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Guo R, Wang P. Tumor-derived extracellular vesicles: Hijacking T cell function through exhaustion. Pathol Res Pract 2025; 269:155948. [PMID: 40168777 DOI: 10.1016/j.prp.2025.155948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 03/17/2025] [Accepted: 03/26/2025] [Indexed: 04/03/2025]
Abstract
Extracellular vesicles (EVs) play a vital role in intercellular communication within the tumor microenvironment (TME). These vesicles, secreted by tumor cells, contain proteins, lipids, and nucleic acids that significantly influence immune responses, particularly impacting T-cell function. In cancer, T cell dysfunction and exhaustion-marked by reduced proliferation, diminished cytokine production, and impaired cytotoxic activity-are key barriers to effective immune responses. Tumor-derived extracellular vesicles (TEVs) contribute to this dysfunction by carrying immunosuppressive molecules, such as transforming growth factor-beta (TGF-β) and various microRNAs (miRNAs). These TEV-mediated mechanisms promote T cell exhaustion and foster a broader immunosuppressive environment, enabling tumor progression and immune evasion. Furthermore, TEVs have been implicated in resistance to cancer immunotherapies, including immune checkpoint inhibitors and T cell therapies. Understanding the molecular pathways and cargoes within TEVs that drive T cell dysfunction is crucial for developing novel therapeutic strategies aimed at reinvigorating exhausted T cells, enhancing anti-tumor immunity, and improving cancer treatment outcomes.
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Affiliation(s)
- RuiJuan Guo
- Department of Oncology, Yantaishan Hospital Affiliated to Binzhou Medical University, Yantai, Shandong 264003, China
| | - Ping Wang
- Department of Oncology, Yantaishan Hospital Affiliated to Binzhou Medical University, Yantai, Shandong 264003, China.
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Liu X, To KK, Zeng Q, Fu L. Effect of Extracellular Vesicles Derived From Tumor Cells on Immune Evasion. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2417357. [PMID: 39899680 PMCID: PMC11948033 DOI: 10.1002/advs.202417357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Indexed: 02/05/2025]
Abstract
The crosstalk between immunity and cancer in the regulation of tumor growth is considered a hallmark of cancer. Antitumor immunity refers to the innate and adaptive immune responses that regulate cancer development and proliferation. Tumor immune evasion represents a major hindrance to effective anticancer treatment. Extracellular vesicles (EVs) are nano-sized and lipid-bilayer-enclosed particles that are secreted to the extracellular space by all cell types. They are critically involved in numerous biological functions including intercellular communication. Tumor-derived extracellular vesicles (TEVs) can transport a variety of cargo to modulate immune cells in the tumor microenvironment (TME). This review provides the latest update about how tumor cells evade immune surveillance by exploiting TEVs. First, the biogenesis of EVs and the cargo-sorting machinery are discussed. Second, how tumor cells modulate immune cell differentiation, activation, and function via TEVs to evade immune surveillance is illustrated. Last but not least, the novel antitumor strategies that can reverse immune escape are summarized.
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Affiliation(s)
- Xuanfan Liu
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerCollaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteSun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
- Department of UrologyThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhou510080P. R. China
| | - Kenneth K.W. To
- School of PharmacyThe Chinese University of Hong KongHong Kong999077P. R. China
| | - Qinsong Zeng
- Department of UrologyThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhou510080P. R. China
- Guangxi Hospital Division of The First Affiliated HospitalSun Yat‐sen UniversityNanning530025P. R. China
| | - Liwu Fu
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerCollaborative Innovation Center for Cancer MedicineGuangdong Esophageal Cancer InstituteSun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
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Grunewald L, Andersch L, Helmsauer K, Schwiebert S, Klaus A, Henssen AG, Straka T, Lodrini M, Wicha SG, Fuchs S, Hertwig F, Westermann F, Vitali A, Caramel C, Büchel G, Eilers M, Astrahantseff K, Eggert A, Höpken UE, Schulte JH, Blankenstein T, Anders K, Künkele A. Targeting MYCN upregulates L1CAM tumor antigen in MYCN-dysregulated neuroblastoma to increase CAR T cell efficacy. Pharmacol Res 2025; 212:107608. [PMID: 39828101 DOI: 10.1016/j.phrs.2025.107608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Revised: 12/18/2024] [Accepted: 01/14/2025] [Indexed: 01/22/2025]
Abstract
Current treatment protocols have limited success against MYCN-amplified neuroblastoma. Adoptive T cell therapy presents an innovative strategy to improve cure rates. However, L1CAM-targeting CAR T cells achieved only limited response against refractory/relapsed neuroblastoma so far. We investigated how oncogenic MYCN levels influence tumor cell response to CAR T cells, as one possible factor limiting clinical success. A MYCN-inducible neuroblastoma cell model was created. L1CAM-CAR T cell effector function was assessed (activation markers, cytokine release, tumor cytotoxicity) after coculture with the model or MYCN-amplified neuroblastoma cell lines. RNA sequencing datasets characterizing the model were compared to publicly available RNA/proteomic datasets. MYCN-directed L1CAM regulation was explored using public ChIP-sequencing datasets. Synergism between CAR T cells and the indirect MYCN inhibitor, MLN8237, was assessed in vitro using the Bliss model and in vivo in an immunocompromised mouse model. Inducing high MYCN levels in the neuroblastoma cell model reduced L1CAM expression and, consequently, L1CAM-CAR T cell effector function in vitro. Primary neuroblastomas possessing high MYCN levels expressed lower levels of both the L1CAM transcript and L1CAM tumor antigen. MLN8237 treatment restored L1CAM tumor expression and L1CAM-CAR T cell effector function. Combining MLN8237 and L1CAM-CAR T cell treatment synergistically enhanced MYCN-overexpressing tumor cytotoxicity in vitro and in vivo concomitant with severe in vivo toxicity. We identify target antigen downregulation as source of resistance against L1CAM-CAR T cells in MYCN-driven neuroblastoma cells. These data suggest that L1CAM-CAR T cell therapy combined with pharmacological MYCN inhibition may benefit patients with MYCN-amplified neuroblastoma.
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Affiliation(s)
- Laura Grunewald
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Oncology and Hematology, Augustenburger Platz 1, Berlin 13353, Germany; German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
| | - Lena Andersch
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Oncology and Hematology, Augustenburger Platz 1, Berlin 13353, Germany; German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany; Freie Universität Berlin, Kaiserswerther Str. 16-18, Berlin 14195, Germany
| | - Konstantin Helmsauer
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Oncology and Hematology, Augustenburger Platz 1, Berlin 13353, Germany; Neuroblastoma Research Group, Experimental and Clinical Research Center (ECRC) of the Charité and the Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, Lindenberger Weg 80, Berlin 13125, Germany
| | - Silke Schwiebert
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Oncology and Hematology, Augustenburger Platz 1, Berlin 13353, Germany
| | - Anika Klaus
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Oncology and Hematology, Augustenburger Platz 1, Berlin 13353, Germany
| | - Anton G Henssen
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Oncology and Hematology, Augustenburger Platz 1, Berlin 13353, Germany; Neuroblastoma Research Group, Experimental and Clinical Research Center (ECRC) of the Charité and the Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, Lindenberger Weg 80, Berlin 13125, Germany
| | - Teresa Straka
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Oncology and Hematology, Augustenburger Platz 1, Berlin 13353, Germany
| | - Marco Lodrini
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Oncology and Hematology, Augustenburger Platz 1, Berlin 13353, Germany
| | - Sebastian G Wicha
- Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Bundesstrasse 45, Hamburg 20146, Germany
| | - Steffen Fuchs
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Oncology and Hematology, Augustenburger Platz 1, Berlin 13353, Germany; German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany; German Cancer Consortium (DKTK), Partner Site Berlin, Virchowweg 23, Berlin 10117, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Anna-Louisa-Karsch-Strasse 2, Berlin 10178, Germany
| | - Falk Hertwig
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Oncology and Hematology, Augustenburger Platz 1, Berlin 13353, Germany
| | - Frank Westermann
- German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
| | - Alice Vitali
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Oncology and Hematology, Augustenburger Platz 1, Berlin 13353, Germany
| | - Carlotta Caramel
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Oncology and Hematology, Augustenburger Platz 1, Berlin 13353, Germany
| | - Gabriele Büchel
- Department of Biochemistry and Molecular Biology, Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, Würzburg 97074, Germany; Mildred Scheel Early Career Center, University Hospital Würzburg, Josef-Schneider-Str. 6, Würzburg 97080, Germany
| | - Martin Eilers
- Department of Biochemistry and Molecular Biology, Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, Würzburg 97074, Germany
| | - Kathy Astrahantseff
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Oncology and Hematology, Augustenburger Platz 1, Berlin 13353, Germany
| | - Angelika Eggert
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Oncology and Hematology, Augustenburger Platz 1, Berlin 13353, Germany; German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany; German Cancer Consortium (DKTK), Partner Site Berlin, Virchowweg 23, Berlin 10117, Germany
| | - Uta E Höpken
- Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, Robert-Rössle Str. 10, Berlin 13125, Germany
| | - Johannes H Schulte
- Universitätsklinik für Kinder, und Jugendmedizin, Department of Pediatric Hematology and Oncology, Hoppe-Seyler-Straße 1, Tübingen 72076, Germany
| | - Thomas Blankenstein
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Oncology and Hematology, Augustenburger Platz 1, Berlin 13353, Germany; Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, Robert-Rössle Str. 10, Berlin 13125, Germany
| | - Kathleen Anders
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Oncology and Hematology, Augustenburger Platz 1, Berlin 13353, Germany
| | - Annette Künkele
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Oncology and Hematology, Augustenburger Platz 1, Berlin 13353, Germany; German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany; German Cancer Consortium (DKTK), Partner Site Berlin, Virchowweg 23, Berlin 10117, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Anna-Louisa-Karsch-Strasse 2, Berlin 10178, Germany.
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Oliveira I, Rodrigues-Santos P, Ferreira L, Pires das Neves R. Synthetic and biological nanoparticles for cancer immunotherapy. Biomater Sci 2024; 12:5933-5960. [PMID: 39441658 DOI: 10.1039/d4bm00995a] [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: 10/25/2024]
Abstract
Cancer is becoming the main public health problem globally. Conventional chemotherapy approaches are slowly being replaced or complemented by new therapies that avoid the loss of healthy tissue, limit off-targets, and eradicate cancer cells. Immunotherapy is nowadays an important strategy for cancer treatment, that uses the host's anti-tumor response by activating the immune system and increasing the effector cell number, while, minimizing cancer's immune-suppressor mechanisms. Its efficacy is still limited by poor therapeutic targeting, low immunogenicity, antigen presentation deficiency, impaired T-cell trafficking and infiltration, heterogeneous microenvironment, multiple immune checkpoints and unwanted side effects, which could benefit from improved delivery systems, able to release immunotherapeutic agents to tumor microenvironment and immune cells. Nanoparticles (NPs) for immunotherapy (Nano-IT), have a huge potential to solve these limitations. Natural and/or synthetic, targeted and/or stimuli-responsive nanoparticles can be used to deliver immunotherapeutic agents in their native conformations to the site of interest to enhance their antitumor activity. They can also be used as co-adjuvants that enhance the activity of IT effector cells. These nanoparticles can be engineered in the natural context of cell-derived extracellular vesicles (EVs) or exosomes or can be fully synthetic. In this review, a detailed SWOT analysis is done through the comparison of engineered-synthetic and naturaly-derived nanoparticles in terms of their current and future use in cancer immunotherapy.
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Affiliation(s)
- Inês Oliveira
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-504 Coimbra, Portugal.
| | - Paulo Rodrigues-Santos
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-504 Coimbra, Portugal.
- Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504 Coimbra, Portugal
- Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Lino Ferreira
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-504 Coimbra, Portugal.
- Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504 Coimbra, Portugal
- Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Ricardo Pires das Neves
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-504 Coimbra, Portugal.
- Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504 Coimbra, Portugal
- IIIUC-Institute of Interdisciplinary Research, University of Coimbra, 3004-517 Coimbra, Portugal
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Zhang SH, Peng LL, Chen YF, Xu Y, Moradi V. Focusing on exosomes to overcome the existing bottlenecks of CAR-T cell therapy. Inflamm Regen 2024; 44:45. [PMID: 39490997 PMCID: PMC11533312 DOI: 10.1186/s41232-024-00358-x] [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: 07/15/2024] [Accepted: 10/22/2024] [Indexed: 11/05/2024] Open
Abstract
Since chimeric antigen receptor T (CAR-T) cells were introduced three decades ago, the treatment using these cells has led to outstanding outcomes, and at the moment, CAR-T cell therapy is a well-established mainstay for treating CD19 + malignancies and multiple myeloma. Despite the astonishing results of CAR-T cell therapy in B-cell-derived malignancies, several bottlenecks must be overcome to promote its safety and efficacy and broaden its applicability. These bottlenecks include cumbersome production process, safety concerns of viral vectors, poor efficacy in treating solid tumors, life-threatening side effects, and dysfunctionality of infused CAR-T cells over time. Exosomes are nano-sized vesicles that are secreted by all living cells and play an essential role in cellular crosstalk by bridging between cells. In this review, we discuss how the existing bottlenecks of CAR-T cell therapy can be overcome by focusing on exosomes. First, we delve into the effect of tumor-derived exosomes on the CAR-T cell function and discuss how inhibiting their secretion can enhance the efficacy of CAR-T cell therapy. Afterward, the application of exosomes to the manufacturing of CAR-T cells in a non-viral approach is discussed. We also review the latest advancements in ex vivo activation and cultivation of CAR-T cells using exosomes, as well as the potential of engineered exosomes to in vivo induction or boost the in vivo proliferation of CAR-T cells. Finally, we discuss how CAR-engineered exosomes can be used as a versatile tool for the direct killing of tumor cells or delivering intended therapeutic payloads in a targeted manner.
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Affiliation(s)
- Si-Heng Zhang
- Faculty of Medicine, Macau University of Science and Technology, Taipa, Macao SAR, 999078, China
- Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, Zhejiang, 310000, China
| | - Ling-Long Peng
- Wuhu Hospital, East China Normal University (The Second People's Hospital of Wuhu), Wuhu, 241000, China
| | - Yi-Fei Chen
- Faculty of Medicine, Macau University of Science and Technology, Taipa, Macao SAR, 999078, China
| | - Yan Xu
- Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, Zhejiang, 310000, China.
| | - Vahid Moradi
- Hematology and Bood Transfusion Science Department, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran.
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Batista IA, Machado JC, Melo SA. Advances in exosomes utilization for clinical applications in cancer. Trends Cancer 2024; 10:947-968. [PMID: 39168775 DOI: 10.1016/j.trecan.2024.07.010] [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: 03/28/2024] [Revised: 07/04/2024] [Accepted: 07/25/2024] [Indexed: 08/23/2024]
Abstract
Exosomes are regarded as having transformative potential for clinical applications. Exosome-based liquid biopsies offer a noninvasive method for early cancer detection and real-time disease monitoring. Clinical trials are underway to validate the efficacy of exosomal biomarkers for enhancing diagnostic accuracy and predicting treatment responses. Additionally, engineered exosomes are being developed as targeted drug delivery systems that can navigate the bloodstream to deliver therapeutic agents to tumor sites, thus enhancing treatment efficacy while minimizing systemic toxicity. Exosomes also exhibit immunomodulatory properties, which are being harnessed to boost antitumor immune responses. In this review, we detail the latest advances in clinical trials and research studies, underscoring the potential of exosomes to revolutionize cancer care.
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Affiliation(s)
- Inês A Batista
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, Porto, Portugal
| | - José C Machado
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Departamento de Patologia, Faculdade de Medicina, Universidade do Porto, Porto, Portugal; P.CCC Porto Comprehensive Cancer Centre, Raquel Seruca, Portugal
| | - Sonia A Melo
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Departamento de Patologia, Faculdade de Medicina, Universidade do Porto, Porto, Portugal; P.CCC Porto Comprehensive Cancer Centre, Raquel Seruca, Portugal.
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Aghakhani A, Pezeshki PS, Rezaei N. The role of extracellular vesicles in immune cell exhaustion and resistance to immunotherapy. Expert Opin Investig Drugs 2024; 33:721-740. [PMID: 38795060 DOI: 10.1080/13543784.2024.2360209] [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: 11/17/2023] [Accepted: 05/22/2024] [Indexed: 05/27/2024]
Abstract
INTRODUCTION Extracellular vesicles (EVs) are membrane-bound nanoparticles for intercellular communication. Subtypes of EVs, namely exosomes and microvesicles transfer diverse, bioactive cargo to their target cells and eventually interfere with immune responses. Despite being a promising approach, cancer immunotherapy currently faces several challenges including immune resistance. EVs secreted from various sources in the tumor microenvironment provoke immune cell exhaustion and lower the efficacy of immunological treatments, such as CAR T cells and immune checkpoint inhibitors. AREAS COVERED This article goes through the mechanisms of action of various types of EVs in inhibiting immune response and immunotherapies, and provides a comprehensive review of EV-based treatments. EXPERT OPINION By making use of the distinctive features of EVs, natural or modified EVs are innovatively utilized as novel cancer therapeutics. They are occasionally coupled with currently established treatments to overcome their inadequacies. Investigating the properties and interactions of EVs and EV-based treatments is crucial for determining future steps in cancer therapeutics.
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Affiliation(s)
- Ava Aghakhani
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- International Hematology/Oncology of Pediatrics Experts (IHOPE), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Parmida Sadat Pezeshki
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- International Hematology/Oncology of Pediatrics Experts (IHOPE), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Dhamdhere MR, Spiegelman VS. Extracellular vesicles in neuroblastoma: role in progression, resistance to therapy and diagnostics. Front Immunol 2024; 15:1385875. [PMID: 38660306 PMCID: PMC11041043 DOI: 10.3389/fimmu.2024.1385875] [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: 02/13/2024] [Accepted: 03/22/2024] [Indexed: 04/26/2024] Open
Abstract
Neuroblastoma (NB) is the most common extracranial solid pediatric cancer, and is one of the leading causes of cancer-related deaths in children. Despite the current multi-modal treatment regimens, majority of patients with advanced-stage NBs develop therapeutic resistance and relapse, leading to poor disease outcomes. There is a large body of knowledge on pathophysiological role of small extracellular vesicles (EVs) in progression and metastasis of multiple cancer types, however, the importance of EVs in NB was until recently not well understood. Studies emerging in the last few years have demonstrated the involvement of EVs in various aspects of NB pathogenesis. In this review we summarize these recent findings and advances on the role EVs play in NB progression, such as tumor growth, metastasis and therapeutic resistance, that could be helpful for future investigations in NB EV research. We also discuss different strategies for therapeutic targeting of NB-EVs as well as utilization of NB-EVs as potential biomarkers.
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Affiliation(s)
| | - Vladimir S. Spiegelman
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, PA, United States
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Aishvarya Rukmani P, Shanmugam R, Manigandan P. Anti-Inflammatory Effect of Herbal Mouthwash Prepared Using Andrographis Paniculata and Rosa Formulation. JOURNAL OF PHARMACY AND BIOALLIED SCIENCES 2024; 16:S1345-S1349. [PMID: 38882775 PMCID: PMC11174168 DOI: 10.4103/jpbs.jpbs_581_23] [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: 08/12/2023] [Revised: 10/15/2023] [Accepted: 11/17/2023] [Indexed: 06/18/2024] Open
Abstract
Andrographis (A.) paniculata contains andrograpanin, which is both anti-inflammatory and anti-infective. Rosa comprises over 150-200 species from the family Rosaceae. Rosa exerts various properties, including anti-inflammatory property. Herbal mouthwash was made using A. paniculata leaf powder and Rosa extract. The anti-inflammatory effect was evaluated using an albumin denaturation assay and egg albumin denaturation. The percentage of protein denaturation that is inhibited by the formulation of A. paniculata and Rosa indicates that it has strong anti-inflammatory effect. According to the findings, as concentration is raised, the formulation's anti-inflammatory activity rises. The formulation's percentage inhibition values are also equivalent to those of a typical anti-inflammatory medicine, indicating that it may be effective as a natural anti-inflammatory agent.
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Affiliation(s)
- P Aishvarya Rukmani
- Nanobiomedicine Lab, Centre for Global Health Research, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India
| | - Rajeshkumar Shanmugam
- Nanobiomedicine Lab, Centre for Global Health Research, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India
| | - Pradeep Manigandan
- Nanobiomedicine Lab, Centre for Global Health Research, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India
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10
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Hao Y, Chen P, Guo S, Li M, Jin X, Zhang M, Deng W, Li P, Lei W, Liang A, Qian W. Tumor-derived exosomes induce initial activation by exosomal CD19 antigen but impair the function of CD19-specific CAR T-cells via TGF-β signaling. Front Med 2024; 18:128-146. [PMID: 37870681 DOI: 10.1007/s11684-023-1010-1] [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: 11/29/2022] [Accepted: 05/19/2023] [Indexed: 10/24/2023]
Abstract
Tumor-derived exosomes (TEXs) enriched in immune suppressive molecules predominantly drive T-cell dysfunction and impair antitumor immunity. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment for refractory and relapsed hematological malignancies, but whether lymphoma TEXs have the same impact on CAR T-cell remains unclear. Here, we demonstrated that B-cell lymphoma-derived exosomes induce the initial activation of CD19-CAR T-cells upon stimulation with exosomal CD19. However, lymphoma TEXs might subsequently induce CAR T-cell apoptosis and impair the tumor cytotoxicity of the cells because of the upregulated expression of the inhibitory receptors PD-1, TIM3, and LAG3 upon prolonged exposure. Similar results were observed in the CAR T-cells exposed to plasma exosomes from patients with lymphoma. More importantly, single-cell RNA sequencing revealed that CAR T-cells typically showed differentiated phenotypes and regulatory T-cell (Treg) phenotype conversion. By blocking transforming growth factor β (TGF-β)-Smad3 signaling with TGF-β inhibitor LY2109761, the negative effects of TEXs on Treg conversion, terminal differentiation, and immune checkpoint expression were rescued. Collectively, although TEXs lead to the initial activation of CAR T-cells, the effect of TEXs suppressed CAR T-cells, which can be rescued by LY2109761. A treatment regimen combining CAR T-cell therapy and TGF-β inhibitors might be a novel therapeutic strategy for refractory and relapsed B-cell lymphoma.
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Affiliation(s)
- Yuanyuan Hao
- Department of Hematology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310009, China
- Department of Hematology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, 450003, China
| | - Panpan Chen
- Department of Hematology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310009, China
| | - Shanshan Guo
- Department of Hematology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310009, China
| | - Mengyuan Li
- Department of Hematology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310009, China
| | - Xueli Jin
- Department of Hematology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310009, China
| | - Minghuan Zhang
- Department of Hematology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310009, China
| | - Wenhai Deng
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325000, China
| | - Ping Li
- Department of Hematology, Tongji Hospital of Tongji University, Shanghai, 200065, China
| | - Wen Lei
- Department of Hematology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310009, China.
| | - Aibin Liang
- Department of Hematology, Tongji Hospital of Tongji University, Shanghai, 200065, China.
| | - Wenbin Qian
- Department of Hematology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310009, China.
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11
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Lyu C, Sun H, Sun Z, Liu Y, Wang Q. Roles of exosomes in immunotherapy for solid cancers. Cell Death Dis 2024; 15:106. [PMID: 38302430 PMCID: PMC10834551 DOI: 10.1038/s41419-024-06494-z] [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: 09/14/2023] [Revised: 01/18/2024] [Accepted: 01/23/2024] [Indexed: 02/03/2024]
Abstract
Although immunotherapy has made breakthrough progress, its efficacy in solid tumours remains unsatisfactory. Exosomes are the main type of extracellular vesicles that can deliver various intracellular molecules to adjacent or distant cells and organs, mediating various biological functions. Studies have found that exosomes can both activate the immune system and inhibit the immune system. The antigen and major histocompatibility complex (MHC) carried in exosomes make it possible to develop them as anticancer vaccines. Exosomes derived from blood, urine, saliva and cerebrospinal fluid can be used as ideal biomarkers in cancer diagnosis and prognosis. In recent years, exosome-based therapy has made great progress in the fields of drug transportation and immunotherapy. Here, we review the composition and sources of exosomes in the solid cancer immune microenvironment and further elaborate on the potential mechanisms and pathways by which exosomes influence immunotherapy for solid cancers. Moreover, we summarize the potential clinical application prospects of engineered exosomes and exosome vaccines in immunotherapy for solid cancers. Eventually, these findings may open up avenues for determining the potential of exosomes for diagnosis, treatment, and prognosis in solid cancer immunotherapy.
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Affiliation(s)
- Cong Lyu
- Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
- Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Haifeng Sun
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Zhenqiang Sun
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
| | - Yang Liu
- Department of Radiotherapy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China.
| | - Qiming Wang
- Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China.
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12
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Noraldeen SAM, Rasulova I, Lalitha R, Hussin F, Alsaab HO, Alawadi AH, Alsaalamy A, Sayyid NH, Alkhafaji AT, Mustafa YF, Shayan SK. Involving stemness factors to improve CAR T-cell-based cancer immunotherapy. Med Oncol 2023; 40:313. [PMID: 37779152 DOI: 10.1007/s12032-023-02191-7] [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: 08/14/2023] [Accepted: 09/09/2023] [Indexed: 10/03/2023]
Abstract
Treatment with chimeric antigen receptor (CAR) T cells indicated remarkable clinical responses with liquid cancers such as hematological malignancies; however, their therapeutic efficacy faced with many challenges in solid tumors due to severe toxicities, antigen evasion, restricted and limited tumor tissue trafficking and infiltration, and, more importantly, immunosuppressive tumor microenvironment (TME) factors that impair the CAR T-cell function adds support survival of cancer stem cells (CSCs), responsible for tumor recurrence and resistance to current cancer therapies. Therefore, in-depth identification of TME and development of more potent CAR platform targeting CSCs may overcome the raised challenges, as presented in this review. We also discuss recent stemness-based innovations in CAR T-cell production and engineering to improve their efficacy in vivo, and finally, we propose solutions and strategies such as oncolytic virus-based therapy and combination therapy to revive the function of CAR T-cell therapy, especially in TME of solid tumors in future.
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Affiliation(s)
| | - Irodakhon Rasulova
- School of Humanities, Natural & Social Sciences, New Uzbekistan University, 54 Mustaqillik Ave., 100007, Tashkent, Uzbekistan
| | - Repudi Lalitha
- Department of Pharmaceutical Analysis, Chaitanya Deemed to be University, Hyderabad, Telangana, India.
| | - Farah Hussin
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | - Hashem O Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, Taif University, 21944, Taif, Saudi Arabia
| | - Ahmed Hussien Alawadi
- College of Technical Engineering, The Islamic University, Najaf, Iraq
- College of Technical Engineering, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- College of Technical Engineering, The Islamic University of Babylon, Babylon, Iraq
| | - Ali Alsaalamy
- College of Technical Engineering, Imam Ja'afar Al-Sadiq University, Al-Muthanna, 66002, Iraq
| | - Nidhal Hassan Sayyid
- College of Nursing, National University of Science and Technology, Dhi Qar, Iraq
| | | | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Sepideh Karkon Shayan
- Student Research Committee, School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran.
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13
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Proestler E, Donzelli J, Nevermann S, Breitwieser K, Koch LF, Best T, Fauth M, Wickström M, Harter PN, Kogner P, Lavieu G, Larsson K, Saul MJ. The multiple functions of miR-574-5p in the neuroblastoma tumor microenvironment. Front Pharmacol 2023; 14:1183720. [PMID: 37731742 PMCID: PMC10507178 DOI: 10.3389/fphar.2023.1183720] [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: 03/10/2023] [Accepted: 08/07/2023] [Indexed: 09/22/2023] Open
Abstract
Neuroblastoma is the most common extracranial solid tumor in childhood and arises from neural crest cells of the developing sympathetic nervous system. Prostaglandin E2 (PGE2) has been identified as a key pro-inflammatory mediator of the tumor microenvironment (TME) that promotes neuroblastoma progression. We report that the interaction between the microRNA miR-574-5p and CUG-binding protein 1 (CUGBP1) induces the expression of microsomal prostaglandin E2 synthase 1 (mPGES-1) in neuroblastoma cells, which contributes to PGE2 biosynthesis. PGE2 in turn specifically induces the sorting of miR-574-5p into small extracellular vesicles (sEV) in neuroblastoma cell lines. sEV are one of the major players in intercellular communication in the TME. We found that sEV-derived miR-574-5p has a paracrine function in neuroblastoma. It acts as a direct Toll-like receptor 7/8 (TLR7/8) ligand and induces α-smooth muscle actin (α-SMA) expression in fibroblasts, contributing to fibroblast differentiation. This is particularly noteworthy as it has an opposite function to that in the TME of lung carcinoma, another PGE2 dependent tumor type. Here, sEV-derived miR-574-5p has an autokrine function that inhibits PGE2 biosynthesis in lung cancer cells. We report that the tetraspanin composition on the surface of sEV is associated with the function of sEV-derived miR-574-5p. This suggests that the vesicles do not only transport miRs, but also appear to influence their mode of action.
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Affiliation(s)
- Eva Proestler
- Fachbereich Biologie, Technische Universität Darmstadt, Darmstadt, Germany
| | - Julia Donzelli
- Fachbereich Biologie, Technische Universität Darmstadt, Darmstadt, Germany
| | - Sheila Nevermann
- Fachbereich Biologie, Technische Universität Darmstadt, Darmstadt, Germany
| | - Kai Breitwieser
- Fachbereich Biologie, Technische Universität Darmstadt, Darmstadt, Germany
| | - Leon F. Koch
- Fachbereich Biologie, Technische Universität Darmstadt, Darmstadt, Germany
| | - Tatjana Best
- Fachbereich Biologie, Technische Universität Darmstadt, Darmstadt, Germany
- Merck KGaA, Darmstadt, Germany
| | - Maria Fauth
- Fachbereich Biologie, Technische Universität Darmstadt, Darmstadt, Germany
- Prolytic GmbH, a Kymos Company, Frankfurt, Germany
| | - Malin Wickström
- Childhood Cancer Research Unit, Department of Children’s and Women’s Health, Karolinska Institutet, Stockholm, Sweden
| | - Patrick N. Harter
- Institute of Neurology (Edinger-Institute), University Hospital Frankfurt, Goethe University, Frankfurt am Main, Frankfurt, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- Frankfurt Cancer Institute (FCI), Frankfurt am Main, Frankfurt, Germany
| | - Per Kogner
- Childhood Cancer Research Unit, Department of Children’s and Women’s Health, Karolinska Institutet, Stockholm, Sweden
| | - Grégory Lavieu
- INSERM U1316, UMR7057, Centre National de la Recherche Scientifique (CNRS), Université Paris Cité, Paris, France
| | - Karin Larsson
- Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Meike J. Saul
- Fachbereich Biologie, Technische Universität Darmstadt, Darmstadt, Germany
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14
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Zhong W, Xiao Z, Qin Z, Yang J, Wen Y, Yu Z, Li Y, Sheppard NC, Fuchs SY, Xu X, Herlyn M, June CH, Puré E, Guo W. Tumor-Derived Small Extracellular Vesicles Inhibit the Efficacy of CAR T Cells against Solid Tumors. Cancer Res 2023; 83:2790-2806. [PMID: 37115855 PMCID: PMC10524031 DOI: 10.1158/0008-5472.can-22-2220] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 12/22/2022] [Accepted: 04/25/2023] [Indexed: 04/29/2023]
Abstract
Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable success in the treatment of hematologic malignancies. Unfortunately, it has limited efficacy against solid tumors, even when the targeted antigens are well expressed. A better understanding of the underlying mechanisms of CAR T-cell therapy resistance in solid tumors is necessary to develop strategies to improve efficacy. Here we report that solid tumors release small extracellular vesicles (sEV) that carry both targeted tumor antigens and the immune checkpoint protein PD-L1. These sEVs acted as cell-free functional units to preferentially interact with cognate CAR T cells and efficiently inhibited their proliferation, migration, and function. In syngeneic mouse tumor models, blocking tumor sEV secretion not only boosted the infiltration and antitumor activity of CAR T cells but also improved endogenous antitumor immunity. These results suggest that solid tumors use sEVs as an active defense mechanism to resist CAR T cells and implicate tumor sEVs as a potential therapeutic target to optimize CAR T-cell therapy against solid tumors. SIGNIFICANCE Small extracellular vesicles secreted by solid tumors inhibit CAR T cells, which provide a molecular explanation for CAR T-cell resistance and suggests that strategies targeting exosome secretion may enhance CAR T-cell efficacy. See related commentary by Ortiz-Espinosa and Srivastava, p. 2637.
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Affiliation(s)
- Wenqun Zhong
- Department of Biology, School of Arts & Sciences, University of Pennsylvania, Philadelphia, PA, U.S.A
| | - Zebin Xiao
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, U.S.A
| | - Zhiyuan Qin
- Department of Biology, School of Arts & Sciences, University of Pennsylvania, Philadelphia, PA, U.S.A
| | - Jingbo Yang
- Department of Biology, School of Arts & Sciences, University of Pennsylvania, Philadelphia, PA, U.S.A
| | - Yi Wen
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, U.S.A
| | - Ziyan Yu
- Department of Biology, School of Arts & Sciences, University of Pennsylvania, Philadelphia, PA, U.S.A
| | - Yumei Li
- Department of Biology, School of Arts & Sciences, University of Pennsylvania, Philadelphia, PA, U.S.A
| | - Neil C. Sheppard
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, U.S.A
| | - Serge Y. Fuchs
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, U.S.A
| | - Xiaowei Xu
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, U.S.A
| | - Meenhard Herlyn
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, U.S.A
| | - Carl H. June
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, U.S.A
| | - Ellen Puré
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, U.S.A
| | - Wei Guo
- Department of Biology, School of Arts & Sciences, University of Pennsylvania, Philadelphia, PA, U.S.A
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15
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Joseph J, Premeaux TA, Pinto DO, Rao A, Guha S, Panfil AR, Carey AJ, Ndhlovu LC, Bergmann‐Leitner ES, Jain P. Retroviral b-Zip protein (HBZ) contributes to the release of soluble and exosomal immune checkpoint molecules in the context of neuroinflammation. JOURNAL OF EXTRACELLULAR BIOLOGY 2023; 2:e102. [PMID: 37547182 PMCID: PMC10399615 DOI: 10.1002/jex2.102] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 06/13/2023] [Accepted: 07/01/2023] [Indexed: 08/08/2023]
Abstract
HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive, neuroinflammatory demyelinating condition of the spinal cord. We have previously shown that aberrant expression and activity of immune checkpoint (ICP) molecules such as PD-1 and PD-L1/PD-L2, negatively associates with the cytolytic potential of T cells in individuals with HAM/TSP. Interestingly, ICPs can exist in a soluble cell-free form and can be carried on extracellular vesicles (EVs) and exosomes (small EVs, <300nm) while maintaining their immunomodulatory activity. Therefore, we investigated the role of soluble and exosomal ICPs in HTLV-1 associated neuroinflammation. For the very first time, we demonstrate a unique elevated presence of several stimulatory (CD27, CD28, 4-1BB) and inhibitory (BTLA, CTLA-4, LAG-3, PD-1, PD-L2) ICP receptors in HAM/TSP sera, and in purified exosomes from a HAM/TSP-derived HTLV-1-producing (OSP2) cells. These ICPs were found to be co-localized with the endosomal sorting complex required for transport (ESCRT) pathway proteins and exhibited functional binding with their respective ligands. Viral proteins and cytokines (primarily IFNγ) were found to be present in purified exosomes. IFNγ exposure enhanced the release of ICP molecules while antiretroviral drugs (Azidothymidine and Lopinavir) significantly inhibited this process. HTLV-1 b-Zip protein (HBZ) has been linked to factors that enhance EV release and concurrent knockdown here led to the reduced expression of ESCRT associated genes (eg. Hrs, Vsp4, Alix, Tsg101) as well as abrogated the release of ICP molecules, suggesting HBZ involvement in this process. Moreso, exosomes from OSP2 cells adversely affected CD8 T-cell functions by dimishing levels of cytokines and cytotoxic factors. Collectively, these findings highlight exosome-mediated immunmodulation of T-cell functions with HBZ and ESCRT pathways as an underlying mechanism in the context of HTLV-1-induced neuroinflammation.
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Affiliation(s)
- Julie Joseph
- Department of Microbiology & ImmunologyDrexel University College of MedicinePhiladelphiaPAUSA
| | - Thomas A. Premeaux
- Weill Cornel Medicine Department of MedicineDivision of Infectious DiseasesNew YorkNYUSA
| | - Daniel O. Pinto
- Immunology Core, Biologics Research and DevelopmentWalter Reed Army Institute of ResearchSilver SpringsMDUSA
- Oak Ridge Institute for Science and EducationOak RidgeTNUSA
| | - Abhishek Rao
- Department of Microbiology & ImmunologyDrexel University College of MedicinePhiladelphiaPAUSA
| | - Shrobona Guha
- Department of Neurobiology and AnatomyDrexel University College of MedicinePhiladelphiaPAUSA
| | - Amanda R. Panfil
- The Ohio State University, College of Veterinary Medicine, Center for Retrovirus ResearchColumbusOhioUSA
| | - Alison J. Carey
- Department of Microbiology & ImmunologyDrexel University College of MedicinePhiladelphiaPAUSA
- Department of PediatricsDrexel University College of MedicinePhiladelphiaPAUSA
| | - Lishomwa C. Ndhlovu
- Weill Cornel Medicine Department of MedicineDivision of Infectious DiseasesNew YorkNYUSA
| | - Elke S. Bergmann‐Leitner
- Immunology Core, Biologics Research and DevelopmentWalter Reed Army Institute of ResearchSilver SpringsMDUSA
| | - Pooja Jain
- Department of Microbiology & ImmunologyDrexel University College of MedicinePhiladelphiaPAUSA
- Department of Neurobiology and AnatomyDrexel University College of MedicinePhiladelphiaPAUSA
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16
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CAR-tropic extracellular vesicles carry tumor-associated antigens and modulate CAR T cell functionality. Sci Rep 2023; 13:463. [PMID: 36627334 PMCID: PMC9832131 DOI: 10.1038/s41598-023-27604-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
Tumor-derived extracellular vesicles (EVs) are active contributors in metastasis and immunosuppression in tumor microenvironment. At least some of the EVs carry tumor surface molecules such as tumor-associated antigens (TAAs) and/or checkpoint inhibitors, and potentially could interact with T cells or CAR T cells. Upon contact with T cells, EVs could alter their phenotype and functions by triggering signaling through TCR or CAR reprogramming them to escape immune response. We hypothesize that EVs that possess TAA on the surface will probably interact with CAR T cells which can recognize and bind corresponding TAA. This interaction between EVs and CAR T cells may change the outcome of CAR T-based cancer immunotherapy since it should affect CAR T cells. Also, EVs could serve as adjuvants and antigenic components of antitumor vaccines. Herein, we isolated EVs from B cell precursor leukemia cell line (pre-B ALL) Nalm-6 and demonstrated that recognition and binding of CD19+EVs with CD19-CAR T cells strongly depends on the presence of CD19 antigen. CD19+EVs induce secretion of pro-inflammatory cytokines (IL-2 and IFN-y) and upregulated transcription of activation-related genes (IFNG, IFNGR1, FASLG, IL2) in CD19-CAR T cells. Tumor necrosis factor receptor superfamily (TNFRSF4 and TNFRSF9) and T-cell exhaustion markers (CTLA4, LAG3, TIM3 and PDCD1LG2) were also upregulated in CD19-CAR T cells after incubation with CD19+EVs. Long-term cultivation of CD19+ or PD-L1+EVs with CD19-CAR T cells led to increased terminal differentiation and functional exhaustion according to elevated expression of PD-1, TIGIT, CD57. In summary, our results suggest that chronic exposure of CD19-CAR T cells to CD19+EVs mediates activation and systemic exhaustion in antigen-specific manner, and this negative effect is accompanied by the impaired cytotoxic activity in vitro.
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17
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Ivasko SM, Anders K, Grunewald L, Launspach M, Klaus A, Schwiebert S, Ruf P, Lindhofer H, Lode HN, Andersch L, Schulte JH, Eggert A, Hundsdoerfer P, Künkele A, Zirngibl F. Combination of GD2-directed bispecific trifunctional antibody therapy with Pd-1 immune checkpoint blockade induces anti-neuroblastoma immunity in a syngeneic mouse model. Front Immunol 2023; 13:1023206. [PMID: 36700232 PMCID: PMC9869131 DOI: 10.3389/fimmu.2022.1023206] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 11/22/2022] [Indexed: 01/11/2023] Open
Abstract
Introduction Despite advances in treating high-risk neuroblastoma, 50-60% of patients still suffer relapse, necessitating new treatment options. Bispecific trifunctional antibodies (trAbs) are a promising new class of immunotherapy. TrAbs are heterodimeric IgG-like molecules that bind CD3 and a tumor-associated antigen simultaneously, whereby inducing a TCR-independent anti-cancer T cell response. Moreover, via their functional Fc region they recruit and activate cells of the innate immune system like antigen-presenting cells potentially enhancing induction of adaptive tumor-specific immune responses. Methods We used the SUREK trAb, which is bispecific for GD2 and murine Cd3. Tumor-blind trAb and the monoclonal ch14.18 antibody were used as controls. A co-culture model of murine dendritic cells (DCs), T cells and a neuroblastoma cell line was established to evaluate the cytotoxic effect and the T cell effector function in vitro. Expression of immune checkpoint molecules on tumor-infiltrating T cells and the induction of an anti-neuroblastoma immune response using a combination of whole cell vaccination and trAb therapy was investigated in a syngeneic immunocompetent neuroblastoma mouse model (NXS2 in A/J background). Finally, vaccinated mice were assessed for the presence of neuroblastoma-directed antibodies. We show that SUREK trAb-mediated effective killing of NXS2 cells in vitro was strictly dependent on the combined presence of DCs and T cells. Results Using a syngeneic neuroblastoma mouse model, we showed that vaccination with irradiated tumor cells combined with SUREK trAb treatment significantly prolonged survival of tumor challenged mice and partially prevent tumor outgrowth compared to tumor vaccination alone. Treatment led to upregulation of programmed cell death protein 1 (Pd-1) on tumor infiltrating T cells and combination with anti-Pd-1 checkpoint inhibition enhanced the NXS2-directed humoral immune response. Conclusion Here, we provide first preclinical evidence that a tumor vaccination combined with SUREK trAb therapy induces an endogenous anti-neuroblastoma immune response reducing tumor recurrence. Furthermore, a combination with anti-Pd-1 immune checkpoint blockade might even further improve this promising immunotherapeutic concept in order to prevent relapse in high-risk neuroblastoma patients.
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Affiliation(s)
- Sara Marie Ivasko
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt – Universität zu Berlin and Berlin Institute of Health, Berlin, Germany,Berlin Institute of Health (BIH), Berlin, Germany
| | - Kathleen Anders
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt – Universität zu Berlin and Berlin Institute of Health, Berlin, Germany,German Cancer Consortium (DKTK), Berlin, Germany
| | - Laura Grunewald
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt – Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Michael Launspach
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt – Universität zu Berlin and Berlin Institute of Health, Berlin, Germany,Berlin Institute of Health (BIH), Berlin, Germany
| | - Anika Klaus
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt – Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Silke Schwiebert
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt – Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Peter Ruf
- Trion Research, Martinsried, Germany
| | | | - Holger N. Lode
- Pediatric Hematology and Oncology, University Medicine Greifswald, Greifswald, Germany
| | - Lena Andersch
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt – Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Johannes H. Schulte
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt – Universität zu Berlin and Berlin Institute of Health, Berlin, Germany,German Cancer Consortium (DKTK), Berlin, Germany,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Angelika Eggert
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt – Universität zu Berlin and Berlin Institute of Health, Berlin, Germany,German Cancer Consortium (DKTK), Berlin, Germany,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Patrick Hundsdoerfer
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt – Universität zu Berlin and Berlin Institute of Health, Berlin, Germany,Department of Pediatrics, HELIOS Klinikum Berlin Buch, Berlin, Germany
| | - Annette Künkele
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt – Universität zu Berlin and Berlin Institute of Health, Berlin, Germany,Berlin Institute of Health (BIH), Berlin, Germany,German Cancer Consortium (DKTK), Berlin, Germany,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Felix Zirngibl
- Department of Pediatric Oncology and Hematology, Berlin Institute of Health, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt – Universität zu Berlin and Berlin Institute of Health, Berlin, Germany,Berlin Institute of Health (BIH), Berlin, Germany,*Correspondence: Felix Zirngibl,
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18
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Hao YY, Chen PP, Yuan XG, Zhao AQ, Liang Y, Liu H, Qian WB. Chidamide and sintilimab combination in diffuse large B-cell lymphoma progressing after chimeric antigen receptor T therapy. World J Clin Cases 2022; 10:6555-6562. [PMID: 35979312 PMCID: PMC9294888 DOI: 10.12998/wjcc.v10.i19.6555] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 04/10/2022] [Accepted: 05/12/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Diffuse large B-cell lymphoma (DLBCL) is curable with first-line chemoimmunotherapy but patients with relapsed/refractory (R/R) DLBCL still face a poor prognosis. For patients with R/R DLBCL, the complete response rate to traditional next-line therapy is only 7% and the median overall survival is 6.3 mo. Recently, CD19-targeting chimeric antigen receptor T cells (CAR-T) have shown promise in clinical trials. However, approximately 50% of patients treated with CAR-T cells ultimately progress and few salvage therapies are effective. CASE SUMMARY Here, we report on 7 patients with R/R DLBCL whose disease progressed after CAR-T infusion. They received a PD-1 inhibitor (sintilimab) and a histone deacetylase inhibitor (chidamide). Five of the 7 patients tolerated the treatment without any serious adverse events. Two patients discontinued the treatment due to lung infection and rash. At the 20-mo follow-up, the median overall survival of these 7 patients was 6 mo. Of note, there were 2 complete response rates (CRs) and 2 partial response rates (PRs) during this novel therapy, with an overall response rate (ORR) of 57.1%, and one patient had a durable CR that lasted at least 20 mo. CONCLUSION In conclusion, chidamide combined with sintilimab may be a choice for DLBCL patients progressing after CD19-targeting CAR-T therapy.
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Affiliation(s)
- Yuan-Yuan Hao
- Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Pan-Pan Chen
- Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Xiang-Gui Yuan
- Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Ai-Qi Zhao
- Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Yun Liang
- Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Hui Liu
- Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Wen-Bin Qian
- Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
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Zhu X, Hu H, Xiao Y, Li Q, Zhong Z, Yang J, Zou P, Cao Y, Meng F, Li W, You Y, Guo AY, Zhu X. Tumor-derived extracellular vesicles induce invalid cytokine release and exhaustion of CD19 CAR-T Cells. Cancer Lett 2022; 536:215668. [PMID: 35367518 DOI: 10.1016/j.canlet.2022.215668] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 03/13/2022] [Accepted: 03/28/2022] [Indexed: 11/02/2022]
Abstract
Although CD19 chimeric antigen receptor-T (CAR-T) cells therapy has achieved unparalleled success in B cell malignancies. The dysfunction of CAR-T cells due to exhaustion is considered as a key factor for treatment failure, and the mechanisms of exhaustion remain elusive. Extracellular vesicles (EVs), important media for communication between tumor and immune cells, may contribute to CAR-T cell exhaustion. Here, we demonstrated that CD19+ tumor cells derived EVs (NALM6-EVs) can carry CD19 antigen and activate CD19 CAR-T cells. The transient activation induced a supraphysiologic inflammatory state with increased release of multiple cytokines. Besides, the sustained activation led CD19 CAR-T cells to enter an exhausted state with upregulated inhibitory receptors, decreased expansion ability, exaggerated effector cell differentiation and impaired antitumor activity. Transcriptomic profiling validated these findings and identified dynamic changes in CD8+ effector T, CD8+ exhausted T, CD8+RRM2+ T and T helper cell subpopulations during activation to exhaustion, as well as changes in many cytokines, inflammatory and immune-related pathways. Our findings identify a credible mechanism of CAR-T cell exhaustion that driven by tumor-derived EVs and provide a novel possible trigger for early cytokine release syndrome.
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Affiliation(s)
- Xiaoying Zhu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China
| | - Hui Hu
- Center for Artificial Intelligence Biology, Hubei Bioinformatics & Molecular Imaging Key Laboratory, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China
| | - Yi Xiao
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China
| | - Qing Li
- Department of Hematology, Wuhan No.1 Hospital, Wuhan, 430022, PR China
| | - Zhaodong Zhong
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China
| | - Jingmin Yang
- Center for Artificial Intelligence Biology, Hubei Bioinformatics & Molecular Imaging Key Laboratory, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China
| | - Ping Zou
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China
| | - Yang Cao
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China
| | - Fankai Meng
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China
| | - Wei Li
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China
| | - Yong You
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China.
| | - An-Yuan Guo
- Center for Artificial Intelligence Biology, Hubei Bioinformatics & Molecular Imaging Key Laboratory, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China.
| | - Xiaojian Zhu
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.
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20
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Ferreira D, Moreira JN, Rodrigues LR. New Advances in Exosome-based Targeted Drug Delivery Systems. Crit Rev Oncol Hematol 2022; 172:103628. [PMID: 35189326 DOI: 10.1016/j.critrevonc.2022.103628] [Citation(s) in RCA: 73] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/14/2022] [Accepted: 02/16/2022] [Indexed: 02/07/2023] Open
Abstract
In recent years, various drug nano-delivery platforms have emerged to enhance drug effectiveness in cancer treatment. However, their successful translation to clinics have been hampered by unwanted side effects, as well as associated toxicity. Therefore, there is an imperative need for drug delivery vehicles capable of surpassing cellular barriers and also efficiently transfer therapeutic payloads to tumor cells. Exosomes, a class of small extracellular vesicles naturally released from all cells, have been exploited as a favorable delivery vehicle due to their natural role in intracellular communication and biocompatibility. In this review, information on exosome biogenesis, contents, forms of isolation and their natural functions is discussed, further complemented with the various successful methodologies for therapeutic payloads encapsulation, including distinct loading approaches. In addition, grafting of molecules to improve pharmacokinetics, tumor homing-ligands, as well as stimuli-responsive elements to enhance cell specificity are also debated. In the end, the current status of clinical-grade exosome-based therapies is outlined.
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Affiliation(s)
- Débora Ferreira
- CEB - Centre of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal
| | - João Nuno Moreira
- CNC - Center for Neurosciences and Cell Biology, Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Faculty of Medicine (Polo 1), Rua Larga, 3004-504 Coimbra, Portugal; Univ Coimbra - University of Coimbra, CIBB, Faculty of Pharmacy, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal
| | - Lígia R Rodrigues
- CEB - Centre of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal.
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21
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Zirngibl F, Ivasko SM, Grunewald L, Klaus A, Schwiebert S, Ruf P, Lindhofer H, Astrahantseff K, Andersch L, Schulte JH, Lode HN, Eggert A, Anders K, Hundsdoerfer P, Künkele A. GD2-directed bispecific trifunctional antibody outperforms dinutuximab beta in a murine model for aggressive metastasized neuroblastoma. J Immunother Cancer 2021; 9:jitc-2021-002923. [PMID: 34285106 PMCID: PMC8292814 DOI: 10.1136/jitc-2021-002923] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/18/2021] [Indexed: 11/13/2022] Open
Abstract
Background Neuroblastoma is the most common extracranial solid tumor of childhood. Patients with high-risk disease undergo extremely aggressive therapy and nonetheless have cure rates below 50%. Treatment with the ch14.18 monoclonal antibody (dinutuximab beta), directed against the GD2 disialoganglioside, improved 5-year event-free survival in high-risk patients when administered in postconsolidation therapy and was recently implemented in standard therapy. Relapse still occurred in 57% of these patients, necessitating new therapeutic options. Bispecific trifunctional antibodies (trAbs) are IgG-like molecules directed against T cells and cancer surface antigens, redirecting T cells (via their CD3 specificity) and accessory immune cells (via their functioning Fc-fragment) toward tumor cells. We sought proof-of-concept for GD2/CD3-directed trAb efficacy against neuroblastoma. Methods We used two GD2-specific trAbs differing only in their CD3-binding specificity: EKTOMUN (GD2/human CD3) and SUREK (GD2/mouse Cd3). This allowed trAb evaluation in human and murine experimental settings. Tumor-blind trAb and the ch14.18 antibody were used as controls. A coculture model of human peripheral blood mononuclear cells (PBMCs) and neuroblastoma cell lines was established to evaluate trAb antitumor efficacy by assessing expression of T-cell surface markers for activation, proinflammatory cytokine release and cytotoxicity assays. Characteristics of tumor-infiltrating T cells and response of neuroblastoma metastases to SUREK treatment were investigated in a syngeneic immunocompetent neuroblastoma mouse model mimicking minimal residual disease. Results We show that EKTOMUN treatment caused effector cell activation and release of proinflammatory cytokines in coculture with neuroblastoma cell lines. Furthermore, EKTOMUN mediated GD2-dependent cytotoxic effects in human neuroblastoma cell lines in coculture with PBMCs, irrespective of the level of target antigen expression. This effect was dependent on the presence of accessory immune cells. Treatment with SUREK reduced the intratumor Cd4/Cd8 ratio and activated tumor infiltrating T cells in vivo. In a minimal residual disease model for neuroblastoma, we demonstrated that single-agent treatment with SUREK strongly reduced or eliminated neuroblastoma metastases in vivo. SUREK as well as EKTOMUN demonstrated superior tumor control compared with the anti-GD2 antibody, ch14.18. Conclusions Here we provide proof-of-concept for EKTOMUN preclinical efficacy against neuroblastoma, presenting this bispecific trAb as a promising new agent to fight neuroblastoma.
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Affiliation(s)
- Felix Zirngibl
- Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany .,Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Sara M Ivasko
- Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.,Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Laura Grunewald
- Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Anika Klaus
- Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Silke Schwiebert
- Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Peter Ruf
- Trion Research, Martinsried, Germany
| | | | - Kathy Astrahantseff
- Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Lena Andersch
- Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Johannes H Schulte
- Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.,Partner Site Berlin CCCC, German Cancer Consortium, Berlin, Berlin, Germany
| | - Holger N Lode
- Pediatric Hematology and Oncology, University Medicine Greifswald, Greifswald, Germany
| | - Angelika Eggert
- Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.,Partner Site Berlin CCCC, German Cancer Consortium, Berlin, Berlin, Germany
| | - Kathleen Anders
- Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.,Partner Site Berlin CCCC, German Cancer Consortium, Berlin, Berlin, Germany
| | - Patrick Hundsdoerfer
- Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.,Department of Pediatrics, HELIOS Klinikum Berlin-Buch, Berlin, Germany
| | - Annette Künkele
- Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.,Partner Site Berlin CCCC, German Cancer Consortium, Berlin, Berlin, Germany
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22
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Advances in immunotherapeutic targets for childhood cancers: A focus on glypican-2 and B7-H3. Pharmacol Ther 2021; 223:107892. [PMID: 33992682 DOI: 10.1016/j.pharmthera.2021.107892] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 05/05/2021] [Accepted: 05/10/2021] [Indexed: 12/16/2022]
Abstract
Cancer immunotherapies have revolutionized how we can treat adult malignancies and are being translated to pediatric oncology. Chimeric antigen receptor T-cell therapy and bispecific antibodies targeting CD19 have shown success for the treatment of pediatric patients with B-cell acute lymphoblastic leukemia. Anti-GD2 monoclonal antibody has demonstrated efficacy in neuroblastoma. In this review, we summarize the immunotherapeutic agents that have been approved for treating childhood cancers and provide an updated review of molecules expressed by pediatric cancers that are under study or are emerging candidates for future immunotherapies. Advances in our knowledge of tumor immunology and in genome profiling of cancers has led to the identification of new tumor-specific/associated antigens. While cell surface antigens are normally targeted in a major histocompatibility complex (MHC)-independent manner using antibody-based therapies, intracellular antigens are normally targeted with MHC-dependent T cell therapies. Glypican 2 (GPC2) and B7-H3 (CD276) are two cell surface antigens that are expressed by a variety of pediatric tumors such as neuroblastoma and potentially can have a positive impact on the treatment of pediatric cancers in the clinic.
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23
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The Role of Extracellular Vesicles in the Progression of Human Neuroblastoma. Int J Mol Sci 2021; 22:ijms22083964. [PMID: 33921337 PMCID: PMC8069919 DOI: 10.3390/ijms22083964] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 04/09/2021] [Accepted: 04/09/2021] [Indexed: 12/25/2022] Open
Abstract
The long-underestimated role of extracellular vesicles in cancer is now reconsidered worldwide by basic and clinical scientists, who recently highlighted novel and crucial activities of these moieties. Extracellular vesicles are now considered as king transporters of specific cargoes, including molecular components of parent cells, thus mediating a wide variety of cellular activities both in normal and neoplastic tissues. Here, we discuss the multifunctional activities and underlying mechanisms of extracellular vesicles in neuroblastoma, the most frequent common extra-cranial tumor in childhood. The ability of extracellular vesicles to cross-talk with different cells in the tumor microenvironment and to modulate an anti-tumor immune response, tumorigenesis, tumor growth, metastasis and drug resistance will be pinpointed in detail. The results obtained on the role of extracellular vesicles may represent a panel of suggestions potentially useful in practice, due to their involvement in the response to chemotherapy, and, moreover, their ability to predict resistance to standard therapies—all issues of clinical relevance.
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24
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Cox MJ, Lucien F, Sakemura R, Boysen JC, Kim Y, Horvei P, Manriquez Roman C, Hansen MJ, Tapper EE, Siegler EL, Forsman C, Crotts SB, Schick KJ, Hefazi M, Ruff MW, Can I, Adada M, Bezerra E, Kankeu Fonkoua LA, Nevala WK, Braggio E, Ding W, Parikh SA, Kay NE, Kenderian SS. Leukemic extracellular vesicles induce chimeric antigen receptor T cell dysfunction in chronic lymphocytic leukemia. Mol Ther 2021; 29:1529-1540. [PMID: 33388419 PMCID: PMC8058445 DOI: 10.1016/j.ymthe.2020.12.033] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 12/11/2020] [Accepted: 12/23/2020] [Indexed: 12/13/2022] Open
Abstract
Chimeric antigen receptor (CAR) T cell therapy has yielded unprecedented outcomes in some patients with hematological malignancies; however, inhibition by the tumor microenvironment has prevented the broader success of CART cell therapy. We used chronic lymphocytic leukemia (CLL) as a model to investigate the interactions between the tumor microenvironment and CART cells. CLL is characterized by an immunosuppressive microenvironment, an abundance of systemic extracellular vesicles (EVs), and a relatively lower durable response rate to CART cell therapy. In this study, we characterized plasma EVs from untreated CLL patients and identified their leukemic cell origin. CLL-derived EVs were able to induce a state of CART cell dysfunction characterized by phenotypical, functional, and transcriptional changes of exhaustion. We demonstrate that, specifically, PD-L1+ CLL-derived EVs induce CART cell exhaustion. In conclusion, we identify an important mechanism of CART cell exhaustion induced by EVs from CLL patients.
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MESH Headings
- B7-H1 Antigen/blood
- B7-H1 Antigen/genetics
- Cell Line, Tumor
- Extracellular Vesicles/genetics
- Extracellular Vesicles/immunology
- Female
- Humans
- Immunotherapy, Adoptive/methods
- Leukemia, Lymphocytic, Chronic, B-Cell/blood
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- Leukemia, Lymphocytic, Chronic, B-Cell/therapy
- Male
- Receptors, Antigen, T-Cell/blood
- Receptors, Antigen, T-Cell/genetics
- Receptors, Antigen, T-Cell/immunology
- Receptors, Chimeric Antigen/genetics
- Receptors, Chimeric Antigen/immunology
- T-Lymphocytes/immunology
- Tumor Microenvironment/drug effects
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Affiliation(s)
- Michelle J Cox
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA; Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA; University of Minnesota Graduate School, Bioinformatics and Computational Biology, Minneapolis, MN, USA
| | | | - Reona Sakemura
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA; Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA
| | - Justin C Boysen
- Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA
| | - Yohan Kim
- Department of Urology, Mayo Clinic, Rochester, MN, USA
| | - Paulina Horvei
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA; Department of Pediatric Hematology/Oncology, Mayo Clinic, Rochester, MN, USA
| | - Claudia Manriquez Roman
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA; Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA; Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA; Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA
| | | | - Erin E Tapper
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA; Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA
| | - Elizabeth L Siegler
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA; Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA
| | | | - Sydney B Crotts
- Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA; Department of Immunology, Mayo Clinic, Rochester, MN, USA
| | - Kendall J Schick
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA; Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA; Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA; Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Mehrdad Hefazi
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA; Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA
| | - Michael W Ruff
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA; Department of Neurology, Mayo Clinic, Rochester, MN, USA
| | - Ismail Can
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA; Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA; Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | - Mohamad Adada
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA; Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA; Department of Oncology, Mayo Clinic, Rochester, MN, USA
| | - Evandro Bezerra
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA; Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA; Department of Oncology, Mayo Clinic, Rochester, MN, USA
| | - Lionel Aurelien Kankeu Fonkoua
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA; Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA; Department of Oncology, Mayo Clinic, Rochester, MN, USA
| | - Wendy K Nevala
- Department of Immunology, Mayo Clinic, Rochester, MN, USA
| | | | - Wei Ding
- Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA
| | - Sameer A Parikh
- Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA
| | - Neil E Kay
- Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA; Department of Immunology, Mayo Clinic, Rochester, MN, USA
| | - Saad S Kenderian
- T Cell Engineering, Mayo Clinic, Rochester, MN, USA; Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA; Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA; Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA; Department of Immunology, Mayo Clinic, Rochester, MN, USA.
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25
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The Functional Heterogeneity of Neutrophil-Derived Extracellular Vesicles Reflects the Status of the Parent Cell. Cells 2020; 9:cells9122718. [PMID: 33353087 PMCID: PMC7766779 DOI: 10.3390/cells9122718] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 12/12/2020] [Accepted: 12/15/2020] [Indexed: 12/16/2022] Open
Abstract
Similar to other cell types, neutrophilic granulocytes also release extracellular vesicles (EVs), mainly medium-sized microvesicles/microparticles. According to published data, authors have reached a consensus on the physical parameters (size, density) and chemical composition (surface proteins, proteomics) of neutrophil-derived EVs. In contrast, there is large diversity and even controversy in the reported functional properties. Part of the discrepancy may be ascribed to differences in the viability of the starting cells, in eliciting factors, in separation techniques and in storage conditions. However, the most recent data from our laboratory prove that the same population of neutrophils is able to generate EVs with different functional properties, transmitting pro-inflammatory or anti-inflammatory effects on neighboring cells. Previously we have shown that Mac-1 integrin is a key factor that switches anti-inflammatory EV generation into pro-inflammatory and antibacterial EV production. This paper reviews current knowledge on the functional alterations initiated by neutrophil-derived EVs, listing their effects according to the triggering agents and target cells. We summarize the presence of neutrophil-derived EVs in pathological processes and their perspectives in diagnostics and therapy. Finally, the functional heterogeneity of differently triggered EVs indicates that neutrophils are capable of producing a broad spectrum of EVs, depending on the environmental conditions prevailing at the time of EV genesis.
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26
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Sawaisorn P, Atjanasuppat K, Anurathapan U, Chutipongtanate S, Hongeng S. Strategies to Improve Chimeric Antigen Receptor Therapies for Neuroblastoma. Vaccines (Basel) 2020; 8:vaccines8040753. [PMID: 33322408 PMCID: PMC7768386 DOI: 10.3390/vaccines8040753] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 12/04/2020] [Accepted: 12/10/2020] [Indexed: 02/07/2023] Open
Abstract
Chimeric antigen receptors (CARs) are among the curative immunotherapeutic approaches that exploit the antigen specificity and cytotoxicity function of potent immune cells against cancers. Neuroblastomas, the most common extracranial pediatric solid tumors with diverse characteristics, could be a promising candidate for using CAR therapies. Several methods harness CAR-modified cells in neuroblastoma to increase therapeutic efficiency, although the assessment has been less successful. Regarding the improvement of CARs, various trials have been launched to overcome insufficient capacity. However, the reasons behind the inadequate response against neuroblastoma of CAR-modified cells are still not well understood. It is essential to update the present state of comprehension of CARs to improve the efficiency of CAR therapies. This review summarizes the crucial features of CARs and their design for neuroblastoma, discusses challenges that impact the outcomes of the immunotherapeutic competence, and focuses on devising strategies currently being investigated to improve the efficacy of CARs for neuroblastoma immunotherapy.
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Affiliation(s)
- Piamsiri Sawaisorn
- Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand; (P.S.); (K.A.); (U.A.)
| | - Korakot Atjanasuppat
- Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand; (P.S.); (K.A.); (U.A.)
| | - Usanarat Anurathapan
- Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand; (P.S.); (K.A.); (U.A.)
| | - Somchai Chutipongtanate
- Pediatric Translational Research Unit, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand
- Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand
- Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakan 10540, Thailand
- Correspondence: (S.C.); (S.H.)
| | - Suradej Hongeng
- Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand; (P.S.); (K.A.); (U.A.)
- Correspondence: (S.C.); (S.H.)
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