of Molecular and Cellular Pathology, Russian University of Medicine (Formerly A.I. Evdokimov Moscow State University of Medicine and Dentistry), Ministry of Health of the Russian Federation, Bld 4, Dolgorukovskaya Str, 1127006 Moscow, Russia; (A.V.K.); (O.P.P.)
- Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 26 Vavilov Street, 119334 Moscow, Russia
| | - Xenia A. Glukhova
- Onni Biotechnologies Ltd., Aalto University Campus, Metallimiehenkuja 10, 02150 Espoo, Finland; (X.A.G.); (I.P.B.)
| | - Olga P. Popova
- Laboratory of Molecular and Cellular Pathology, Russian University of Medicine (Formerly A.I. Evdokimov Moscow State University of Medicine and Dentistry), Ministry of Health of the Russian Federation, Bld 4, Dolgorukovskaya Str, 1127006 Moscow, Russia; (A.V.K.); (O.P.P.)
| | - Igor P. Beletsky
- Onni Biotechnologies Ltd., Aalto University Campus, Metallimiehenkuja 10, 02150 Espoo, Finland; (X.A.G.); (I.P.B.)
| | - Alexey A. Ivanov
- Laboratory of Molecular and Cellular Pathology, Russian University of Medicine (Formerly A.I. Evdokimov Moscow State University of Medicine and Dentistry), Ministry of Health of the Russian Federation, Bld 4, Dolgorukovskaya Str, 1127006 Moscow, Russia; (A.V.K.); (O.P.P.)
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22
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Li X, Li W, Xu L, Song Y. Chimeric antigen receptor-immune cells against solid tumors: Structures, mechanisms, recent advances, and future developments. Chin Med J (Engl) 2024; 137:1285-1302. [PMID: 37640679 PMCID: PMC11191032 DOI: 10.1097/cm9.0000000000002818] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Indexed: 08/31/2023] Open
Abstract
ABSTRACT The advent of chimeric antigen receptor (CAR)-T cell immunotherapies has led to breakthroughs in the treatment of hematological malignancies. However, their success in treating solid tumors has been limited. CAR-natural killer (NK) cells have several advantages over CAR-T cells because NK cells can be made from pre-existing cell lines or allogeneic NK cells with a mismatched major histocompatibility complex (MHC), which means they are more likely to become an "off-the-shelf" product. Moreover, they can kill cancer cells via CAR-dependent/independent pathways and have limited toxicity. Macrophages are the most malleable immune cells in the body. These cells can efficiently infiltrate into tumors and are present in large numbers in tumor microenvironments (TMEs). Importantly, CAR-macrophages (CAR-Ms) have recently yielded exciting preclinical results in several solid tumors. Nevertheless, CAR-T, CAR-NK, and CAR-M all have their own advantages and limitations. In this review, we systematically discuss the current status, progress, and the major hurdles of CAR-T cells, CAR-NK cells, and CAR-M as they relate to five aspects: CAR structure, therapeutic mechanisms, the latest research progress, current challenges and solutions, and comparison according to the existing research in order to provide a reasonable option for treating solid tumors in the future.
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Affiliation(s)
- Xudong Li
- Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan 450008, China
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Wei Li
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Linping Xu
- Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan 450008, China
| | - Yongping Song
- Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan 450008, China
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
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23
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Qi Y, Li Y, Wang H, Wang A, Liu X, Liang Z, Gao Y, Wei L. Natural killer cell-related anti-tumour adoptive cell immunotherapy. J Cell Mol Med 2024; 28:e18362. [PMID: 38837666 PMCID: PMC11151221 DOI: 10.1111/jcmm.18362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 04/04/2024] [Accepted: 04/16/2024] [Indexed: 06/07/2024] Open
Abstract
Chimeric antigen receptor- (CAR-)modified T cells have been successfully used to treat blood cancer. With the improved research on anti-tumour adoptive cell therapy, researchers have focused on immune cells other than T lymphocytes. Natural killer (NK) cells have received widespread attention as barriers to natural immunity. Compared to T lymphocyte-related adoptive cell therapy, the use of NK cells to treat tumours does not cause graft-versus-host disease, significantly improving immunity. Moreover, NK cells have more sources than T cells, and the related modified cells are less expensive. NK cells function through several pathways in anti-tumour mechanisms. Currently, many anti-tumour clinical trials have used NK cell-related adoptive cell therapies. In this review, we have summarized the recent progress in NK cell-related adoptive cellular immunotherapy for tumour treatment and propose the current challenges faced by CAR-NK cell therapy.
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Affiliation(s)
- Yuwen Qi
- Department of Gynecological OncologyZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumor Biological BehaviorsWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Ying Li
- Physical Examination CenterRenmin Hospital of Wuhan UniversityWuhanChina
| | - Hua Wang
- Department of Gynecological OncologyZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumor Biological BehaviorsWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Anjin Wang
- Department of Gynecological OncologyZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumor Biological BehaviorsWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Xuelian Liu
- Department of Gynecological OncologyZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumor Biological BehaviorsWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Ziyan Liang
- Department of Gynecological OncologyZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumor Biological BehaviorsWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Yang Gao
- Department of Gynecological OncologyZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei Key Laboratory of Tumor Biological BehaviorsWuhanChina
- Hubei Cancer Clinical Study CenterWuhanChina
| | - Liqing Wei
- Wuhan Wuchang HospitalWuhan University of Science and TechnologyWuhanChina
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24
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Decker JT, Hall MS, Nanua D, Orbach SM, Roy J, Angadi A, Caton J, Hesse L, Jeruss JS, Shea LD. Dynamic Transcriptional Programs During Single NK Cell Killing: Connecting Form to Function in Cellular Immunotherapy. Cell Mol Bioeng 2024; 17:177-188. [PMID: 39050513 PMCID: PMC11263395 DOI: 10.1007/s12195-024-00812-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 07/03/2024] [Indexed: 07/27/2024] Open
Abstract
Introduction Natural killer (NK) cell-based therapies are a promising new method for treating indolent cancer, however engineering new therapies is complex and progress towards therapy for solid tumors is slow. New methods for determining the underlying intracellular signaling driving the killing phenotype would significantly improve this progress. Methods We combined single-cell RNA sequencing with live cell imaging of a model system of NK cell killing to correlate transcriptomic data with functional output. A model of NK cell activity, the NK-92 cell line killing of HeLa cervical cancer cells, was used for these studies. NK cell killing activity was observed by microscopy during co-culture with target HeLa cells and killing activity subsequently manually mapped based on NK cell location and Annexin V expression. NK cells from this culture system were profiled by single-cell RNA sequencing using the 10× Genomics platform, and transcription factor activity inferred using the Viper and DoRothEA R packages. Luminescent microscopy of reporter constructs in the NK cells was then used to correlate activity of inferred transcriptional activity with killing activity. Results NK cells had heterogeneous killing activity during 10 h of culture with target HeLa cells. Analysis of the single cell sequencing data identified Nuclear Factor Kappa B (NF-κB), Signal Transducer and Activator of Transcription 1 (STAT1) and MYC activity as potential drivers of NK cell functional phenotype in our model system. Live cell imaging of the transcription factor activity found NF-κB activity was significantly correlated with past killing activity. No correlation was observed between STAT1 or MYC activity and NK cell killing. Conclusions Combining luminescent microscopy of transcription factor activity with single-cell RNA sequencing is an effective means of assigning functional phenotypes to inferred transcriptomics data. Supplementary Information The online version contains supplementary material available at 10.1007/s12195-024-00812-3.
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Affiliation(s)
- Joseph T. Decker
- Department of Biomedical Engineering, University of Michigan, 1600 Huron Parkway, Ann Arbor, MI 48109 USA
- Department of Cariology, Restorative Sciences, and Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI 48109 USA
| | - Matthew S. Hall
- Department of Biomedical Engineering, University of Michigan, 1600 Huron Parkway, Ann Arbor, MI 48109 USA
| | - Devak Nanua
- Department of Biomedical Engineering, University of Michigan, 1600 Huron Parkway, Ann Arbor, MI 48109 USA
| | - Sophia M. Orbach
- Department of Biomedical Engineering, University of Michigan, 1600 Huron Parkway, Ann Arbor, MI 48109 USA
- Department of Biomedical Engineering, Rowan University, Glassboro, NJ 08028 USA
| | - Jyotirmoy Roy
- Department of Biomedical Engineering, University of Michigan, 1600 Huron Parkway, Ann Arbor, MI 48109 USA
| | - Amogh Angadi
- Department of Biomedical Engineering, University of Michigan, 1600 Huron Parkway, Ann Arbor, MI 48109 USA
| | - Julianna Caton
- Department of Biomedical Engineering, University of Michigan, 1600 Huron Parkway, Ann Arbor, MI 48109 USA
| | - Lauren Hesse
- Department of Biomedical Engineering, University of Michigan, 1600 Huron Parkway, Ann Arbor, MI 48109 USA
| | - Jacqueline S. Jeruss
- Department of Biomedical Engineering, University of Michigan, 1600 Huron Parkway, Ann Arbor, MI 48109 USA
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109 USA
| | - Lonnie D. Shea
- Department of Biomedical Engineering, University of Michigan, 1600 Huron Parkway, Ann Arbor, MI 48109 USA
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25
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Sadowski K, Jażdżewska A, Kozłowski J, Zacny A, Lorenc T, Olejarz W. Revolutionizing Glioblastoma Treatment: A Comprehensive Overview of Modern Therapeutic Approaches. Int J Mol Sci 2024; 25:5774. [PMID: 38891962 PMCID: PMC11172387 DOI: 10.3390/ijms25115774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 05/22/2024] [Accepted: 05/25/2024] [Indexed: 06/21/2024] Open
Abstract
Glioblastoma is the most common malignant primary brain tumor in the adult population, with an average survival of 12.1 to 14.6 months. The standard treatment, combining surgery, radiotherapy, and chemotherapy, is not as efficient as we would like. However, the current possibilities are no longer limited to the standard therapies due to rapid advancements in biotechnology. New methods enable a more precise approach by targeting individual cells and antigens to overcome cancer. For the treatment of glioblastoma, these are gamma knife therapy, proton beam therapy, tumor-treating fields, EGFR and VEGF inhibitors, multiple RTKs inhibitors, and PI3K pathway inhibitors. In addition, the increasing understanding of the role of the immune system in tumorigenesis and the ability to identify tumor-specific antigens helped to develop immunotherapies targeting GBM and immune cells, including CAR-T, CAR-NK cells, dendritic cells, and immune checkpoint inhibitors. Each of the described methods has its advantages and disadvantages and faces problems, such as the inefficient crossing of the blood-brain barrier, various neurological and systemic side effects, and the escape mechanism of the tumor. This work aims to present the current modern treatments of glioblastoma.
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Affiliation(s)
- Karol Sadowski
- The Department of Histology and Embryology, Medical University of Warsaw, Chalubinskiego 5, 02-004 Warsaw, Poland; (K.S.)
- Department of Biochemistry and Pharmacogenomics, Faculty of Pharmacy, Medical University of Warsaw, 02-091 Warsaw, Poland;
- Centre for Preclinical Research, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Adrianna Jażdżewska
- The Department of Anatomy and Neurobiology, Medical University of Gdansk, Dębinki 1, 80-211 Gdansk, Poland;
| | - Jan Kozłowski
- The Department of Histology and Embryology, Medical University of Warsaw, Chalubinskiego 5, 02-004 Warsaw, Poland; (K.S.)
| | - Aleksandra Zacny
- The Department of Histology and Embryology, Medical University of Warsaw, Chalubinskiego 5, 02-004 Warsaw, Poland; (K.S.)
| | - Tomasz Lorenc
- Department of Radiology I, The Maria Sklodowska-Curie National Research Institute of Oncology, Roentgena 5, 02-781 Warsaw, Poland
| | - Wioletta Olejarz
- Department of Biochemistry and Pharmacogenomics, Faculty of Pharmacy, Medical University of Warsaw, 02-091 Warsaw, Poland;
- Centre for Preclinical Research, Medical University of Warsaw, 02-091 Warsaw, Poland
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26
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Gordon KS, Perez CR, Garmilla A, Lam MSY, Aw JJ, Datta A, Lauffenburger DA, Pavesi A, Birnbaum ME. Pooled screening for CAR function identifies novel IL13Rα2-targeted CARs for treatment of glioblastoma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.04.586240. [PMID: 38766252 PMCID: PMC11100612 DOI: 10.1101/2024.04.04.586240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
Chimeric antigen receptor therapies have demonstrated potent efficacy in treating B cell malignancies, but have yet to meaningfully translate to solid tumors. Here, we utilize our pooled screening platform, CARPOOL, to expedite the discovery of CARs with anti-tumor functions necessary for solid tumor efficacy. We performed selections in primary human T cells expressing a library of 1.3×10 6 3 rd generation CARs targeting IL13Rα2, a cancer testis antigen commonly expressed in glioblastoma. Selections were performed for cytotoxicity, proliferation, memory formation, and persistence upon repeated antigen challenge. Each enriched CAR robustly produced the phenotype for which it was selected, and one enriched CAR triggered potent cytotoxicity and long-term proliferation upon in vitro tumor rechallenge. It also showed significantly improved persistence and comparable antigen-specific tumor control in a microphysiological human in vitro model and a xenograft model of human glioblastoma. Taken together, this work demonstrates the utility of extending CARPOOL to diseases beyond hematological malignancies and represents the largest exploration of signaling combinations in human primary cells to date.
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27
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Deng M, Yang R, Sun Q, Zhang J, Miao J. Small-molecule inhibitor HI-TOPK-032 improves NK-92MI cell infiltration into ovarian tumours. Basic Clin Pharmacol Toxicol 2024; 134:629-642. [PMID: 38501576 DOI: 10.1111/bcpt.14002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 02/24/2024] [Accepted: 02/26/2024] [Indexed: 03/20/2024]
Abstract
The effectiveness of natural killer (NK) cells transferred adoptively in combating solid tumours is limited by challenges such as their difficulty in penetrating tumours from the bloodstream and maintaining viability without the support of interleukin-2 (IL-2). Genetically modified NK-92MI cells, which can release IL-2 to sustain their viability, have been identified as a promising alternative. This adaptation addresses the negative consequences of systemic IL-2 administration. The role of PSD-95/discs large/ZO-1 (PDZ)-binding kinase (PBK) in cancer development is recognized, but its effects on immunity are not fully understood. This study explores how PBK expression influences the ability of NK-92MI cells to infiltrate ovarian tumours. Elevated levels of PBK expression have been found in various cancers, including ovarian cancer (OV), with analyses showing higher PBK mRNA levels in tumour tissues compared to normal ones. Immunohistochemistry has confirmed increased PBK expression in OV tissues. Investigations into PBK's role in immune regulation reveal its association with immune cell infiltration, indicating a potentially compromised immune environment in OV with high PBK expression. The small-molecule inhibitor HI-TOPK-032, which inhibits PBK, enhances the cytotoxicity of NK-92MI cells toward OV cells. It increases the production of interferon-γ and tumour necrosis factor-α, reduces apoptosis and encourages cell proliferation. Mechanistic studies showed that contact with OV cells treated with HI-TOPK-032 upregulates CD107a on NK-92 cells. In vivo studies demonstrated that HI-TOPK-032 improves the antitumour effects of NK-92MI cells in OVCAR3Luc xenografts, extending survival without significant side effects. Safety assessments in mice confirm HI-TOPK-032's favourable safety profile, highlighting its potential as a viable antitumour therapy. These results suggest that combining NK-92MI cells with HI-TOPK-032 enhances antitumour effectiveness against OV, indicating a promising, safe and effective treatment strategy that warrants further clinical investigation.
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Affiliation(s)
- Mengqi Deng
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, China
| | - Ruiye Yang
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, China
| | - Qi Sun
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, China
| | - Jiamin Zhang
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, China
| | - Jinwei Miao
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, China
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28
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Page A, Chuvin N, Valladeau-Guilemond J, Depil S. Development of NK cell-based cancer immunotherapies through receptor engineering. Cell Mol Immunol 2024; 21:315-331. [PMID: 38443448 PMCID: PMC10978891 DOI: 10.1038/s41423-024-01145-x] [Citation(s) in RCA: 56] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 02/09/2024] [Indexed: 03/07/2024] Open
Abstract
Natural killer (NK) cell-based immunotherapies are attracting increasing interest in the field of cancer treatment. Early clinical trials have shown promising outcomes, alongside satisfactory product efficacy and safety. Recent developments have greatly increased the therapeutic potential of NK cells by endowing them with enhanced recognition and cytotoxic capacities. This review focuses on surface receptor engineering in NK cell therapy and discusses its impact, challenges, and future directions.Most approaches are based on engineering with chimeric antigen receptors to allow NK cells to target specific tumor antigens independent of human leukocyte antigen restriction. This approach has increased the precision and potency of NK-mediated recognition and elimination of cancer cells. In addition, engineering NK cells with T-cell receptors also mediates the recognition of intracellular epitopes, which broadens the range of target peptides. Indirect tumor peptide recognition by NK cells has also been improved by optimizing immunoglobulin constant fragment receptor expression and signaling. Indeed, engineered NK cells have an improved ability to recognize and destroy target cells coated with specific antibodies, thereby increasing their antibody-dependent cellular cytotoxicity. The ability of NK cell receptor engineering to promote the expansion, persistence, and infiltration of transferred cells in the tumor microenvironment has also been explored. Receptor-based strategies for sustained NK cell functionality within the tumor environment have also been discussed, and these strategies providing perspectives to counteract tumor-induced immunosuppression.Overall, receptor engineering has led to significant advances in NK cell-based cancer immunotherapies. As technical challenges are addressed, these innovative treatments will likely reshape cancer immunotherapy.
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Affiliation(s)
- Audrey Page
- Centre de Recherche en Cancérologie de Lyon, UMR INSERM U1052 CNRS 5286, Centre Léon Bérard, Lyon, France.
| | | | - Jenny Valladeau-Guilemond
- Centre de Recherche en Cancérologie de Lyon, UMR INSERM U1052 CNRS 5286, Centre Léon Bérard, Lyon, France
| | - Stéphane Depil
- Centre de Recherche en Cancérologie de Lyon, UMR INSERM U1052 CNRS 5286, Centre Léon Bérard, Lyon, France.
- ErVimmune, Lyon, France.
- Centre Léon Bérard, Lyon, France.
- Université Claude Bernard Lyon 1, Lyon, France.
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29
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Yoon JH, Yoon HN, Kang HJ, Yoo H, Choi MJ, Chung JY, Seo M, Kim M, Lim SO, Kim YJ, Lee JK, Jang M. Empowering pancreatic tumor homing with augmented anti-tumor potency of CXCR2-tethered CAR-NK cells. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200777. [PMID: 38596297 PMCID: PMC10926211 DOI: 10.1016/j.omton.2024.200777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 01/16/2024] [Accepted: 02/15/2024] [Indexed: 04/11/2024]
Abstract
Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells are a promising immunotherapy for solid cancers; however, their effectiveness against pancreatic cancer is limited by the immunosuppressive tumor microenvironment. In particular, low NK cell infiltration poses a major obstacle that reduces cytotoxicity. The current study aimed to enhance the tumor-homing capacity of CAR-NK cells by targeting the chemokine-chemokine receptor axis between NK and pancreatic cancer cells. To this end, data from a chemokine array and The Cancer Genome Atlas pan-cancer cohort were analyzed. Pancreatic cancer cells were found to secrete high levels of ligands for C-X-C motif receptor 1 (CXCR1) and CXCR2. Subsequently, we generated anti-mesothelin CAR-NK cells incorporating CXCR1 or CXCR2 and evaluated their tumor-killing abilities in 2D cancer cell co-culture and 3D tumor-mimetic organoid models. CAR-NK cells engineered with CXCR2 demonstrated enhanced tumor killing and strong infiltration of tumor sites. Collectively, these findings highlight the potential of CXCR2-augmented CAR-NK cells as a clinically relevant modality for effective pancreatic cancer treatment. By improving their infiltration and tumor-killing capabilities, these CXCR2-augmented CAR-NK cells have the potential to overcome the challenges posed by the immunosuppressive tumor microenvironment, providing improved therapeutic outcomes.
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Affiliation(s)
- Jong Hyeon Yoon
- Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
| | - Han-Na Yoon
- Rare & Pediatric Cancer Branch, Division of Rare and Refractory Cancer, Research Institute, National Cancer Center, Goyang 10408, Republic of Korea
| | - Hyun Ju Kang
- Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 03080, Republic of Korea
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Hyejin Yoo
- Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
| | - Moon Jung Choi
- Division of Hematology and Oncology, Brown University, Providence, RI, USA
| | - Joo-Yoon Chung
- Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
- KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Minkoo Seo
- Corporate Research & Development Center, UCI Therapeutics, Seoul 04784, Republic of Korea
| | - Minsung Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Si On Lim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Yong Jun Kim
- Department of Pathology, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
- KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Jin-Ku Lee
- Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 03080, Republic of Korea
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
- Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Mihue Jang
- Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
- KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea
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30
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Guo F, Zhang Y, Cui J. Manufacturing CAR-NK against tumors: Who is the ideal supplier? Chin J Cancer Res 2024; 36:1-16. [PMID: 38455373 PMCID: PMC10915637 DOI: 10.21147/j.issn.1000-9604.2024.01.01] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 01/12/2024] [Indexed: 03/09/2024] Open
Abstract
Chimeric antigen receptor-natural killer (CAR-NK) cells have emerged as another prominent player in the realm of tumor immunotherapy following CAR-T cells. The unique features of CAR-NK cells make it possible to compensate for deficiencies in CAR-T therapy, such as the complexity of the manufacturing process, clinical adverse events, and solid tumor challenges. To date, CAR-NK products from different allogeneic sources have exhibited remarkable anti-tumor effects on preclinical studies and have gradually been applied in clinical practice. However, each source has advantages and disadvantages. Selecting a suitable source may help maximize CAR-NK cell efficacy and increase the feasibility of clinical transformation. Therefore, this review discusses the development and challenges of CAR-NK cells from different sources to provide a reference for future exploration.
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Affiliation(s)
- Feifei Guo
- The First Hospital of Jilin University, Cancer Center, Changchun 133021, China
| | - Yi Zhang
- The First Hospital of Jilin University, Cancer Center, Changchun 133021, China
| | - Jiuwei Cui
- The First Hospital of Jilin University, Cancer Center, Changchun 133021, China
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Patterson C, Hazime KS, Zelenay S, Davis DM. Prostaglandin E₂ impacts multiple stages of the natural killer cell antitumor immune response. Eur J Immunol 2024; 54:e2350635. [PMID: 38059519 DOI: 10.1002/eji.202350635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 12/04/2023] [Accepted: 12/05/2023] [Indexed: 12/08/2023]
Abstract
Tumor immune escape is a major factor contributing to cancer progression and unresponsiveness to cancer therapies. Tumors can produce prostaglandin E2 (PGE2 ), an inflammatory mediator that directly acts on Natural killer (NK) cells to inhibit antitumor immunity. However, precisely how PGE2 influences NK cell tumor-restraining functions remains unclear. Here, we report that following PGE₂ treatment, human NK cells exhibited altered expression of specific activating receptors and a reduced ability to degranulate and kill cancer targets. Transcriptional analysis uncovered that PGE₂ also differentially modulated the expression of chemokine receptors by NK cells, inhibiting CXCR3 but increasing CXCR4. Consistent with this, PGE₂-treated NK cells exhibited decreased migration to CXCL10 but increased ability to migrate toward CXCL12. Using live cell imaging, we showed that in the presence of PGE2 , NK cells were slower and less likely to kill cancer target cells following conjugation. Imaging the sequential stages of NK cell killing revealed that PGE₂ impaired NK cell polarization, but not the re-organization of synaptic actin or the release of perforin itself. Together, these findings demonstrate that PGE₂ affects multiple but select NK cell functions. Understanding how cancer cells subvert NK cells is necessary to more effectively harness the cancer-inhibitory function of NK cells in treatments.
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Affiliation(s)
- Chloe Patterson
- The Lydia Becker Institute of Immunology and Inflammation, The University of Manchester, Manchester, United Kingdom
| | - Khodor S Hazime
- Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, South Kensington, London, United Kingdom
| | - Santiago Zelenay
- The Lydia Becker Institute of Immunology and Inflammation, The University of Manchester, Manchester, United Kingdom
- Cancer Inflammation and Immunity Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom
| | - Daniel M Davis
- Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, South Kensington, London, United Kingdom
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32
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Lekan AA, Weiner LM. The Role of Chemokines in Orchestrating the Immune Response to Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2024; 16:559. [PMID: 38339310 PMCID: PMC10854906 DOI: 10.3390/cancers16030559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 01/24/2024] [Accepted: 01/26/2024] [Indexed: 02/12/2024] Open
Abstract
Chemokines are small molecules that function as chemotactic factors which regulate the migration, infiltration, and accumulation of immune cells. Here, we comprehensively assess the structural and functional role of chemokines, examine the effects of chemokines that are present in the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME), specifically those produced by cancer cells and stromal components, and evaluate their impact on immune cell trafficking, both in promoting and suppressing anti-tumor responses. We further explore the impact of chemokines on patient outcomes in PDAC and their role in the context of immunotherapy treatments, and review clinical trials that have targeted chemokine receptors and ligands in the treatment of PDAC. Lastly, we highlight potential strategies that can be utilized to harness chemokines in order to increase cytotoxic immune cell infiltration and the anti-tumor effects of immunotherapy.
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Affiliation(s)
| | - Louis M. Weiner
- Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3970 Reservoir Road NW, Washington, DC 20057, USA;
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Esmaeilzadeh A, Hadiloo K, Jabbari M, Elahi R. Current progress of chimeric antigen receptor (CAR) T versus CAR NK cell for immunotherapy of solid tumors. Life Sci 2024; 337:122381. [PMID: 38145710 DOI: 10.1016/j.lfs.2023.122381] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 12/07/2023] [Accepted: 12/19/2023] [Indexed: 12/27/2023]
Abstract
Equipping cancer-fighting immune cells with chimeric antigen receptor (CAR) has gained immense attention for cancer treatment. CAR-engineered T cells (CAR T cells) are the first immune-engineered cells that have achieved brilliant results in anti-cancer therapy. Despite promising anti-cancer features, CAR T cells could also cause fatal side effects and have shown inadequate efficacy in some studies. This has led to the introduction of other candidates for CAR transduction, e.g., Natural killer cells (NK cells). Regarding the better safety profile and anti-cancer properties, CAR-armored NK cells (CAR NK cells) could be a beneficial and suitable alternative to CAR T cells. Since introducing these two cells as anti-cancer structures, several studies have investigated their efficacy and safety, and most of them have focused on hematological malignancies. Solid tumors have unique properties that make them more resistant and less curable cancers than hematological malignancies. In this review article, we conduct a comprehensive review of the structure and properties of CAR NK and CAR T cells, compare the recent experience of immunotherapy with CAR T and CAR NK cells in various solid cancers, and overview current challenges and future solutions to battle solid cancers using CARNK cells.
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Affiliation(s)
- Abdolreza Esmaeilzadeh
- Department of Immunology, Zanjan University of Medical Sciences, Zanjan, Iran; Cancer Gene Therapy Research Center (CGRC), Zanjan University of Medical Sciences, Zanjan, Iran.
| | - Kaveh Hadiloo
- Student Research Committee, Department of Immunology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran; School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Marjan Jabbari
- School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Reza Elahi
- School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
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34
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Zheng W, Ling S, Cao Y, Shao C, Sun X. Combined use of NK cells and radiotherapy in the treatment of solid tumors. Front Immunol 2024; 14:1306534. [PMID: 38264648 PMCID: PMC10803658 DOI: 10.3389/fimmu.2023.1306534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 12/22/2023] [Indexed: 01/25/2024] Open
Abstract
Natural killer (NK) cells are innate lymphocytes possessing potent tumor surveillance and elimination activity. Increasing attention is being focused on the role of NK cells in integral antitumor strategies (especially immunotherapy). Of note, therapeutic efficacy is considerable dependent on two parameters: the infiltration and cytotoxicity of NK cells in tumor microenvironment (TME), both of which are impaired by several obstacles (e.g., chemokines, hypoxia). Strategies to overcome such barriers are needed. Radiotherapy is a conventional modality employed to cure solid tumors. Recent studies suggest that radiotherapy not only damages tumor cells directly, but also enhances tumor recognition by immune cells through altering molecular expression of tumor or immune cells via the in situ or abscopal effect. Thus, radiotherapy may rebuild a NK cells-favored TME, and thus provide a cost-effective approach to improve the infiltration of NK cells into solid tumors, as well as elevate immune-activity. Moreover, the radioresistance of tumor always hampers the response to radiotherapy. Noteworthy, the puissant cytotoxic activity of NK cells not only kills tumor cells directly, but also increases the response of tumors to radiation via activating several radiosensitization pathways. Herein, we review the mechanisms by which NK cells and radiotherapy mutually promote their killing function against solid malignancies. We also discuss potential strategies harnessing such features in combined anticancer care.
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Affiliation(s)
- Wang Zheng
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Sunkai Ling
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yuandong Cao
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chunlin Shao
- Institution of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xinchen Sun
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Fei X, Wu J, Tian H, Jiang D, Chen H, Yan K, Wang Y, Zhao Y, Chen H, Xie X, Wang Z, Zhu W, Huang Q. Glioma stem cells remodel immunotolerant microenvironment in GBM and are associated with therapeutic advancements. Cancer Biomark 2024; 41:1-24. [PMID: 39240627 PMCID: PMC11492047 DOI: 10.3233/cbm-230486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 07/19/2024] [Indexed: 09/07/2024]
Abstract
Glioma is the most common primary tumor of the central nervous system (CNS). Glioblastoma (GBM) is incurable with current treatment strategies. Additionally, the treatment of recurrent GBM (rGBM) is often referred to as terminal treatment, necessitating hospice-level care and management. The presence of the blood-brain barrier (BBB) gives GBM a more challenging or "cold" tumor microenvironment (TME) than that of other cancers and gloma stem cells (GSCs) play an important role in the TME remodeling, occurrence, development and recurrence of giloma. In this review, our primary focus will be on discussing the following topics: niche-associated GSCs and macrophages, new theories regarding GSC and TME involving pyroptosis and ferroptosis in GBM, metabolic adaptations of GSCs, the influence of the cold environment in GBM on immunotherapy, potential strategies to transform the cold GBM TME into a hot one, and the advancement of GBM immunotherapy and GBM models.
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Affiliation(s)
- Xifeng Fei
- Department of Neurosurgery, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, Jiangsu, China
| | - Jie Wu
- Department of Neurosurgery, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, Jiangsu, China
- Department of Neurosurgery, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing University Medical School, Suzhou, Jiangsu, China
| | - Haiyan Tian
- Department of Neurosurgery, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, Jiangsu, China
- Department of GCP, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, Jiangsu, China
| | - Dongyi Jiang
- Department of Neurosurgery, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, Jiangsu, China
| | - Hanchun Chen
- Department of Neurosurgery, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, Jiangsu, China
| | - Ke Yan
- Department of Neurosurgery, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing University Medical School, Suzhou, Jiangsu, China
| | - Yuan Wang
- Pediatric Cancer Center, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Yaodong Zhao
- Department of Neurosurgery, Shanghai General Hospital, Shanghai, China
| | - Hua Chen
- Department of Neurosurgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiangtong Xie
- Department of Neurosurgery, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, Jiangsu, China
| | - Zhimin Wang
- Department of Neurosurgery, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, Jiangsu, China
- Department of Neurosurgery, Dushu Lake Hospital Affiliated to Soochow University, Suzhou, Jiangsu, China
| | - Wenyu Zhu
- Department of Neurosurgery, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing University Medical School, Suzhou, Jiangsu, China
| | - Qiang Huang
- Department of Neurosurgery, Second Affiliated Hospital of Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
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Amin T, Hossain A, Jerin N, Mahmud I, Rahman MA, Rafiqul Islam SM, Islam SMBUL. Immunoediting Dynamics in Glioblastoma: Implications for Immunotherapy Approaches. Cancer Control 2024; 31:10732748241290067. [PMID: 39353594 PMCID: PMC11459535 DOI: 10.1177/10732748241290067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 09/14/2024] [Accepted: 09/23/2024] [Indexed: 10/04/2024] Open
Abstract
Glioblastoma is an aggressive primary brain tumor that poses many therapeutic difficulties because of the high rate of proliferation, genetic variability, and its immunosuppressive microenvironment. The theory of cancer immunoediting, which includes the phases of elimination, equilibrium, and escape, offers a paradigm for comprehending interactions between the immune system and glioblastoma. Immunoediting indicates the process by which immune cells initially suppress tumor development, but thereafter select for immune-resistant versions leading to tumor escape and progression. The tumor microenvironment (TME) in glioblastoma is particularly immunosuppressive, with regulatory T cells and myeloid-derived suppressor cells being involved in immune escape. To achieve an efficient immunotherapy for glioblastoma, it is crucial to understand these mechanisms within the TME. Existing immunotherapeutic modalities such as chimeric antigen receptor T cells and immune checkpoint inhibitors have been met with some level of resistance because of the heterogeneous nature of the immune response to glioblastoma. Solving these issues is critical to develop novel strategies capable of modulating the TME and re-establishing normal immune monitoring. Further studies should be conducted to identify the molecular and cellular events that underlie the immunosuppressive tumor microenvironment in glioblastoma. Comprehending and modifying the stages of immunoediting in glioblastoma could facilitate the development of more potent and long-lasting therapies.
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Affiliation(s)
- Tasbir Amin
- Department of Biochemistry & Microbiology, North South University, Dhaka, Bangladesh
| | - Amana Hossain
- Department of Biochemistry & Microbiology, North South University, Dhaka, Bangladesh
| | - Nusrat Jerin
- Department of Biochemistry & Microbiology, North South University, Dhaka, Bangladesh
| | - Imteaz Mahmud
- Department of Public Health, North South University, Dhaka, Bangladesh
| | - Md Ahasanur Rahman
- Department of Physiology and Biophysics, Howard University, College of Medicine, Washington, DC, USA
| | - SM Rafiqul Islam
- Surgery Branch, National Cancer Institute, National Institute of Health, Bethesda, USA
| | - S M Bakhtiar UL Islam
- Department of Biochemistry & Microbiology, North South University, Dhaka, Bangladesh
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Pawlowski KD, Duffy JT, Gottschalk S, Balyasnikova IV. Cytokine Modification of Adoptive Chimeric Antigen Receptor Immunotherapy for Glioblastoma. Cancers (Basel) 2023; 15:5852. [PMID: 38136398 PMCID: PMC10741789 DOI: 10.3390/cancers15245852] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 11/14/2023] [Accepted: 12/12/2023] [Indexed: 12/24/2023] Open
Abstract
Chimeric antigen receptor (CAR) cell-based therapies have demonstrated limited success in solid tumors, including glioblastoma (GBM). GBMs exhibit high heterogeneity and create an immunosuppressive tumor microenvironment (TME). In addition, other challenges exist for CAR therapy, including trafficking and infiltration into the tumor site, proliferation, persistence of CARs once in the tumor, and reduced functionality, such as suboptimal cytokine production. Cytokine modification is of interest, as one can enhance therapy efficacy and minimize off-target toxicity by directly combining CAR therapy with cytokines, antibodies, or oncolytic viruses that alter cytokine response pathways. Alternatively, one can genetically modify CAR T-cells or CAR NK-cells to secrete cytokines or express cytokines or cytokine receptors. Finally, CARs can be genetically altered to augment or suppress intracellular cytokine signaling pathways for a more direct approach. Codelivery of cytokines with CARs is the most straightforward method, but it has associated toxicity. Alternatively, combining CAR therapy with antibodies (e.g., anti-IL-6, anti-PD1, and anti-VEGF) or oncolytic viruses has enhanced CAR cell infiltration into GBM tumors and provided proinflammatory signals to the TME. CAR T- or NK-cells secreting cytokines (e.g., IL-12, IL-15, and IL-18) have shown improved efficacy within multiple GBM subtypes. Likewise, expressing cytokine-modulating receptors in CAR cells that promote or inhibit cytokine signaling has enhanced their activity. Finally, gene editing approaches are actively being pursued to directly influence immune signaling pathways in CAR cells. In this review, we summarize these cytokine modification methods and highlight any existing gaps in the hope of catalyzing an improved generation of CAR-based therapies for glioblastoma.
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Affiliation(s)
- Kristen D. Pawlowski
- Department of Neurological Surgery, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA;
| | - Joseph T. Duffy
- Department of Neurological Surgery, Northwestern University, Chicago, IL 60208, USA;
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60208, USA
| | - Stephen Gottschalk
- Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA;
| | - Irina V. Balyasnikova
- Department of Neurological Surgery, Northwestern University, Chicago, IL 60208, USA;
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60208, USA
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38
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Wang Y, Jin S, Zhuang Q, Liu N, Chen R, Adam SA, Jin J, Sun J. Chimeric antigen receptor natural killer cells: a promising antitumor immunotherapy. MedComm (Beijing) 2023; 4:e422. [PMID: 38045827 PMCID: PMC10691297 DOI: 10.1002/mco2.422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 10/05/2023] [Accepted: 10/12/2023] [Indexed: 12/05/2023] Open
Abstract
Chimeric antigen receptor (CAR) T cells have been successfully used in adoptive cell therapy for malignancies. However, some obstacles, including side effects such as graft-versus-host disease and cytokine release syndrome, therapy resistance, limited sources, as well as high cost, limited the application of CAR T cells. Recently, CAR natural killer (NK) cells have been pursued as the effector cells for adoptive immunotherapy for their attractive merits of strong intrinsic antitumor activity and relatively mild side effects. Additionally, CAR NK cells can be available from various sources and do not require strict human leukocyte antigen matching, which suggests them as promising "off-the-shelf" products for clinical application. Although the use of CAR NK cells is restrained by the limited proliferation and impaired efficiency within the immunosuppressive tumor microenvironment, further investigation in optimizing CAR structure and combination therapies will overcome these challenges. This review will summarize the advancement of CAR NK cells, CAR NK cell manufacture, the clinical outcomes of CAR NK therapy, the challenges in the field, and prospective solutions. Besides, we will discuss the emerging application of other immune cells for CAR engineering. Collectively, this comprehensive review will provide a valuable and informative summary of current progress and evaluate challenges and future opportunities of CAR NK cells in tumor treatment.
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Affiliation(s)
- Yan Wang
- Department of HematologyThe First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Key Laboratory of Hematologic MalignanciesDiagnosis, and TreatmentHangzhouZhejiangChina
| | - Shengjie Jin
- Department of HematologyThe First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Key Laboratory of Hematologic MalignanciesDiagnosis, and TreatmentHangzhouZhejiangChina
| | - Qiqi Zhuang
- Department of HematologyThe First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Key Laboratory of Hematologic MalignanciesDiagnosis, and TreatmentHangzhouZhejiangChina
| | - Na Liu
- Department of HematologyThe First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Key Laboratory of Hematologic MalignanciesDiagnosis, and TreatmentHangzhouZhejiangChina
- Department of OncologyAffiliated Hospital of Weifang Medical UniversitySchool of Clinical MedicineWeifang Medical UniversityWeifangShandongChina
| | - Ruyi Chen
- Department of HematologyThe First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Key Laboratory of Hematologic MalignanciesDiagnosis, and TreatmentHangzhouZhejiangChina
| | - Sofia Abdulkadir Adam
- Key Laboratory of Hematologic MalignanciesDiagnosis, and TreatmentHangzhouZhejiangChina
| | - Jie Jin
- Department of HematologyThe First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Key Laboratory of Hematologic MalignanciesDiagnosis, and TreatmentHangzhouZhejiangChina
- Zhejiang University Cancer CenterHangzhouZhejiangChina
- Zhejiang Provincial Clinical Research Center for Hematological DisordersHangzhouZhejiangChina
| | - Jie Sun
- Department of HematologyThe First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Key Laboratory of Hematologic MalignanciesDiagnosis, and TreatmentHangzhouZhejiangChina
- Zhejiang Provincial Clinical Research Center for Hematological DisordersHangzhouZhejiangChina
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Hibler W, Merlino G, Yu Y. CAR NK Cell Therapy for the Treatment of Metastatic Melanoma: Potential & Prospects. Cells 2023; 12:2750. [PMID: 38067178 PMCID: PMC10706172 DOI: 10.3390/cells12232750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 11/22/2023] [Accepted: 11/26/2023] [Indexed: 12/18/2023] Open
Abstract
Melanoma is among the most lethal forms of cancer, accounting for 80% of deaths despite comprising just 5% of skin cancer cases. Treatment options remain limited due to the genetic and epigenetic mechanisms associated with melanoma heterogeneity that underlie the rapid development of secondary drug resistance. For this reason, the development of novel treatments remains paramount to the improvement of patient outcomes. Although the advent of chimeric antigen receptor-expressing T (CAR-T) cell immunotherapies has led to many clinical successes for hematological malignancies, these treatments are limited in their utility by their immune-induced side effects and a high risk of systemic toxicities. CAR natural killer (CAR-NK) cell immunotherapies are a particularly promising alternative to CAR-T cell immunotherapies, as they offer a more favorable safety profile and have the capacity for fine-tuned cytotoxic activity. In this review, the discussion of the prospects and potential of CAR-NK cell immunotherapies touches upon the clinical contexts of melanoma, the immunobiology of NK cells, the immunosuppressive barriers preventing endogenous immune cells from eliminating tumors, and the structure and design of chimeric antigen receptors, then finishes with a series of proposed design innovations that could improve the efficacy CAR-NK cell immunotherapies in future studies.
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Affiliation(s)
| | | | - Yanlin Yu
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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40
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Giardino Torchia ML, Moody G. DIALing-up the preclinical characterization of gene-modified adoptive cellular immunotherapies. Front Immunol 2023; 14:1264882. [PMID: 38090585 PMCID: PMC10713823 DOI: 10.3389/fimmu.2023.1264882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 10/27/2023] [Indexed: 12/18/2023] Open
Abstract
The preclinical characterization of gene modified adoptive cellular immunotherapy candidates for clinical development often requires the use of mouse models. Gene-modified lymphocytes (GML) incorporating chimeric antigen receptors (CAR) and T-cell receptors (TCR) into immune effector cells require in vivo characterization of biological activity, mechanism of action, and preclinical safety. Typically, this characterization involves the assessment of dose-dependent, on-target, on-tumor activity in severely immunocompromised mice. While suitable for the purpose of evaluating T cell-expressed transgene function in a living host, this approach falls short in translating cellular therapy efficacy, safety, and persistence from preclinical models to humans. To comprehensively characterize cell therapy products in mice, we have developed a framework called "DIAL". This framework aims to enable an end-to-end understanding of genetically engineered cellular immunotherapies in vivo, from infusion to tumor clearance and long-term immunosurveillance. The acronym DIAL stands for Distribution, Infiltration, Accumulation, and Longevity, compartmentalizing the systemic attributes of gene-modified cellular therapy and providing a platform for optimization with the ultimate goal of improving therapeutic efficacy. This review will discuss both existent and emerging examples of DIAL characterization in mouse models, as well as opportunities for future development and optimization.
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Affiliation(s)
| | - Gordon Moody
- Cell Therapy Unit, Oncology Research, AstraZeneca, Gaithersburg, MD, United States
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Portillo AL, Monteiro JK, Rojas EA, Ritchie TM, Gillgrass A, Ashkar AA. Charting a killer course to the solid tumor: strategies to recruit and activate NK cells in the tumor microenvironment. Front Immunol 2023; 14:1286750. [PMID: 38022679 PMCID: PMC10663242 DOI: 10.3389/fimmu.2023.1286750] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 10/23/2023] [Indexed: 12/01/2023] Open
Abstract
The ability to expand and activate natural Killer (NK) cells ex vivo has dramatically changed the landscape in the development of novel adoptive cell therapies for treating cancer over the last decade. NK cells have become a key player for cancer immunotherapy due to their innate ability to kill malignant cells while not harming healthy cells, allowing their potential use as an "off-the-shelf" product. Furthermore, recent advancements in NK cell genetic engineering methods have enabled the efficient generation of chimeric antigen receptor (CAR)-expressing NK cells that can exert both CAR-dependent and antigen-independent killing. Clinically, CAR-NK cells have shown promising efficacy and safety for treating CD19-expressing hematologic malignancies. While the number of pre-clinical studies using CAR-NK cells continues to expand, it is evident that solid tumors pose a unique challenge to NK cell-based adoptive cell therapies. Major barriers for efficacy include low NK cell trafficking and infiltration into solid tumor sites, low persistence, and immunosuppression by the harsh solid tumor microenvironment (TME). In this review we discuss the barriers posed by the solid tumor that prevent immune cell trafficking and NK cell effector functions. We then discuss promising strategies to enhance NK cell infiltration into solid tumor sites and activation within the TME. This includes NK cell-intrinsic and -extrinsic mechanisms such as NK cell engineering to resist TME-mediated inhibition and use of tumor-targeted agents such as oncolytic viruses expressing chemoattracting and activating payloads. We then discuss opportunities and challenges for using combination therapies to extend NK cell therapies for the treatment of solid tumors.
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Affiliation(s)
- Ana L. Portillo
- Department of Medicine, McMaster University, Hamilton, ON, Canada
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada
- Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada
| | - Jonathan K. Monteiro
- Department of Medicine, McMaster University, Hamilton, ON, Canada
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada
- Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada
| | - Eduardo A. Rojas
- Department of Medicine, McMaster University, Hamilton, ON, Canada
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada
| | - Tyrah M. Ritchie
- Department of Medicine, McMaster University, Hamilton, ON, Canada
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada
| | - Amy Gillgrass
- Department of Medicine, McMaster University, Hamilton, ON, Canada
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada
- Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada
| | - Ali A. Ashkar
- Department of Medicine, McMaster University, Hamilton, ON, Canada
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada
- Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada
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Thai K, Prat A. CNS therapeutics: Immune cells break the barriers. Sci Transl Med 2023; 15:eadh1150. [PMID: 37939159 DOI: 10.1126/scitranslmed.adh1150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2023]
Abstract
Peripheral immune cells can be seen as attractive vectors and drug carriers for central nervous system therapeutics because these cells have unique properties that allow them to migrate across the blood-brain barrier, enabling drug delivery to brain regions that are inaccessible to free drugs.
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Affiliation(s)
- Karine Thai
- Neuroimmunology Research Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC H2X 0A9, Canada
- Department of Neuroscience, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada
| | - Alexandre Prat
- Neuroimmunology Research Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC H2X 0A9, Canada
- Department of Neuroscience, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada
- Multiple Sclerosis Clinic, Division of Neurology, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC H2L 4M1, Canada
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Li Y, Rezvani K, Rafei H. Next-generation chimeric antigen receptors for T- and natural killer-cell therapies against cancer. Immunol Rev 2023; 320:217-235. [PMID: 37548050 PMCID: PMC10841677 DOI: 10.1111/imr.13255] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 07/12/2023] [Indexed: 08/08/2023]
Abstract
Adoptive cellular therapy using chimeric antigen receptor (CAR) T cells has led to a paradigm shift in the treatment of various hematologic malignancies. However, the broad application of this approach for myeloid malignancies and solid cancers has been limited by the paucity and heterogeneity of target antigen expression, and lack of bona fide tumor-specific antigens that can be targeted without cross-reactivity against normal tissues. This may lead to unwanted on-target off-tumor toxicities that could undermine the desired antitumor effect. Recent advances in synthetic biology and genetic engineering have enabled reprogramming of immune effector cells to enhance their selectivity toward tumors, thus mitigating on-target off-tumor adverse effects. In this review, we outline the current strategies being explored to improve CAR selectivity toward tumor cells with a focus on natural killer (NK) cells, and the progress made in translating these strategies to the clinic.
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Affiliation(s)
- Ye Li
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Katayoun Rezvani
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hind Rafei
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Ge M, Zhu Y, Wei M, Piao H, He M. Improving the efficacy of anti-EGFR drugs in GBM: Where we are going? Biochim Biophys Acta Rev Cancer 2023; 1878:188996. [PMID: 37805108 DOI: 10.1016/j.bbcan.2023.188996] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 09/11/2023] [Accepted: 09/29/2023] [Indexed: 10/09/2023]
Abstract
The therapies targeting mutations of driver genes in cancer have advanced into clinical trials for a variety of tumors. In glioblastoma (GBM), epidermal growth factor receptor (EGFR) is the most commonly mutated oncogene, and targeting EGFR has been widely investigated as a promising direction. However, the results of EGFR pathway inhibitors have not been satisfactory. Limited blood-brain barrier (BBB) permeability, drug resistance, and pathway compensation mechanisms contribute to the failure of anti-EGFR therapies. This review summarizes recent research advances in EGFR-targeted therapy for GBM and provides insight into the reasons for the unsatisfactory results of EGFR-targeted therapy. By combining the results of preclinical studies with those of clinical trials, we discuss that improved drug penetration across the BBB, the use of multi-target combinations, and the development of peptidomimetic drugs under the premise of precision medicine may be promising strategies to overcome drug resistance in GBM.
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Affiliation(s)
- Manxi Ge
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China; Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Shenyang, China
| | - Yan Zhu
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China; Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Shenyang, China
| | - Minjie Wei
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China; Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Shenyang, China; Liaoning Medical Diagnosis and Treatment Center, Shenyang, China.
| | - Haozhe Piao
- Department of Neurosurgery, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Shenyang, China.
| | - Miao He
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China; Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Shenyang, China.
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Allemailem KS, Alsahli MA, Almatroudi A, Alrumaihi F, Al Abdulmonem W, Moawad AA, Alwanian WM, Almansour NM, Rahmani AH, Khan AA. Innovative Strategies of Reprogramming Immune System Cells by Targeting CRISPR/Cas9-Based Genome-Editing Tools: A New Era of Cancer Management. Int J Nanomedicine 2023; 18:5531-5559. [PMID: 37795042 PMCID: PMC10547015 DOI: 10.2147/ijn.s424872] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 09/16/2023] [Indexed: 10/06/2023] Open
Abstract
The recent developments in the study of clustered regularly interspaced short palindromic repeats/associated protein 9 (CRISPR/Cas9) system have revolutionized the art of genome-editing and its applications for cellular differentiation and immune response behavior. This technology has further helped in understanding the mysteries of cancer progression and possible designing of novel antitumor immunotherapies. CRISPR/Cas9-based genome-editing is now often used to engineer universal T-cells, equipped with recombinant T-cell receptor (TCR) or chimeric antigen receptor (CAR). In addition, this technology is used in cytokine stimulation, antibody designing, natural killer (NK) cell transfer, and to overcome immune checkpoints. The innovative potential of CRISPR/Cas9 in preparing the building blocks of adoptive cell transfer (ACT) immunotherapy has opened a new window of antitumor immunotherapy and some of them have gained FDA approval. The manipulation of immunogenetic regulators has opened a new interface for designing, implementation and interpretation of CRISPR/Cas9-based screening in immuno-oncology. Several cancers like lymphoma, melanoma, lung, and liver malignancies have been treated with this strategy, once thought to be impossible. The safe and efficient delivery of CRISPR/Cas9 system within the immune cells for the genome-editing strategy is a challenging task which needs to be sorted out for efficient immunotherapy. Several targeting approaches like virus-mediated, electroporation, microinjection and nanoformulation-based methods have been used, but each procedure offers some limitations. Here, we elaborate the recent updates of cancer management through immunotherapy in partnership with CRISPR/Cas9 technology. Further, some innovative methods of targeting this genome-editing system within the immune system cells for reprogramming them, as a novel strategy of anticancer immunotherapy is elaborated. In addition, future prospects and clinical trials are also discussed.
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Affiliation(s)
- Khaled S Allemailem
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Mohammed A Alsahli
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Ahmad Almatroudi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Faris Alrumaihi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Waleed Al Abdulmonem
- Department of Pathology, College of Medicine, Qassim University, Buraydah, Saudi Arabia
| | - Amira A Moawad
- Friedrich-Loeffler-Institut, Institute of Bacterial Infections and Zoonoses, Jena, Germany
| | - Wanian M Alwanian
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Nahlah Makki Almansour
- Department of Biology, College of Science, University of Hafr Al Batin, Hafr Al Batin, Saudi Arabia
| | - Arshad Husain Rahmani
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Amjad Ali Khan
- Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
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Wang X, Qiu W, Liu H, He M, He W, Li Z, Wu Z, Xu X, Chen P. The inducible secreting TLR5 agonist, CBLB502, enhances the anti-tumor activity of CAR133-NK92 cells in colorectal cancer. Cancer Biol Med 2023; 20:j.issn.2095-3941.2023.0033. [PMID: 37731205 PMCID: PMC10546094 DOI: 10.20892/j.issn.2095-3941.2023.0033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Accepted: 07/17/2023] [Indexed: 09/22/2023] Open
Abstract
OBJECTIVE CAR-T/NK cells have had limited success in the treatment of solid tumors, such as colorectal cancer (CRC), in part because of the heterogeneous nature of tumor-associated antigens that lead to antigen-negative relapse after the initial response. This barrier might be overcome by enhancing the recruitment and durability of endogenous immune cells. METHODS Immunohistochemistry and flow cytometry were used to assess the expression of CD133 antigen in tissue microarrays and cell lines, respectively. Retroviral vector transduction was used to generate CBLB502-secreting CAR133-NK92 cells (CAR133-i502-NK92). The tumor killing capacity of CAR133-NK92 cells in vitro and in vivo were quantified via LDH release, the RTCA assay, and the degranulation test, as well as measuring tumor bioluminescence signal intensity in mice xenografts. RESULTS We engineered CAR133-i502-NK92 cells and demonstrated that those cells displayed enhanced proliferation (9.0 × 104 cells vs. 7.0 × 104 cells) and specific anti-tumor activities in vitro and in a xenogeneic mouse model, and were well-tolerated. Notably, CBLB502 secreted by CAR133-i502-NK92 cells effectively activated endogenous immune cells. Furthermore, in hCD133+/hCD133- mixed cancer xenograft models, CAR133-i502-NK92 cells suppressed cancer growth better than the counterparts (n = 5, P = 0.0297). Greater T-cell infiltration was associated with greater anti-tumor potency (P < 0.0001). CONCLUSIONS Armed with a CBLB502 TLR5 agonist, CAR133-NK92 cells were shown to be capable of specifically eliminating CD133-positive colon cancer cells in a CAR133-dependent manner and indirectly eradicating CD133-negative colon cancer cells in a CBLB502-specific endogenous immune response manner. This study describes a novel technique for optimizing CAR-T/NK cells for the treatment of antigenically-diverse solid tumors.
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Affiliation(s)
- Xiaohui Wang
- College of Biotechnology, Southwest University, Chongqing 400715, China
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Wei Qiu
- Department of Dermatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China
| | - Haoyu Liu
- College of Biotechnology, Southwest University, Chongqing 400715, China
| | - Min He
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Wei He
- College of Biotechnology, Southwest University, Chongqing 400715, China
| | - Zhan Li
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Zhiqiang Wu
- Department of Biotherapeutics, The First Medical Center, Chinese PLA General Hospital, Beijing 100038, China
| | - Xiang Xu
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Ping Chen
- College of Biotechnology, Southwest University, Chongqing 400715, China
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Zhang N, Liu X, Qin J, Sun Y, Xiong H, Lin B, Liu K, Tan B, Zhang C, Huang C, Ren S, Liu M, Du B. LIGHT/TNFSF14 promotes CAR-T cell trafficking and cytotoxicity through reversing immunosuppressive tumor microenvironment. Mol Ther 2023; 31:2575-2590. [PMID: 37408308 PMCID: PMC10491984 DOI: 10.1016/j.ymthe.2023.06.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 03/30/2023] [Accepted: 06/28/2023] [Indexed: 07/07/2023] Open
Abstract
Tertiary lymphoid structures (TLSs) in tumor tissues facilitate immune cell trafficking and cytotoxicity, which benefits survival and favorable responses in immune therapy. Here, we observed a high correlation of tumor necrosis factor superfamily member 14 (LIGHT) expression with TLS signature genes, which are all markers for immune cell accumulation and better prognosis, through retrieving RNA sequencing (RNA-seq) data from patients with cancer, suggesting the potential of LIGHT in reconstituting a high immune-infiltrated tumor microenvironment. Accordingly, LIGHT co-expressed chimeric antigen receptor T (LIGHT CAR-T) cells not only showed enhanced cytotoxicity and cytokine production but also improved CCL19 and CCL21 expression by surrounding cells. And the supernatant of LIGHT CAR-T cells promoted T cell migration in a paracrine manner. Furthermore, LIGHT CAR-T cells showed superior anti-tumor efficacy and improved infiltration in comparison with conventional CAR-T cells in immunodeficient NSG mice. Accordingly, murine LIGHT-OT-1 T cells normalized tumor blood vessels and enforced intratumoral lymphoid structures in C57BL/6 syngeneic tumor mouse models, implying the potential of LIGHT CAR-T in clinical application. Taken together, our data revealed a straightforward strategy to optimize trafficking and cytotoxicity of CAR-T cells by redirecting TLSs through LIGHT expression, which has great potential to expand and optimize the application of CAR-T therapy in solid tumors.
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Affiliation(s)
- Na Zhang
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology and School of Life Sciences, East China Normal University, Shanghai 200241, China; BRL Medicine, Inc, Shanghai 201109, China
| | - Xiaohong Liu
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Juliang Qin
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Yue Sun
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Hao Xiong
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Boxu Lin
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Kexin Liu
- BRL Medicine, Inc, Shanghai 201109, China
| | - Binghe Tan
- BRL Medicine, Inc, Shanghai 201109, China
| | - Chenglin Zhang
- Department of Orthopedics, Shanghai Changzheng Hospital, Shanghai 200003, China
| | - Chenshen Huang
- Department of Gastrointestinal Surgery, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou 350001, China
| | - Shancheng Ren
- Department of Urology, Shanghai Changzheng Hospital, Shanghai 200003, China.
| | - Mingyao Liu
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology and School of Life Sciences, East China Normal University, Shanghai 200241, China.
| | - Bing Du
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology and School of Life Sciences, East China Normal University, Shanghai 200241, China.
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Kiaei SZF, Nouralishahi A, Ghasemirad M, Barkhordar M, Ghaffari S, Kheradjoo H, Saleh M, Mohammadzadehsaliani S, Molaeipour Z. Advances in natural killer cell therapies for breast cancer. Immunol Cell Biol 2023; 101:705-726. [PMID: 37282729 DOI: 10.1111/imcb.12658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/28/2023] [Accepted: 05/06/2023] [Indexed: 06/08/2023]
Abstract
Breast cancer (BC) is the most common cause of cancer death in women. According to the American Cancer Society's yearly cancer statistics, BC constituted almost 15% of all the newly diagnosed cancer cases in 2022 for both sexes. Metastatic disease occurs in 30% of patients with BC. The currently available treatments fail to cure metastatic BC, and the average survival time for patients with metastatic BC is approximately 2 years. Developing a treatment method that terminates cancer stem cells without harming healthy cells is the primary objective of novel therapeutics. Adoptive cell therapy is a branch of cancer immunotherapy that utilizes the immune cells to attack cancer cells. Natural killer (NK) cells are an essential component of innate immunity and are critical in destroying tumor cells without prior stimulation with antigens. With the advent of chimeric antigen receptors (CARs), the autologous or allogeneic use of NK/CAR-NK cell therapy has raised new hopes for treating patients with cancer. Here, we describe recent developments in NK and CAR-NK cell immunotherapy, including the biology and function of NK cells, clinical trials, different sources of NK cells and their future perspectives on BC.
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Affiliation(s)
- Seyedeh Zahra Fotook Kiaei
- Department of Pulmonary and Critical Care, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Mohammad Ghasemirad
- Department of Periodontics, Faculty of Dentistry, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Maryam Barkhordar
- Hematology, Oncology and Stem Cell Transplantation Research Center (HORCSCT), Tehran University of Medical Sciences, Tehran, Iran
| | - Sasan Ghaffari
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | | | - Mahshid Saleh
- Wisconsin National Primate Research Center, University of Wisconsin Graduate School, Madison, WI, USA
| | | | - Zahra Molaeipour
- Hematology Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Lin X, Sun Y, Dong X, Liu Z, Sugimura R, Xie G. IPSC-derived CAR-NK cells for cancer immunotherapy. Biomed Pharmacother 2023; 165:115123. [PMID: 37406511 DOI: 10.1016/j.biopha.2023.115123] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 06/24/2023] [Accepted: 07/02/2023] [Indexed: 07/07/2023] Open
Abstract
Adoptive cell therapies (ACT) based on chimeric antigen receptor (CAR)-modified immune cells have made great progress with six CAR-T cell products approved by the U.S. FDA for hematological malignancies. Compared with CAR-T cells, CAR-NK cells have attracted increasing attention owing to their multiple killing mechanisms, higher safety profile, and broad sources. Induced pluripotent stem cell (iPSC)-derived NK (iPSC-NK) cells possess a mature phenotype and potent cytolytic activity, and can provide a homogeneous population of CAR-NK cells that can be expanded to clinical scale. Thus, iPSC-derived CAR-NK (CAR-iNK) cells could be used as a standardized and "off-the-shelf" product for cancer immunotherapy. In this review, we summarize the current status of the manufacturing techniques, genetic modification strategies, preclinical and clinical evidence of CAR-iNK cells, and discuss the challenges and future prospects of CAR-iNK cell therapy as a novel cellular immunotherapy in cancer.
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Affiliation(s)
- Xiaotong Lin
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Yao Sun
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Xin Dong
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Zishen Liu
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Ryohichi Sugimura
- Centre for Translational Stem Cell Biology, School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region of China.
| | - Guozhu Xie
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China.
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50
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Zhang Y, Zhou W, Yang J, Yang J, Wang W. Chimeric antigen receptor engineered natural killer cells for cancer therapy. Exp Hematol Oncol 2023; 12:70. [PMID: 37563648 PMCID: PMC10413722 DOI: 10.1186/s40164-023-00431-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 07/27/2023] [Indexed: 08/12/2023] Open
Abstract
Natural killer (NK) cells, a unique component of the innate immune system, are inherent killers of stressed and transformed cells. Based on their potent capacity to kill cancer cells and good tolerance of healthy cells, NK cells have been successfully employed in adoptive cell therapy to treat cancer patients. In recent years, the clinical success of chimeric antigen receptor (CAR)-T cells has proven the vast potential of gene-manipulated immune cells as the main force to fight cancer. Following the lessons learned from mature gene-transfer technologies and advanced strategies in CAR-T therapy, NK cells have been rapidly explored as a promising candidate for CAR-based therapy. An exponentially growing number of studies have employed multiple sources of CAR-NK cells to target a wide range of cancer-related antigens, showing remarkable outcomes and encouraging safety profiles. Clinical trials of CAR-NK cells have also shown their impressive therapeutic efficacy in the treatment of hematological tumors, but CAR-NK cell therapy for solid tumors is still in the initial stages. In this review, we present the favorable profile of NK cells as a potential platform for CAR-based engineering and then summarize the outcomes and strategies of CAR-NK therapies in up-to-date preclinical and clinical investigations. Finally, we evaluate the challenges remaining in CAR-NK therapy and describe existing strategies that can assist us in devising future prospective solutions.
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Affiliation(s)
- Yalan Zhang
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Weilin Zhou
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Jiangping Yang
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, 610041, People's Republic of China
- Department of Head and Neck Oncology and Department of Radiation Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China
| | - Jinrong Yang
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, 610041, People's Republic of China
- Hematology Research Laboratory, Department of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China
| | - Wei Wang
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, 610041, People's Republic of China.
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