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Al‐Talib M, Skaria A, Griffin S. Cellular Immunity Against BK Polyomavirus in Kidney Transplant Recipients: A Comprehensive Review. Transpl Infect Dis 2025; 27:e14401. [PMID: 39499036 PMCID: PMC11827742 DOI: 10.1111/tid.14401] [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: 08/21/2024] [Revised: 10/03/2024] [Accepted: 10/13/2024] [Indexed: 11/07/2024]
Abstract
BK polyomavirus (BKPyV) is an important opportunistic viral infection that complicates kidney transplantation. Uncontrolled viral replication may result in BKPyV-associated nephropathy (BKPyVAN), a major cause of premature allograft damage and failure. In the continued absence of proven treatments, management relies on the empirical reduction of immunosuppression to facilitate an effective host immune response to clear the virus. This may be complicated by the risk of allograft rejection. There is compelling evidence that cellular immune responses are key to establishing control after viral reactivation. Measurable peripheral BKPyV-specific T cell responses temporally correlate with declining viral loads and subsequent clearance. Conversely, these responses are delayed or absent in BKPyVAN. How these peripheral findings correspond to the intragraft response, and whether BKPyV-specific T cells contribute to the immunopathology of BKPyVAN, remains poorly understood. Molecular techniques have provided some insights; however, these have been unable to fully discriminate BKPyVAN from cellular rejection to date. Furthermore, the contributions of components of innate cellular immunity, such as natural killer cells, are not known. Herein, we review the role of cellular immunity in BKPyV infection in kidney transplant recipients. We discuss advances in the understanding of how the development, phenotype, and functionality of these responses may determine the balance between viral control and immunopathology, and how this knowledge is being translated into tools to prognosticate and guide individualized immunosuppression reduction. Lastly, we consider how further elucidation of these responses may inform the design of therapies that would revolutionize how BKPyV is managed after transplantation.
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Affiliation(s)
- Mohammed Al‐Talib
- Systems Immunity Research InstituteDivision of Infection and ImmunitySchool of MedicineCardiff UniversityCardiffUK
- Bristol Medical SchoolUniversity of BristolBristolUK
| | - Anna Skaria
- Southmead HospitalNorth Bristol NHS TrustBristolUK
| | - Siân Griffin
- Department of Nephrology and TransplantationCardiff and Vale University Health BoardCardiffUK
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Lara-de-León AG, Mora-Buch R, Cantó E, Peña-Gómez C, Rudilla F. Identification of Candidate Immunodominant Epitopes and Their HLA-Binding Prediction on BK Polyomavirus Proteins in Healthy Donors. HLA 2024; 104:e15722. [PMID: 39435889 DOI: 10.1111/tan.15722] [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: 03/25/2024] [Revised: 09/12/2024] [Accepted: 10/01/2024] [Indexed: 10/23/2024]
Abstract
BK polyomavirus infection is an important cause of graft loss in transplant patients, however, currently available therapies lack effectiveness against this pathogen. Identification of immunological targets for potential treatments is therefore necessary. The aim of this study was to predict candidates of immunodominant epitopes within four BK virus proteins (VP1, VP2, VP3 and LTA) using PBMCs from 44 healthy donors. We used the ELISpot epitope mapping method to evaluate the T-cell response, and HLA-peptide binding was predicted using the NetMHCpan algorithm. A total of 11 potential peptides were selected for VP1, 3 for VP2/VP3 and 13 for LTA. Greater reactivity was observed for VP1 and LTA proteins compared with VP2/VP3. Most of the peptides selected as potential immunodominant candidates were restricted towards several HLA class I and II alleles, with predominant HLA class I binding by computational predictions. Based on these findings, the sequences of the selected immunodominant epitopes candidates and their corresponding HLA restrictions could contribute to the optimisation of functional assays and aid in the design and improvement of immunotherapy strategies against BK virus infections.
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Affiliation(s)
- Ana Gabriela Lara-de-León
- Advanced & Cell Therapy Services, Banc de Sang i Teixits (Blood and Tissue Bank, BST), Barcelona, Spain
| | - Rut Mora-Buch
- Advanced & Cell Therapy Services, Banc de Sang i Teixits (Blood and Tissue Bank, BST), Barcelona, Spain
- Transfusional Medicine Group, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
| | - Ester Cantó
- Advanced & Cell Therapy Services, Banc de Sang i Teixits (Blood and Tissue Bank, BST), Barcelona, Spain
- Transfusional Medicine Group, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
| | - Cleofé Peña-Gómez
- Mental Health and Neurosciences, Mixt Unit, Parc Taulí Research and Innovation Institute (I3PT), Barcelona, Spain
| | - Francesc Rudilla
- Transfusional Medicine Group, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona (VHIR-UAB), Barcelona, Spain
- Immunogenetics and Histocompatibility Laboratory, Banc de Sang i Teixits (Blood and Tissue Bank, BST), Barcelona, Spain
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Moss JE, Muller WJ. BK virus-associated hemorrhagic cystitis in pediatric stem cell transplantation: a case report and scoping review. Front Pediatr 2024; 11:1267678. [PMID: 38406625 PMCID: PMC10884191 DOI: 10.3389/fped.2023.1267678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 12/29/2023] [Indexed: 02/27/2024] Open
Abstract
Introduction BK virus-associated hemorrhagic cystitis (BK-HC) is a debilitating and poorly understood complication of hematopoietic stem cell transplantation (SCT). Hematuria, dysuria, and other symptoms associated with BK-HC are common in the immediate post-SCT period, making BK-HC difficult to distinguish from other conditions presenting with these symptoms. Despite published criteria for diagnosis, the degree to which these criteria are consistently applied to either clinical diagnosis or to studies informing BK-HC management is unclear. We present a case of BK-HC in a pediatric SCT recipient, and discuss the challenges associated with treatment in the absence of rigorous data to inform clinical management. Methods We reviewed all cases of BK viruria at our center in patients undergoing SCT between January 2015 and December 2019. We then performed a scoping review of publications in PubMed addressing BK-HC, specifically focusing on how BK-HC was defined. Publications using the keywords "BK polyomavirus" and "hemorrhagic cystitis" were included if they involved a clinical study of SCT recipients and a full-text article was available in English. Case reports were excluded. Analysis focused on whether BK-HC was explicitly defined and whether the definition incorporated elements of diagnostic criteria published by European Conference on Infections in Leukemia (ECIL). Results A total of 30 studies published between January 2018 and 30 June 2021 met criteria for review, including 4 clinical trials, 7 prospective observational studies, and 19 retrospective observational studies. Fifteen of these studies included pediatric patients (7 pediatric only, 8 combined adult and pediatric). Of the 30 publications, 19 included a definition of either BK-HC or BK cystitis, with only five using ECIL criteria, all of which were observational studies. Multiple interventions are described for treatment of BK-HC, including cidofovir, leflunomide, quinolones, hyperbaric oxygen, keratinocyte growth factor, and BK-specific cytotoxic T lymphocytes. However, evidence to support efficacy for any of these interventions is lacking. Discussion Although BK-HC is a well-known complication of SCT, evidence to support available treatment options is limited. Well-controlled studies that incorporate clear diagnostic criteria are needed to better define the risk factors, natural history, and ideal interventions.
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Affiliation(s)
- Julia E. Moss
- Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - William J. Muller
- Division of Infectious Diseases, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, United States
- Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
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Koukoulias K, Papayanni PG, Jones J, Kuvalekar M, Watanabe A, Velazquez Y, Gilmore S, Papadopoulou A, Leen AM, Vasileiou S. Assessment of the cytolytic potential of a multivirus-targeted T cell therapy using a vital dye-based, flow cytometric assay. Front Immunol 2023; 14:1299512. [PMID: 38187380 PMCID: PMC10766817 DOI: 10.3389/fimmu.2023.1299512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 12/05/2023] [Indexed: 01/09/2024] Open
Abstract
Reliable and sensitive characterization assays are important determinants of the successful clinical translation of immunotherapies. For the assessment of cytolytic potential, the chromium 51 (51Cr) release assay has long been considered the gold standard for testing effector cells. However, attaining the approvals to access and use radioactive isotopes is becoming increasingly complex, while technical aspects [i.e. sensitivity, short (4-6 hours) assay duration] may lead to suboptimal performance. This has been the case with our ex vivo expanded, polyclonal (CD4+ and CD8+) multivirus-specific T cell (multiVST) lines, which recognize 5 difficult-to-treat viruses [Adenovirus (AdV), BK virus (BKV), cytomegalovirus (CMV), Epstein Barr virus (EBV), and human herpes virus 6 (HHV6)] and when administered to allogeneic hematopoietic stem cell (HCT) or solid organ transplant (SOT) recipients have been associated with clinical benefit. However, despite mediating potent antiviral effects in vivo, capturing in vitro cytotoxic potential has proven difficult in a traditional 51Cr release assay. Now, in addition to cytotoxicity surrogates, including CD107a and Granzyme B, we report on an alternative, vital dye -based, flow cytometric platform in which superior sensitivity and prolonged effector:target co-culture duration enabled the reliable detection of both CD4- and CD8-mediated in vitro cytolytic activity against viral targets without non-specific effects.
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Affiliation(s)
- Kiriakos Koukoulias
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, Houston, TX, United States
| | - Penelope G. Papayanni
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, Houston, TX, United States
| | - Julia Jones
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, Houston, TX, United States
| | - Manik Kuvalekar
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, Houston, TX, United States
| | - Ayumi Watanabe
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, Houston, TX, United States
| | - Yovana Velazquez
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, Houston, TX, United States
| | | | - Anastasia Papadopoulou
- Hematology Department- Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center, “George Papanikolaou” Hospital, Thessaloniki, Greece
| | - Ann M. Leen
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, Houston, TX, United States
| | - Spyridoula Vasileiou
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital, Houston, TX, United States
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Gorriceta JH, Lopez Otbo A, Uehara G, Posadas Salas MA. BK viral infection: A review of management and treatment. World J Transplant 2023; 13:309-320. [PMID: 38174153 PMCID: PMC10758681 DOI: 10.5500/wjt.v13.i6.309] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 11/15/2023] [Accepted: 11/30/2023] [Indexed: 12/15/2023] Open
Abstract
BK viral infection remains to be a challenging post-transplant infection, which can result in kidney dysfunction. The mainstay approach to BK infection is reduction of immunosuppression. Alterations in immunosuppressive regimen with minimization of calcineurin inhibitors, use of mechanistic target of rapamycin inhibitors, and leflunomide have been attempted with variable outcomes. Over the past few years, investigators have explored potential therapeutic options for BK infection. Fluoroquinolone prophylaxis and treatment was found to have no benefit in kidney transplant recipients. The utility of cidofovir is limited by its nephrotoxicity. Intravenous immunoglobulin is becoming a popular option for treatment and prophylaxis for BK infection, as it increases the neutralizing antibody titers against the most common BK virus serotypes. Virus-specific T cell therapy is an emerging treatment option for BK viremia. In this review, we will explore management and therapeutic options for BK infection and recent evidence available in literature.
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Affiliation(s)
| | - Amy Lopez Otbo
- Department of Medicine, St. Luke’s Medical Center, Quezon 1112, Philippines
| | - Genta Uehara
- Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC 29425, United States
| | - Maria Aurora Posadas Salas
- Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC 29425, United States
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Anand M, Nysather J, McGraw G, Apewokin S, Khoury R, Grimley MS, Bumb S, Govil A. Viral specific T cell therapy in kidney transplant recipients - A single-center experience. Transpl Infect Dis 2023; 25:e14179. [PMID: 37910558 DOI: 10.1111/tid.14179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 09/14/2023] [Accepted: 10/06/2023] [Indexed: 11/03/2023]
Abstract
BACKGROUND Viral infections such as adenovirus (ADV), BK virus (BKV), and cytomegalovirus (CMV) after kidney transplantation negatively impact outcomes in transplant recipients despite advancements in screening and antiviral therapy. We describe our experience of using the virus-specific T cell therapy (VSTs) in kidney transplant recipients (KTR) at our transplant center. METHODS This is a retrospective, single center review of KTR with ADV, BKV and CMV infections between June 2021 and December 2022. These patients received third party VSTs as part of the management of infections. The immunosuppression, details of infection and outcome data were obtained from electronic medical records. RESULTS Two cases of ADV infection resolved after one infusion of VSTs. The response rate of BKV and CMV infection was not as robust with close to 50% reduction in median viral load after VSTs. Out of 23 patients, two patients developed chronic allograft nephropathy from membranoproliferative glomerulonephritis and acute rejection. CONCLUSION Patients that are resistant to antivirals or who have worsening viremia despite conventional management may benefit from VSTs therapy to treat underlying viral infection. Additional studies are needed to ascertain efficacy and short- and long-term risks secondary to VSTs.
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Affiliation(s)
- Manish Anand
- Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, USA
| | - Jake Nysather
- Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, USA
| | - Gregory McGraw
- Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, USA
| | - Senu Apewokin
- Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, USA
| | - Ruby Khoury
- Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, Ohio, USA
| | - Michael S Grimley
- Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, Ohio, USA
| | - Shalini Bumb
- Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, USA
| | - Amit Govil
- Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, USA
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Probst V, Thomas SJ, Ouellette CP. Adopting a new approach to treat refractory or resistant viral infections in solid organ transplant recipients. Transpl Infect Dis 2023; 25:e14161. [PMID: 37793055 DOI: 10.1111/tid.14161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 09/14/2023] [Accepted: 09/15/2023] [Indexed: 10/06/2023]
Affiliation(s)
- Varvara Probst
- Host Defense Program, Division of Infectious Diseases, Nationwide Children's Hospital, Columbus, Ohio, USA
- The Ohio State University College of Medicine and Public Health, Columbus, Ohio, USA
| | - Sanya J Thomas
- Host Defense Program, Division of Infectious Diseases, Nationwide Children's Hospital, Columbus, Ohio, USA
- The Ohio State University College of Medicine and Public Health, Columbus, Ohio, USA
| | - Christopher P Ouellette
- Host Defense Program, Division of Infectious Diseases, Nationwide Children's Hospital, Columbus, Ohio, USA
- The Ohio State University College of Medicine and Public Health, Columbus, Ohio, USA
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8
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Montiel-Esparza R, Michalak SM, Le AHD, Or C, Nguyen QD, Khoury R, Grimley MS, Bertaina A, Klinger E, Shah AJ, Wood EH. Viral-specific T cells for Cytomegalovirus retinitis following hematopoietic stem cell transplantation: A success story. Pediatr Blood Cancer 2023; 70:e30429. [PMID: 37243390 DOI: 10.1002/pbc.30429] [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: 01/06/2023] [Revised: 04/05/2023] [Accepted: 04/28/2023] [Indexed: 05/28/2023]
Abstract
Cytomegalovirus retinitis (CMVR) following hematopoietic stem cell transplantation (HCT) for a primary immunodeficiency is a rare but highly morbid condition with potential irreversible consequences despite optimal antiviral pharmacotherapy. Viral-specific T cells (VSTs) pose a promising and safe approach eradicating intractable viral disease. We describe the case of a 21-month-old male with Wiskott-Aldrich syndrome (WAS) and CMVR post HCT with sustained long-term virologic and clinical response after CMV-specific T-cell therapy. This case highlights the need to consider VST as an adjunct upfront strategy in refractory CMVR and for routine ophthalmologic screening and surveillance in high-risk patients post HCT.
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Affiliation(s)
- Raul Montiel-Esparza
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University, Palo Alto, California, USA
| | - Suzanne M Michalak
- Spencer Center for Vision Research, Byers Eye Institute, Department of Ophthalmology, Stanford University, Palo Alto, California, USA
| | - Anthony Huy Dinh Le
- University of Missouri - Kansas City School of Medicine, Kansas City, Missouri, USA
| | - Christopher Or
- Spencer Center for Vision Research, Byers Eye Institute, Department of Ophthalmology, Stanford University, Palo Alto, California, USA
| | - Quan Dong Nguyen
- Spencer Center for Vision Research, Byers Eye Institute, Department of Ophthalmology, Stanford University, Palo Alto, California, USA
| | - Ruby Khoury
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Michael S Grimley
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Alice Bertaina
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University, Palo Alto, California, USA
| | - Edna Klinger
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University, Palo Alto, California, USA
| | - Ami J Shah
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University, Palo Alto, California, USA
| | - Edward H Wood
- Spencer Center for Vision Research, Byers Eye Institute, Department of Ophthalmology, Stanford University, Palo Alto, California, USA
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9
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Nguyen NK, Devilder MC, Gautreau-Rolland L, Fourgeux C, Sinha D, Poschmann J, Hourmant M, Bressollette-Bodin C, Saulquin X, McIlroy D. A cluster of broadly neutralizing IgG against BK polyomavirus in a repertoire dominated by IgM. Life Sci Alliance 2023; 6:e202201567. [PMID: 36717250 PMCID: PMC9887757 DOI: 10.26508/lsa.202201567] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 12/30/2022] [Accepted: 01/04/2023] [Indexed: 01/31/2023] Open
Abstract
The BK polyomavirus (BKPyV) is an opportunistic pathogen, which is only pathogenic in immunosuppressed individuals, such as kidney transplant recipients, in whom BKPyV can cause significant morbidity. To identify broadly neutralizing antibodies against this virus, we used fluorescence-labeled BKPyV virus-like particles to sort BKPyV-specific B cells from the PBMC of KTx recipients, then single-cell RNAseq to obtain paired heavy- and light-chain antibody sequences from 2,106 sorted B cells. The BKPyV-specific repertoire was highly diverse in terms of both V-gene usage and clonotype diversity and included most of the IgM B cells, including many with extensive somatic hypermutation. In two patients where sufficient data were available, IgM B cells in the BKPyV-specific dataset had significant differences in V-gene usage compared with IgG B cells from the same patient. CDR3 sequence-based clustering allowed us to identify and characterize three broadly neutralizing "41F17-like" clonotypes that were predominantly IgG, suggesting that some specific BKPyV capsid epitopes are preferentially targeted by IgG.
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Affiliation(s)
- Ngoc-Khanh Nguyen
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France
| | - Marie-Claire Devilder
- Nantes Université, Inserm UMR 1307, CNRS UMR 6075, Université d'Angers, CRCI2NA, Nantes, France
| | - Laetitia Gautreau-Rolland
- Nantes Université, Inserm UMR 1307, CNRS UMR 6075, Université d'Angers, CRCI2NA, Nantes, France
- UFR Sciences et Techniques, Nantes Université, Nantes, France
| | - Cynthia Fourgeux
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France
| | - Debajyoti Sinha
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France
| | - Jeremie Poschmann
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France
| | - Maryvonne Hourmant
- CHU Nantes, Nantes Université, Service de Néphrologie-Immunologie clinique, Nantes, France
| | - Céline Bressollette-Bodin
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France
- CHU Nantes, Nantes Université, Service de Virologie, Nantes, France
- UFR Médecine, Nantes Université, Nantes, France
| | - Xavier Saulquin
- Nantes Université, Inserm UMR 1307, CNRS UMR 6075, Université d'Angers, CRCI2NA, Nantes, France
- UFR Sciences et Techniques, Nantes Université, Nantes, France
| | - Dorian McIlroy
- Nantes Université,, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France
- UFR Sciences et Techniques, Nantes Université, Nantes, France
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10
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Quach DH, Lulla P, Rooney CM. Banking on virus-specific T cells to fulfill the need for off-the-shelf cell therapies. Blood 2023; 141:877-885. [PMID: 36574622 PMCID: PMC10023738 DOI: 10.1182/blood.2022016202] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 11/28/2022] [Accepted: 12/14/2022] [Indexed: 12/28/2022] Open
Abstract
Adoptively transferred virus-specific T cells (VSTs) have shown remarkable safety and efficacy for the treatment of virus-associated diseases and malignancies in hematopoietic stem cell transplant (HSCT) recipients, for whom VSTs are derived from the HSCT donor. Autologous VSTs have also shown promise for the treatment of virus-driven malignancies outside the HSCT setting. In both cases, VSTs are manufactured as patient-specific products, and the time required for procurement, manufacture, and release testing precludes their use in acutely ill patients. Further, Good Manufacturing Practices-compliant products are expensive, and failures are common in virus-naive HSCT donors and patient-derived VSTs that are rendered anergic by immunosuppressive tumors. Hence, highly characterized, banked VSTs (B-VSTs) that can be used for multiple unrelated recipients are highly desirable. The major challenges facing B-VSTs result from the inevitable mismatches in the highly polymorphic and immunogenic human leukocyte antigens (HLA) that present internally processed antigens to the T-cell receptor, leading to the requirement for partial HLA matching between the B-VST and recipient. HLA mismatches lead to rapid rejection of allogeneic T-cell products and graft-versus-host disease induced by alloreactive T cells in the infusion product. Here, we summarize the clinical outcomes to date of trials of B-VSTs used for the treatment of viral infections and malignancies and their potential as a platform for chimeric antigen receptors targeting nonviral tumors. We will highlight the properties of VSTs that make them attractive off-the-shelf cell therapies, as well as the challenges that must be overcome before they can become mainstream.
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Affiliation(s)
- David H. Quach
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, TX
- Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Premal Lulla
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, TX
- Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Cliona M. Rooney
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, TX
- Department of Pediatrics, Baylor College of Medicine, Houston, TX
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX
- Department of Molecular Virology and Immunology, Baylor College of Medicine, Houston, TX
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11
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Pathogen-specific T Cells: Targeting Old Enemies and New Invaders in Transplantation and Beyond. Hemasphere 2023; 7:e809. [PMID: 36698615 PMCID: PMC9831191 DOI: 10.1097/hs9.0000000000000809] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 11/07/2022] [Indexed: 01/27/2023] Open
Abstract
Adoptive immunotherapy with virus-specific cytotoxic T cells (VSTs) has evolved over the last three decades as a strategy to rapidly restore virus-specific immunity to prevent or treat viral diseases after solid organ or allogeneic hematopoietic cell-transplantation (allo-HCT). Since the early proof-of-principle studies demonstrating that seropositive donor-derived T cells, specific for the commonest pathogens post transplantation, namely cytomegalovirus or Epstein-Barr virus (EBV) and generated by time- and labor-intensive protocols, could effectively control viral infections, major breakthroughs have then streamlined the manufacturing process of pathogen-specific T cells (pSTs), broadened the breadth of target recognition to even include novel emerging pathogens and enabled off-the-shelf administration or pathogen-naive donor pST production. We herein review the journey of evolution of adoptive immunotherapy with nonengineered, natural pSTs against infections and virus-associated malignancies in the transplant setting and briefly touch upon recent achievements using pSTs outside this context.
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12
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Incidence, risk factors and outcome of BK virus hemorrhagic cystitis following allogenic hematopoietic cell transplantation: a retrospective cohort study. Bone Marrow Transplant 2022; 57:1287-1294. [PMID: 35596063 DOI: 10.1038/s41409-022-01665-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 03/23/2022] [Accepted: 03/25/2022] [Indexed: 11/08/2022]
Abstract
BK polyomavirus (BKPyV) can cause hemorrhagic cystitis (HC) after allogeneic hematopoietic cell transplantation (allo-HCT). Recent evaluation of BKPyV HC (BKHC) incidence and risk factors are scarce. We conducted a retrospective single-center study on a recent allo-HCT cohort over 3 years in a referral academic hospital for hematological malignancies. Primary objective was to determine BKHC incidence using competitive risk analysis. Secondary objectives were the identification of HC risk factors using Fine and Gray models and the evaluation of mortality. Among 409 allo-HCT recipients (median age 47 years), 41 developed BKHC after a median delay of 41 [32-55] days. Incidence density of BKHC was 2.4 [1.8-3.1] events per 100 days post-allo-HCT. The proportion of BKHC after adjustment for time-dependent competing risk was 9.5 [9.5-9.6]% at 100 days. BK viremia was detected in 63 versus 20% in tested patients with and without BKHC, respectively. After adjustment for confounders, myeloablative conditioning regimen with and without cyclophosphamide and CMV seropositivity were independently associated with BKHC. Post-transplantation cyclophosphamide was not associated with BKHC. BKHC resolved in 90% of the patients. No difference in mortality was found between patients with or without BKHC. In parallel to the recent evolution of allo-HCT protocols, BKHC remains a frequent complication following allo-HCT.
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Holland EM, Gonzalez C, Levy E, Valera VA, Chalfin H, Klicka-Skeels J, Yates B, Kleiner DE, Hadigan C, Dave H, Shalabi H, Hickstein DD, Su HC, Grimley M, Freeman AF, Shah NN. Case Report: Fatal Complications of BK Virus-Hemorrhagic Cystitis and Severe Cytokine Release Syndrome Following BK Virus-Specific T-Cells. Front Immunol 2021; 12:801281. [PMID: 34975916 PMCID: PMC8718506 DOI: 10.3389/fimmu.2021.801281] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 12/01/2021] [Indexed: 11/13/2022] Open
Abstract
BK virus (BKV)-hemorrhagic cystitis (HC) is a well-known and rarely fatal complication of hematopoietic stem cell transplantation (HSCT). Treatment for BKV-HC is limited, but virus-specific T-cells (VST) represent a promising therapeutic option feasible for use posttransplant. We report on the case of a 16-year-old male with dedicator of cytokinesis 8 (DOCK8) deficiency who underwent haploidentical HSCT complicated by severe BKV-HC, catastrophic renal hemorrhage, and VST-associated cytokine release syndrome (CRS). Gross hematuria refractory to multiple interventions began with initiation of posttransplant cyclophosphamide (PT/Cy). Complete left renal arterial embolization (day +43) was ultimately indicated to control intractable renal hemorrhage. Subsequent infusion of anti-BK VSTs was complicated by CRS and progressive multiorgan failure, with postmortem analysis confirming diagnosis of hepatic sinusoidal obstruction syndrome (SOS). This case illustrates opportunities for improvement in the management of severe BKV-HC posttransplant while highlighting rare and potentially life-threatening complications of BKV-HC and VST therapy.
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Affiliation(s)
- Elizabeth M. Holland
- Pediatric Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Corina Gonzalez
- Pediatric Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, United States
- Immune Deficiency- Cellular Therapy Program, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Elliot Levy
- Radiology and Imaging Sciences, NIH Clinical Center (CC), Bethesda, MD, United States
| | - Vladimir A. Valera
- Urologic Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Heather Chalfin
- Urologic Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, United States
| | | | - Bonnie Yates
- Pediatric Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, United States
| | - David E. Kleiner
- Laboratory of Pathology, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Colleen Hadigan
- Pediatric Gastroenterology, NIH Clinical Center (CC), Bethesda, MD, United States
| | - Hema Dave
- Pediatric Oncology, Children’s National Medical Center, Washington, DC, United States
| | - Haneen Shalabi
- Pediatric Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Dennis D. Hickstein
- Immune Deficiency- Cellular Therapy Program, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Helen C. Su
- Laboratory of Clinical Immunology and Microbiology, National Institutes of Allergy and Infectious Disease, NIH Clinical Center (CC), Bethesda, MD, United States
| | - Michael Grimley
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital, Cincinnati, OH, United States
| | - Alexandra F. Freeman
- Laboratory of Clinical Immunology and Microbiology, National Institutes of Allergy and Infectious Disease, NIH Clinical Center (CC), Bethesda, MD, United States
| | - Nirali N. Shah
- Pediatric Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, United States
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Virus-specific T cells for adenovirus infection after stem cell transplantation are highly effective and class II HLA restricted. Blood Adv 2021; 5:3309-3321. [PMID: 34473237 DOI: 10.1182/bloodadvances.2021004456] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 04/25/2021] [Indexed: 11/20/2022] Open
Abstract
Infection with adenoviruses is a common and significant complication in pediatric patients after allogeneic hematopoietic stem cell transplantation. Treatment options with traditional antivirals are limited by poor efficacy and significant toxicities. T-cell reconstitution is critical for the management of adenoviral infections, but it generally takes place months after transplantation. Ex vivo-generated virus-specific T cells (VSTs) are an alternative approach for viral control and can be rapidly generated from either a stem cell donor or a healthy third-party donor. In the context of a single-center phase 1/2 clinical trial, we treated 30 patients with a total of 43 infusions of VSTs for adenoviremia and/or adenoviral disease. Seven patients received donor-derived VSTs, 21 patients received third-party VSTs, and 2 received VSTs from both donor sources. Clinical responses were observed in 81% of patients, with a complete response in 58%. Epitope prediction and potential epitope identification for common HLA molecules helped elucidate HLA restriction in a subset of patients receiving third-party products. Intracellular interferon-γ expression in T cells in response to single peptides and response to cell lines stably transfected with a single HLA molecule demonstrated HLA-restricted CD4+ T-cell response, and these results correlated with clinical outcomes. Taken together, these data suggest that VSTs are a highly safe and effective therapy for the management of adenoviral infection in immunocompromised hosts. The trials were registered at www.clinicaltrials.gov as #NCT02048332 and #NCT02532452.
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Sivapalan R, Liu J, Chakraborty K, Arthofer E, Choudhry M, Barie PS, Barouch DH, Henley T. Virus Induced Lymphocytes (VIL) as a novel viral antigen-specific T cell therapy for COVID-19 and potential future pandemics. Sci Rep 2021; 11:15295. [PMID: 34315945 PMCID: PMC8316478 DOI: 10.1038/s41598-021-94654-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 07/13/2021] [Indexed: 12/18/2022] Open
Abstract
The a priori T cell repertoire and immune response against SARS-CoV-2 viral antigens may explain the varying clinical course and prognosis of patients having a mild COVID-19 infection as opposed to those developing more fulminant multisystem organ failure and associated mortality. Using a novel SARS-Cov-2-specific artificial antigen presenting cell (aAPC), coupled with a rapid expansion protocol (REP) as practiced in tumor infiltrating lymphocytes (TIL) therapy, we generate an immune catalytic quantity of Virus Induced Lymphocytes (VIL). Using T cell receptor (TCR)-specific aAPCs carrying co-stimulatory molecules and major histocompatibility complex (MHC) class-I immunodominant SARS-CoV-2 peptide-pentamer complexes, we expand virus-specific VIL derived from peripheral blood mononuclear cells (PBMC) of convalescent COVID-19 patients up to 1000-fold. This is achieved in a clinically relevant 7-day vein-to-vein time-course as a potential adoptive cell therapy (ACT) for COVID-19. We also evaluate this approach for other viral pathogens using Cytomegalovirus (CMV)-specific VIL from donors as a control. Rapidly expanded VIL are enriched in virus antigen-specificity and show an activated, polyfunctional cytokine profile and T effector memory phenotype which may contribute to a robust immune response. Virus-specific T cells can also be delivered allogeneically via MHC-typing and patient human leukocyte antigen (HLA)-matching to provide pragmatic treatment in a large-scale therapeutic setting. These data suggest that VIL may represent a novel therapeutic option that warrants further clinical investigation in the armamentarium against COVID-19 and other possible future pandemics.
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Affiliation(s)
| | - Jinyan Liu
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | | | | | | | - Philip S Barie
- Division of Trauma, Burns, Acute and Critical Care, Department of Surgery; and Division of Medical Ethics, Department of Medicine, Weill Cornell Medicine, New York-Presbyterian Hospital, Weill Cornell Medical Center, New York, NY, USA
| | - Dan H Barouch
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, MA, USA.
| | - Tom Henley
- Intima Bioscience, Inc., New York, NY, USA.
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[Viral infections in urology]. Urologe A 2021; 60:1150-1158. [PMID: 34228144 PMCID: PMC8258472 DOI: 10.1007/s00120-021-01589-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/09/2021] [Indexed: 11/25/2022]
Abstract
Einleitung Die COVID-19-Pandemie („coronavirus disease 2019“) hat eindrucksvoll gezeigt, dass Infektionskrankheiten enorme Auswirkungen auf das Gesundheitswesen und darüber hinaus haben können. In der Urologie spielen Viren bei spezifischen Entitäten eine Rolle, wo sich der Urologe mit Viruserkrankungen beschäftigen muss. Methodik Diese Übersichtsarbeit hat zum Ziel in der Urologie relevante Virusinfektionen zu beschreiben und insbesondere die Impfprävention hervorzuheben. Es erfolgte eine selektive Literaturrecherche zu den Themen „COVID und Urologie“, „Urogenitale Virusinfektionen“, „Virale urologische Infektionen in der Transplantationsmedizin“ sowie „Impfprävention von Viruserkrankungen“. Ergebnisse Coronaviren sind Viren, die bereits 2‑mal lokale Epidemien verursacht haben (SARS- [„severe acute respiratory syndrome“] und MERS-Epidemie [„middle east respiratory syndrome“]). Die Tatsache, dass die SARS-CoV-2-Erkrankung („severe acute respiratory syndrome coronavirus 2“) auch ohne Symptome ansteckend ist, hat im Wesentlichen zu der raschen Ausbreitung und weltweiten Pandemie geführt. Eine Vielzahl von Viren, die auch eine Virämie induzieren können, wurde im Ejakulat nachgewiesen und wird damit mit einer etwaigen urogenitalen Infektion in Verbindung gebracht. Hierzu zählen u. a. das Mumps‑, Coxsackie-Viren oder Enteroviren. Es wurde auch gezeigt, dass auch eine Zika-Virusinfektion sexuell über die Spermien als Carrier übertragen werden kann. Somit spielen Viren auch eine wichtige Rolle in der Reproduktion. Bei der Nierentransplantation sind Urologen häufig mit viralen Infektionen konfrontiert. Die effektivste Waffe gegenüber Viren stellt die Impfprävention dar. Schlussfolgerung Äthiopathogenetisch ist der Urogenitaltrakt im Rahmen einer Virämie oder über eine Reaktivierung durch eine Immunsuppression am häufigsten mitbetroffen. Therapeutisch kommt der Immunmodulation sowie der Impfprophylaxe eine führende Rolle zu.
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BK Polyomavirus Nephropathy in Kidney Transplantation: Balancing Rejection and Infection. Viruses 2021; 13:v13030487. [PMID: 33809472 PMCID: PMC7998398 DOI: 10.3390/v13030487] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 03/12/2021] [Accepted: 03/14/2021] [Indexed: 12/16/2022] Open
Abstract
BK polyomavirus nephropathy (BKVN) and allograft rejection are two closely-associated diseases on opposite ends of the immune scale in kidney transplant recipients. The principle of balancing the immune system remains the mainstay of therapeutic strategy. While patient outcomes can be improved through screening, risk factors identification, and rapid reduction of immunosuppressants, a lack of standard curative therapy is the primary concern during clinical practice. Additionally, difficulty in pathological differential diagnosis and clinicopathology’s dissociation pose problems for a definite diagnosis. This article discusses the delicate evaluation needed to optimize immunosuppression and reviews recent advances in molecular diagnosis and immunological therapy for BKVN patients. New biomarkers for BKVN diagnosis are under development. For example, measurement of virus-specific T cell level may play a role in steering immunosuppressants. The development of cellular therapy may provide prevention, even a cure, for BKVN, a complex post-transplant complication.
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