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Douglas AP, Lamoth F, John TM, Groll AH, Shigle TL, Papanicolaou GA, Chemaly RF, Carpenter PA, Dadwal SS, Walsh TJ, Kontoyiannis DP. American Society of Transplantation and Cellular Therapy Series: #8-Management and Prevention of Non-Aspergillus Molds in Hematopoietic Cell Transplantation Recipients. Transplant Cell Ther 2025; 31:194-223. [PMID: 39923936 DOI: 10.1016/j.jtct.2025.01.892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Accepted: 01/29/2025] [Indexed: 02/11/2025]
Abstract
The Practice Guidelines Committee of the American Society of Transplantation and Cellular Therapy partnered with its Transplant Infectious Disease Special Interest Group to create a guideline focusing on non-Aspergillus invasive molds, which are uncommon yet lethal invasive fungal diseases in the peri-hematopoietic cell transplant (HCT) period. We used a compendium-style approach by dissecting this broad, heterogeneous, and highly complex topic into a series of standalone frequently asked questions (FAQs) and tables. Adult and pediatric infectious diseases and HCT content experts developed, then answered FAQs, and finalized topics with harmonized recommendations. All the evidence for non-Aspergillus invasive mold infection is non-RCT and mostly level III, therefore there are no recommendation grades, and instead key references are provided. Through this format, this "8th" topic in the series focuses on the relevant risk factors, diagnostic considerations, prophylaxis, and treatment approaches relevant to rare mold infections in the pre- and post-transplant periods.
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Affiliation(s)
- Abby P Douglas
- Department of Infectious Diseases, National Centre for Infections in Cancer, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia; Department of Infectious Diseases and Immunology, Austin Health, Heidelberg, Victoria, Australia
| | - Frederic Lamoth
- Infectious Diseases Service and Institute of Microbiology, University Hospital of Lausanne and Lausanne University, Lausanne, Switzerland
| | - Teny M John
- Department of Infectious Diseases, Infection Control and Employee Health, Unit 1460, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Andreas H Groll
- Center for Bone Marrow Transplantation and Department of Pediatric Hematology and Oncology, Infectious Disease Research Program, University Children's Hospital Muenster, Muenster, Germany
| | - Terri Lynn Shigle
- Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Genovefa A Papanicolaou
- Department of Medicine, Memorial Sloan Kettering Cancer Center, Infectious Diseases Service, New York, New York
| | - Roy F Chemaly
- Department of Infectious Diseases, Infection Control and Employee Health, Unit 1460, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Paul A Carpenter
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington
| | - Sanjeet S Dadwal
- Department of Medicine, Division of Infectious Disease, City of Hope National Medical Center, Duarte, California
| | - Thomas J Walsh
- Departments of Medicine and Microbiology & Immunology, University of Maryland School of Medicine, Baltimore, Maryland; Center for Innovative Therapeutics and Diagnostics, Richmond, Virginia
| | - Dimitrios P Kontoyiannis
- Department of Infectious Diseases, Infection Control and Employee Health, Unit 1460, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Hensley MK, Dela Cruz CS. Host-Directed Adjunctive Therapies in Immunocompromised Patients with Pneumonia. Clin Chest Med 2025; 46:37-48. [PMID: 39890291 DOI: 10.1016/j.ccm.2024.10.003] [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] [Indexed: 02/03/2025]
Abstract
Immunocompromised (IC) hosts represent a unique patient population at risk for not only typical pathogens, but also opportunistic microorganisms. While antimicrobials remain the main treatment, new investigations have demonstrated the importance of host-response to pathogens. In this article, we highlight previously discovered and new areas of investigation for adjunctive host-response treatments for IC host pneumonia.
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Affiliation(s)
- Matthew K Hensley
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
| | - Charles S Dela Cruz
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Ji J, Roland LT. Invasive fungal rhinosinusitis: current evidence and research opportunities. Curr Opin Otolaryngol Head Neck Surg 2025; 33:20-30. [PMID: 39146258 DOI: 10.1097/moo.0000000000000993] [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: 08/17/2024]
Abstract
PURPOSE OF REVIEW To summarize the evidence surrounding diagnosis, treatment, prognosis, and surveillance of patients with acute invasive fungal sinusitis (AIFS) and discuss future research needs. RECENT FINDINGS New risk factors for AIFS such as COVID have been identified, and a new prognostic staging system has been developed. SUMMARY Most patients who develop AIFS are immunocompromised, with the majority having a history of diabetes or a hematologic malignancy. Unfortunately, there are not any highly sensitive and specific diagnostic tools. Therefore, a combination of signs and symptoms, imaging, endoscopy, biopsy, and labs should be used to diagnosis AIFS. Although surgery and systemic antifungals are known to improve outcomes, there is limited data on time to intervention, duration of antifungals, and surveillance patterns. There is also limited information on factors that can predict outcomes in AIFS patients. However, sensory/perceptual changes, prolonged neutropenia duration, and comorbidity burden may be associated with a poor prognosis.
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Affiliation(s)
- Jenny Ji
- Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine in St Louis, St Louis, Missouri, USA
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Rai P, Mehrotra S, Prajapati VK. Exploring immunotherapy to control human infectious diseases. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2024; 144:389-429. [PMID: 39978973 DOI: 10.1016/bs.apcsb.2024.10.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/22/2025]
Abstract
Infectious diseases continue to pose significant challenges to global health, especially with the rise of antibiotic resistance and emerging pathogens. Traditional treatments, while effective, are often limited in the face of rapidly evolving pathogens. Immunotherapy, which harnesses and enhances the body's immune response, offers a promising alternative to conventional approaches for the treatment of infectious diseases. By employing use of monoclonal antibodies, vaccines, cytokine therapies, and immune checkpoint inhibitors, immunotherapy has demonstrated considerable potential in overcoming treatment resistance and improving patient outcomes. Key innovations, including the development of mRNA vaccines, use of immune modulators, adoptive cell transfer, and chimeric antigen receptor (CAR)-T cell therapy are paving the way for more targeted pathogen clearance. Further, combining immunotherapy with conventional antibiotic treatment has demonstrated effectiveness against drug-resistant strains, but this chapter explores the evolving field of immunotherapy for the treatment of bacterial, viral, fungal, and parasitic infections. The chapter also explores the recent breakthroughs and ongoing clinical trials in infectious disease immunotherapy.
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Affiliation(s)
- Praveen Rai
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, India
| | - Sanjana Mehrotra
- Department of Human Genetics, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Vijay Kumar Prajapati
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, India.
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Londema M, Nijsten MWN, Bart J, Wiegersma JS, Sinha BNM, Postma DF. Delayed Diagnosis of Disseminated Invasive Aspergillosis with Purulent Myocarditis in an Immunocompromised Host. Infect Dis Rep 2024; 16:1182-1190. [PMID: 39728015 DOI: 10.3390/idr16060093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 11/19/2024] [Accepted: 11/20/2024] [Indexed: 12/28/2024] Open
Abstract
Introduction: Invasive aspergillosis (IA) is an opportunistic fungal infection that typically occurs in the immunocompromised host and is associated with severe morbidity and mortality. Myocardial abscess formation is seldomly described. Detailed Case Description: We present a case of IA with purulent myocarditis. The patient was on long-term high-dose corticosteroid and mycophenolate mofetil therapy for severe lupus nephritis. After multiple visits to his general practitioner and nephrologist for general malaise, he was admitted to our hospital with visual complaints. Within several days, he developed atrial fibrillation, respiratory insufficiency, and, finally, a decreased level of consciousness. After admission to the intensive care unit, the broncho alveolar lavage (BAL) fluid galactomannan (GM) index was normal, but the serum GM index was severely elevated. Despite initiation of antifungal therapy, the patient passed away shortly thereafter. Autopsy revealed massive intracranial hemorrhage and disseminated IA affecting the lungs, brain, and myocardium, with macroscopic myocardial abscess formation. Discussion: This classic case of diagnostic uncertainty illustrates how invasive fungal infections can progress to disseminated disease while showing nonspecific symptoms only. It emphasizes the importance of vigilance for opportunistic fungal infections in a growing category of immunocompromised patients. Conclusion: Clinicians should have a low threshold of suspicion for fungal infections in patients on combination immunosuppressive medication, such as high-dose corticosteroid therapy in combination with T-cell inhibitors like MMF.
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Affiliation(s)
- Mark Londema
- Department of Critical Care, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands
| | - Maarten W N Nijsten
- Department of Critical Care, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands
| | - Joost Bart
- Department of Pathology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands
| | - Janke S Wiegersma
- Department of Internal Medicine and Nephrology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands
| | - Bhanu N M Sinha
- Department of Medical Microbiology and Infection Prevention, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands
| | - Douwe F Postma
- Department of Internal Medicine and Infectious Diseases, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands
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Brown GD, Ballou ER, Bates S, Bignell EM, Borman AM, Brand AC, Brown AJP, Coelho C, Cook PC, Farrer RA, Govender NP, Gow NAR, Hope W, Hoving JC, Dangarembizi R, Harrison TS, Johnson EM, Mukaremera L, Ramsdale M, Thornton CR, Usher J, Warris A, Wilson D. The pathobiology of human fungal infections. Nat Rev Microbiol 2024; 22:687-704. [PMID: 38918447 DOI: 10.1038/s41579-024-01062-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/14/2024] [Indexed: 06/27/2024]
Abstract
Human fungal infections are a historically neglected area of disease research, yet they cause more than 1.5 million deaths every year. Our understanding of the pathophysiology of these infections has increased considerably over the past decade, through major insights into both the host and pathogen factors that contribute to the phenotype and severity of these diseases. Recent studies are revealing multiple mechanisms by which fungi modify and manipulate the host, escape immune surveillance and generate complex comorbidities. Although the emergence of fungal strains that are less susceptible to antifungal drugs or that rapidly evolve drug resistance is posing new threats, greater understanding of immune mechanisms and host susceptibility factors is beginning to offer novel immunotherapeutic options for the future. In this Review, we provide a broad and comprehensive overview of the pathobiology of human fungal infections, focusing specifically on pathogens that can cause invasive life-threatening infections, highlighting recent discoveries from the pathogen, host and clinical perspectives. We conclude by discussing key future challenges including antifungal drug resistance, the emergence of new pathogens and new developments in modern medicine that are promoting susceptibility to infection.
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Affiliation(s)
- Gordon D Brown
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK.
| | - Elizabeth R Ballou
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK
| | - Steven Bates
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK
| | - Elaine M Bignell
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK
| | - Andrew M Borman
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK
| | - Alexandra C Brand
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK
| | - Alistair J P Brown
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK
| | - Carolina Coelho
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK
| | - Peter C Cook
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK
| | - Rhys A Farrer
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK
| | - Nelesh P Govender
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK
| | - Neil A R Gow
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK
| | - William Hope
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK
| | - J Claire Hoving
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK
| | - Rachael Dangarembizi
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK
| | - Thomas S Harrison
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK
| | - Elizabeth M Johnson
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK
| | - Liliane Mukaremera
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK
| | - Mark Ramsdale
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK
| | | | - Jane Usher
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK
| | - Adilia Warris
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK
| | - Duncan Wilson
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, UK
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Bandeira TFGS, Marti LC, Rother ET, Correia LR, Machado CM. Use of Specific T Lymphocytes in Treating Cytomegalovirus Infection in Hematopoietic Cell Transplant Recipients: A Systematic Review. Pharmaceutics 2024; 16:1321. [PMID: 39458650 PMCID: PMC11510890 DOI: 10.3390/pharmaceutics16101321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 09/08/2024] [Accepted: 09/09/2024] [Indexed: 10/28/2024] Open
Abstract
Cytomegalovirus (CMV) poses a significant threat to post-hematopoietic cell transplantation (HCT). Control strategies include letermovir prophylaxis or ganciclovir pre-emptive therapy (PET). Without prophylaxis, 65-90% of seropositive recipients develop a clinically significant CMV infection. Due to PET drawbacks, letermovir prophylaxis is preferable, as it reduces CMV-related events and improves overall survival. However, refractory or resistant CMV-CS remains a challenge, with maribavir showing limited efficacy. This systematic review followed the Cochrane Manual and PRISMA guidelines and was registered in PROSPERO. Searches were conducted in PubMed, Scopus, Embase, and Web of Science. Out of 1895 identified records, 614 duplicates were removed, and subsequent screening excluded 1153 studies. Eleven included studies (2012-2024) involved 255 HCT recipients receiving adoptive immunotherapy (AI), primarily CMV-specific T-cell therapy. GvHD occurred in 1.82% of cases. Adverse events occurred in 4.4% of cases, while mild CRS was observed in 1.3% of patients. Efficacy, evaluated in 299 patients across eleven studies, showed an average response rate of 78.2%. CMV-CS recurrence was observed in 24.4% of 213 patients, and death due to CMV was reported in 9.7% of 307 patients across nine studies. Adoptive hCMV-specific T-cell immunotherapy appears to be a safe, effective alternative for refractory CMV-CS in HCT.
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Affiliation(s)
| | - Luciana C. Marti
- Instituto Israelita de Ensino e Pesquisa, Hospital Israelita Albert Einstein, Sao Paulo 05652-900, SP, Brazil; (L.C.M.); (E.T.R.)
| | - Edna T. Rother
- Instituto Israelita de Ensino e Pesquisa, Hospital Israelita Albert Einstein, Sao Paulo 05652-900, SP, Brazil; (L.C.M.); (E.T.R.)
| | - Lucas Reis Correia
- PROADI-SUS, Hospital Israelita Albert Einstein, Sao Paulo 05652-900, SP, Brazil;
| | - Clarisse M. Machado
- Laboratório de Virologia, Instituto de Medicina Tropical, Faculdade de Medicina, Universidade de São Paulo, Sao Paulo 05403-000, SP, Brazil;
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Whitehead AJ, Woodring T, Klein BS. Immunity to fungi and vaccine considerations. Cell Host Microbe 2024; 32:1681-1690. [PMID: 39389032 PMCID: PMC11980782 DOI: 10.1016/j.chom.2024.09.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 09/16/2024] [Indexed: 10/12/2024]
Abstract
Fungal disease poses a growing threat to public health that our current antifungal therapies are not well equipped to meet. As the population of immunocompromised hosts expands, and ecological changes favor the emergence of fungal pathogens, the development of new antifungal agents, including vaccines, becomes a global priority. Here, we summarize recent advancements in the understanding of fungal pathogenesis, key features of the host antifungal immune response, and how these findings could be leveraged to design novel approaches to deadly fungal disease.
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Affiliation(s)
- Alexander J Whitehead
- Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Therese Woodring
- Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Bruce S Klein
- Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Medical Microbiology and Immunology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA.
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9
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Bettelli F, Vallerini D, Lagreca I, Barozzi P, Riva G, Nasillo V, Paolini A, D’Amico R, Forghieri F, Morselli M, Pioli V, Gilioli A, Giusti D, Messerotti A, Bresciani P, Cuoghi A, Colaci E, Marasca R, Pagano L, Candoni A, Maertens J, Viale P, Mussini C, Manfredini R, Tagliafico E, Sarti M, Trenti T, Lewis R, Comoli P, Eccher A, Luppi M, Potenza L. Identification and validation of diagnostic cut-offs of the ELISpot assay for the diagnosis of invasive aspergillosis in high-risk patients. PLoS One 2024; 19:e0306728. [PMID: 38980880 PMCID: PMC11233002 DOI: 10.1371/journal.pone.0306728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 06/21/2024] [Indexed: 07/11/2024] Open
Abstract
OBJECTIVE We investigated the performance of enzyme linked immunospot (ELISpot) assay for the diagnosis of invasive aspergillosis (IA) in high-risk patients with hematologic malignancies. METHODS We prospectively enrolled two cohorts of patients undergoing intensive myelosuppressive or immunosuppressive treatments at high risk for IA. ELISpot was performed to detect Aspergillus-specific T cells producing Interleukin-10. RESULTS In the discovery cohort, a derived cut-off of 40 spot forming cells (SFCs)/106 PBMCs has shown to correctly classify IA cases with a sensitivity and specificity of 89.5% and 88.6%, respectively. This cut-off is lowered to 25 SFC when considering the subset of possible IA patients, with sensitivity and specificity of 76% and 93%, respectively. The application of the 40 SFCs cut-off to the validation cohort resulted in a positivity rate of 83.3% in proven/probable cases and a negativity rate of 92.5% in possible/non-IA cases. Adopting the 25 SCFs cut-off, the assay resulted positive in 83.3% of proven/probable cases while it resulted negative in 66.7% of possible/non-IA cases. CONCLUSIONS ELISpot shows promises in the diagnosis of IA and the possibility to use two distinct cut-offs with similar diagnostic performances according to patients' different pre-test probability of infection can widen its use in patients at risk.
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Affiliation(s)
- Francesca Bettelli
- Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Modena, Modena, Italy
| | - Daniela Vallerini
- Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Modena, Modena, Italy
| | - Ivana Lagreca
- Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Modena, Modena, Italy
| | - Patrizia Barozzi
- Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Modena, Modena, Italy
| | - Giovanni Riva
- Diagnostic Hematology and Clinical Genomics, Department of Laboratory Medicine and Pathology, AUSL/AOU Modena, Modena, Italy
| | - Vincenzo Nasillo
- Diagnostic Hematology and Clinical Genomics, Department of Laboratory Medicine and Pathology, AUSL/AOU Modena, Modena, Italy
| | - Ambra Paolini
- Diagnostic Hematology and Clinical Genomics, Department of Laboratory Medicine and Pathology, AUSL/AOU Modena, Modena, Italy
| | - Roberto D’Amico
- Statistic Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Modena, Modena, Italy
| | - Fabio Forghieri
- Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Modena, Modena, Italy
| | - Monica Morselli
- Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Modena, Modena, Italy
| | - Valeria Pioli
- Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Modena, Modena, Italy
| | - Andrea Gilioli
- Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Modena, Modena, Italy
| | - Davide Giusti
- Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Modena, Modena, Italy
| | - Andrea Messerotti
- Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Modena, Modena, Italy
| | - Paola Bresciani
- Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Modena, Modena, Italy
| | - Angela Cuoghi
- Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Modena, Modena, Italy
| | - Elisabetta Colaci
- Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Modena, Modena, Italy
| | - Roberto Marasca
- Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Modena, Modena, Italy
| | - Livio Pagano
- Hematology Division, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli - IRCCS and Università Cattolica del Sacro Cuore, Rome, Italy
| | - Anna Candoni
- Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Modena, Modena, Italy
| | - Johan Maertens
- Department of Hematology, University Hospital UZ Leuven, Leuven, Belgium
| | - Pierluigi Viale
- Infectious Diseases Unit, Department of Medical and Surgical Sciences, University of Bologna, IRCCS-AOU Policlinico Santorsola, Bologna, Italy
| | - Cristina Mussini
- Clinic of Infectious Diseases, Dipartimento Chirurgico, Medico, Odontoiatrico e di Scienze Morfologiche con interesse Trapiantologico, Oncologico e di Medicina Rigenerativa, University of Modena and Reggio Emilia, AOU Modena, Modena, Italy
| | - Rossella Manfredini
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Enrico Tagliafico
- Diagnostic Hematology and Clinical Genomics, Department of Laboratory Medicine and Pathology, AUSL/AOU Modena, Modena, Italy
| | - Mario Sarti
- Diagnostic Hematology and Clinical Genomics, Department of Laboratory Medicine and Pathology, AUSL/AOU Modena, Modena, Italy
| | - Tommaso Trenti
- Diagnostic Hematology and Clinical Genomics, Department of Laboratory Medicine and Pathology, AUSL/AOU Modena, Modena, Italy
| | - Russell Lewis
- Department of Molecular Medicine, University of Padua, Padua, Italy
| | - Patrizia Comoli
- Pediatric Hematology/Oncology Unit and Cell Factory, Foundation IRCCS Policlinico San Matteo, Pavia, Italy
| | - Albino Eccher
- Section of Pathology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Modena, Modena, Italy
| | - Mario Luppi
- Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Modena, Modena, Italy
| | - Leonardo Potenza
- Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Modena, Modena, Italy
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Kumaresan PR, Wurster S, Bavisi K, da Silva TA, Hauser P, Kinnitt J, Albert ND, Bharadwaj U, Neelapu S, Kontoyiannis DP. A novel lentiviral vector-based approach to generate chimeric antigen receptor T cells targeting Aspergillus fumigatus. mBio 2024; 15:e0341323. [PMID: 38415653 PMCID: PMC11005356 DOI: 10.1128/mbio.03413-23] [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: 01/03/2024] [Accepted: 02/08/2024] [Indexed: 02/29/2024] Open
Abstract
Invasive aspergillosis (IA) is a common and deadly mold infection in immunocompromised patients. As morbidity and mortality of IA are primarily driven by poor immune defense, adjunct immunotherapies, such as chimeric antigen receptor (CAR) T cells, are direly needed. Here, we propose a novel approach to generate Aspergillus fumigatus (AF)-CAR T cells using the single-chain variable fragment domain of monoclonal antibody AF-269-5 and a lentiviral vector system. These cells successfully targeted mature hyphal filaments of representative clinical and reference AF isolates and elicited a potent release of cytotoxic effectors and type 1 T cell cytokines. Furthermore, AF-CAR T cells generated from peripheral blood mononuclear cells of four healthy human donors and expanded with either of three cytokine stimulation regimens (IL-2, IL-2 + IL-21, or IL-7 + IL-15) significantly suppressed mycelial growth of AF-293 after 18 hours of co-culture and synergized with the immunomodulatory antifungal agent caspofungin to control hyphal growth for 36 hours. Moreover, cyclophosphamide-immunosuppressed NSG mice with invasive pulmonary aspergillosis that received two doses of 5 million AF-CAR T cells (6 and 48 hours after AF infection) showed significantly reduced morbidity on day 4 post-infection (P < 0.001) and significantly improved 7-day survival (P = 0.049) compared with mice receiving non-targeting control T cells, even without concomitant antifungal chemotherapy. In conclusion, we developed a novel lentiviral strategy to obtain AF-CAR T cells with high targeting efficacy, yielding significant anti-AF activity in vitro and short-term protection in vivo. Our approach could serve as an important steppingstone for future clinical translation of antifungal CAR T-cell therapy after further refinement and thorough preclinical evaluation.IMPORTANCEInvasive aspergillosis (IA) remains a formidable cause of morbidity and mortality in patients with hematologic malignancies and those undergoing hematopoietic stem cell transplantation. Despite the introduction of several new Aspergillus-active antifungals over the last 30 years, the persisting high mortality of IA in the setting of continuous and profound immunosuppression is a painful reminder of the major unmet need of effective antifungal immune enhancement therapies. The success of chimeric antigen receptor (CAR) T-cell therapy in cancer medicine has inspired researchers to translate this approach to opportunistic infections, including IA. Aiming to refine anti-Aspergillus CAR T-cell therapy and improve its feasibility for future clinical translation, we herein developed and validated a novel antibody-based CAR construct and lentiviral transduction method to accelerate the production of CAR T cells with high targeting efficacy against Aspergillus fumigatus. Our unique approach could provide a promising platform for future clinical translation of CAR T-cell-based antifungal immunotherapy.
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Affiliation(s)
- Pappanaicken R. Kumaresan
- Department of Hematopoietic Biology & Malignancy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Sebastian Wurster
- Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Karishma Bavisi
- Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | | | - Paul Hauser
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jordan Kinnitt
- Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Nathaniel D. Albert
- Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Uddalak Bharadwaj
- Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Sattva Neelapu
- Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Dimitrios P. Kontoyiannis
- Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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11
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Puumala E, Fallah S, Robbins N, Cowen LE. Advancements and challenges in antifungal therapeutic development. Clin Microbiol Rev 2024; 37:e0014223. [PMID: 38294218 PMCID: PMC10938895 DOI: 10.1128/cmr.00142-23] [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] [Indexed: 02/01/2024] Open
Abstract
Over recent decades, the global burden of fungal disease has expanded dramatically. It is estimated that fungal disease kills approximately 1.5 million individuals annually; however, the true worldwide burden of fungal infection is thought to be higher due to existing gaps in diagnostics and clinical understanding of mycotic disease. The development of resistance to antifungals across diverse pathogenic fungal genera is an increasingly common and devastating phenomenon due to the dearth of available antifungal classes. These factors necessitate a coordinated response by researchers, clinicians, public health agencies, and the pharmaceutical industry to develop new antifungal strategies, as the burden of fungal disease continues to grow. This review provides a comprehensive overview of the new antifungal therapeutics currently in clinical trials, highlighting their spectra of activity and progress toward clinical implementation. We also profile up-and-coming intracellular proteins and pathways primed for the development of novel antifungals targeting their activity. Ultimately, we aim to emphasize the importance of increased investment into antifungal therapeutics in the current continually evolving landscape of infectious disease.
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Affiliation(s)
- Emily Puumala
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Sara Fallah
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Nicole Robbins
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Leah E. Cowen
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
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12
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Boyer J, Feys S, Zsifkovits I, Hoenigl M, Egger M. Treatment of Invasive Aspergillosis: How It's Going, Where It's Heading. Mycopathologia 2023; 188:667-681. [PMID: 37100963 PMCID: PMC10132806 DOI: 10.1007/s11046-023-00727-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 03/17/2023] [Indexed: 04/28/2023]
Abstract
Despite improvements in treatment and diagnostics over the last two decades, invasive aspergillosis (IA) remains a devastating fungal disease. The number of immunocompromised patients and hence vulnerable hosts increases, which is paralleled by the emergence of a rise in IA cases. Increased frequencies of azole-resistant strains are reported from six continents, presenting a new challenge for the therapeutic management. Treatment options for IA currently consist of three classes of antifungals (azoles, polyenes, echinocandins) with distinctive advantages and shortcomings. Especially in settings of difficult to treat IA, comprising drug tolerance/resistance, limiting drug-drug interactions, and/or severe underlying organ dysfunction, novel approaches are urgently needed. Promising new drugs for the treatment of IA are in late-stage clinical development, including olorofim (a dihydroorotate dehydrogenase inhibitor), fosmanogepix (a Gwt1 enzyme inhibitor), ibrexafungerp (a triterpenoid), opelconazole (an azole optimized for inhalation) and rezafungin (an echinocandin with long half-life time). Further, new insights in the pathophysiology of IA yielding immunotherapy as a potential add-on therapy. Current investigations show encouraging results, so far mostly in preclinical settings. In this review we discuss current treatment strategies, give an outlook on possible new pharmaceutical therapeutic options, and, lastly, provide an overview of the ongoing research in immunotherapy for IA.
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Affiliation(s)
- Johannes Boyer
- Division of Infectious Diseases, Department of Internal Medicine, ECMM Excellence Center for Medical Mycology, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
| | - Simon Feys
- Medical Intensive Care Unit, University Hospitals Leuven, Louvain, Belgium
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Louvain, Belgium
| | - Isabella Zsifkovits
- Division of Infectious Diseases, Department of Internal Medicine, ECMM Excellence Center for Medical Mycology, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
| | - Martin Hoenigl
- Division of Infectious Diseases, Department of Internal Medicine, ECMM Excellence Center for Medical Mycology, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
- BioTechMed, Graz, Austria
| | - Matthias Egger
- Division of Infectious Diseases, Department of Internal Medicine, ECMM Excellence Center for Medical Mycology, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.
- BioTechMed, Graz, Austria.
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13
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Jalili A, Hajifathali A, Mohammadian M, Sankanian G, Sayahinouri M, Dehghani Ghorbi M, Roshandel E, Aghdami N. Virus-Specific T Cells: Promising Adoptive T Cell Therapy Against Infectious Diseases Following Hematopoietic Stem Cell Transplantation. Adv Pharm Bull 2023; 13:469-482. [PMID: 37646062 PMCID: PMC10460803 DOI: 10.34172/apb.2023.046] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 09/25/2022] [Accepted: 11/02/2022] [Indexed: 09/01/2023] Open
Abstract
Hematopoietic stem cell transplantation (HSCT) is a life-saving therapy for various hematologic disorders. Due to the bone marrow suppression and its long recovery period, secondary infections, like cytomegalovirus (CMV), Epstein-Bar virus (EBV), and adenovirus (AdV), are the leading causes of morbidity and mortality in HSCT cases. Drug resistance to the antiviral pharmacotherapies makes researchers develop adoptive T cell therapies like virus-specific T cell therapy. These studies have faced major challenges such as finding the most effective T cell expansion methods, isolating the expected subtype, defining the functionality of the end-cell population, product quality control, and clinical complications after the injection. This review discusses the viral infections after HSCT, T cells characteristics during chronic viral infection, application of virus-specific T cells (VSTs) for refractory infections, standard methods for producing VSTs and their limitation, clinical experiences on VSTs, focusing on outcomes and side effects that can be helpful in decision-making for patients and further researches.
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Affiliation(s)
- Arsalan Jalili
- Department of Applied Cell Sciences, Faculty of Basic Sciences and Advanced Medical Technologies, Royan Institute, ACECR, Tehran, Iran
- Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran
| | - Abbas Hajifathali
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mozhdeh Mohammadian
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ghazaleh Sankanian
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Sayahinouri
- Department of Immunology, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
- Parvaz Research Ideas Supporter institute, Tehran, Iran
| | - Mahmoud Dehghani Ghorbi
- Department of Internal Medicine, Imam Hossein Hospital, School of Medicine Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Elham Roshandel
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nasser Aghdami
- Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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14
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Lionakis MS. Exploiting antifungal immunity in the clinical context. Semin Immunol 2023; 67:101752. [PMID: 37001464 PMCID: PMC10192293 DOI: 10.1016/j.smim.2023.101752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Indexed: 03/31/2023]
Abstract
The continuous expansion of immunocompromised patient populations at-risk for developing life-threatening opportunistic fungal infections in recent decades has helped develop a deeper understanding of antifungal host defenses, which has provided the foundation for eventually devising immune-based targeted interventions in the clinic. This review outlines how genetic variation in certain immune pathway-related genes may contribute to the observed clinical variability in the risk of acquisition and/or severity of fungal infections and how immunogenetic-based patient stratification may enable the eventual development of personalized strategies for antifungal prophylaxis and/or vaccination. Moreover, this review synthesizes the emerging cytokine-based, cell-based, and other immunotherapeutic strategies that have shown promise as adjunctive therapies for boosting or modulating tissue-specific antifungal immune responses in the context of opportunistic fungal infections.
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Affiliation(s)
- Michail S Lionakis
- From the Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy & Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
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15
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Qadri H, Shah AH, Alkhanani M, Almilaibary A, Mir MA. Immunotherapies against human bacterial and fungal infectious diseases: A review. Front Med (Lausanne) 2023; 10:1135541. [PMID: 37122338 PMCID: PMC10140573 DOI: 10.3389/fmed.2023.1135541] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Accepted: 03/15/2023] [Indexed: 05/02/2023] Open
Abstract
Nations' ongoing struggles with a number of novel and reemerging infectious diseases, including the ongoing global health issue, the SARS-Co-V2 (severe acute respiratory syndrome coronavirus 2) outbreak, serve as proof that infectious diseases constitute a serious threat to the global public health. Moreover, the fatality rate in humans is rising as a result of the development of severe infectious diseases brought about by multiple drug-tolerant pathogenic microorganisms. The widespread use of traditional antimicrobial drugs, immunosuppressive medications, and other related factors led to the establishment of such drug resistant pathogenic microbial species. To overcome the difficulties commonly encountered by current infectious disease management and control processes, like inadequate effectiveness, toxicities, and the evolution of drug tolerance, new treatment solutions are required. Fortunately, immunotherapies already hold great potential for reducing these restrictions while simultaneously expanding the boundaries of healthcare and medicine, as shown by the latest discoveries and the success of drugs including monoclonal antibodies (MAbs), vaccinations, etc. Immunotherapies comprise methods for treating diseases that specifically target or affect the body's immune system and such immunological procedures/therapies strengthen the host's defenses to fight those infections. The immunotherapy-based treatments control the host's innate and adaptive immune responses, which are effective in treating different pathogenic microbial infections. As a result, diverse immunotherapeutic strategies are being researched more and more as alternative treatments for infectious diseases, leading to substantial improvements in our comprehension of the associations between pathogens and host immune system. In this review we will explore different immunotherapies and their usage for the assistance of a broad spectrum of infectious ailments caused by various human bacterial and fungal pathogenic microbes. We will discuss about the recent developments in the therapeutics against the growing human pathogenic microbial diseases and focus on the present and future of using immunotherapies to overcome these diseases. Graphical AbstractThe graphical abstract shows the therapeutic potential of different types of immunotherapies like vaccines, monoclonal antibodies-based therapies, etc., against different kinds of human Bacterial and Fungal microbial infections.
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Affiliation(s)
- Hafsa Qadri
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, Jammu and Kashmir, India
| | - Abdul Haseeb Shah
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, Jammu and Kashmir, India
| | - Mustfa Alkhanani
- Department of Biology, College of Sciences, University of Hafr Al Batin, Hafar Al Batin, Saudi Arabia
| | - Abdullah Almilaibary
- Department of Family and Community Medicine, Faculty of Medicine, Al Baha University, Al Baha, Saudi Arabia
| | - Manzoor Ahmad Mir
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, Jammu and Kashmir, India
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16
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Tischer-Zimmermann S, Salzer E, Bitencourt T, Frank N, Hoffmann-Freimüller C, Stemberger J, Maecker-Kolhoff B, Blasczyk R, Witt V, Fritsch G, Paster W, Lion T, Eiz-Vesper B, Geyeregger R. Rapid and sustained T cell-based immunotherapy against invasive fungal disease via a combined two step procedure. Front Immunol 2023; 14:988947. [PMID: 37090716 PMCID: PMC10114046 DOI: 10.3389/fimmu.2023.988947] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 03/09/2023] [Indexed: 04/25/2023] Open
Abstract
Introduction Aspergillus fumigatus (Asp) infections constitute a major cause of morbidity and mortality in patients following allogeneic hematopoietic stem cell transplantation (HSCT). In the context of insufficient host immunity, antifungal drugs show only limited efficacy. Faster and increased T-cell reconstitution correlated with a favorable outcome and a cell-based therapy approach strongly indicated successful clearance of fungal infections. Nevertheless, complex and cost- or time-intensive protocols hampered their implementation into clinical application. Methods To facilitate the clinical-scale manufacturing process of Aspergillus fumigatus-specific T cells (ATCs) and to enable immediate (within 24 hours) and sustained (12 days later) treatment of patients with invasive aspergillosis (IA), we adapted and combined two complementary good manufacturing practice (GMP)-compliant approaches, i) the direct magnetic enrichment of Interferon-gamma (IFN-γ) secreting ATCs using the small-scale Cytokine Secretion Assay (CSA) and ii) a short-term in vitro T-cell culture expansion (STE), respectively. We further compared stimulation with two standardized and commercially available products: Asp-lysate and a pool of overlapping peptides derived from different Asp-proteins (PepMix). Results For the fast CSA-based approach we detected IFN-γ+ ATCs after Asp-lysate- as well as PepMix-stimulation but with a significantly higher enrichment efficiency for stimulation with the Asp-lysate when compared to the PepMix. In contrast, the STE approach resulted in comparably high ATC expansion rates by using Asp-lysate or PepMix. Independent of the stimulus, predominantly CD4+ helper T cells with a central-memory phenotype were expanded while CD8+ T cells mainly showed an effector-memory phenotype. ATCs were highly functional and cytotoxic as determined by secretion of granzyme-B and IFN-γ. Discussion For patients with IA, the immediate adoptive transfer of IFN-γ+ ATCs followed by the administration of short-term in vitro expanded ATCs from the same donor, might be a promising therapeutic option to improve the clinical outcome.
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Affiliation(s)
- Sabine Tischer-Zimmermann
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
| | - Elisabeth Salzer
- St. Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria
- Department of Pediatrics, St. Anna Children’s Hospital, Medical University of Vienna, Vienna, Austria
- Department of Pediatrics, Laboratory for Pediatric Immunology, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, Netherlands
| | | | - Nelli Frank
- St. Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria
| | | | - Julia Stemberger
- St. Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria
| | - Britta Maecker-Kolhoff
- Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany
| | - Rainer Blasczyk
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
| | - Volker Witt
- Department of Pediatrics, St. Anna Children’s Hospital, Medical University of Vienna, Vienna, Austria
- Department of Pediatrics, Medical University of Vienna, Vienna, Austria
| | - Gerhard Fritsch
- St. Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria
| | - Wolfgang Paster
- St. Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria
| | - Thomas Lion
- St. Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria
| | - Britta Eiz-Vesper
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany
| | - René Geyeregger
- St. Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria
- Department of Pediatrics, St. Anna Children’s Hospital, Medical University of Vienna, Vienna, Austria
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17
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Loh JT, Lam KP. Fungal infections: Immune defense, immunotherapies and vaccines. Adv Drug Deliv Rev 2023; 196:114775. [PMID: 36924530 DOI: 10.1016/j.addr.2023.114775] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 03/05/2023] [Accepted: 03/07/2023] [Indexed: 03/17/2023]
Abstract
Invasive fungal infection is an under recognized and emerging global health threat. Recently, the World Health Organization (WHO) released the first ever list of health-threatening fungi to guide research and public health interventions to strengthen global response to fungi infections and antifungal resistance. Currently, antifungal drugs only demonstrate partial success in improving prognosis of infected patients, and this is compounded by the rapid evolution of drug resistance among fungi species. The increased prevalence of fungal infections in individuals with underlying immunological deficiencies reflects the importance of an intact host immune system in controlling mycoses, and further highlights immunomodulation as a potential new avenue for the treatment of disseminated fungal diseases. In this review, we will summarize how host innate immune cells sense invading fungi through their pattern recognition receptors, and subsequently initiate a series of effector mechanisms and adaptive immune responses to mediate fungal clearance. In addition, we will discuss emerging preclinical and clinical data on antifungal immunotherapies and fungal vaccines which can potentially expand our antifungal armamentarium in future.
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Affiliation(s)
- Jia Tong Loh
- Singapore Immunology Network, Agency for Science, Technology and Research, 8A Biomedical Grove, S138648, Republic of Singapore.
| | - Kong-Peng Lam
- Singapore Immunology Network, Agency for Science, Technology and Research, 8A Biomedical Grove, S138648, Republic of Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5, Science Drive 2, S117545, Republic of Singapore; School of Biological Sciences, College of Science, Nanyang Technological University, 60, Nanyang Drive, S637551, Republic of Singapore.
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18
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Velasco-de Andrés M, Muñoz-Sánchez G, Carrillo-Serradell L, Gutiérrez-Hernández MDM, Català C, Isamat M, Lozano F. Chimeric antigen receptor-based therapies beyond cancer. Eur J Immunol 2023; 53:e2250184. [PMID: 36649259 DOI: 10.1002/eji.202250184] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 11/29/2022] [Accepted: 01/16/2023] [Indexed: 01/18/2023]
Abstract
Adoptive cell transfer (ACT) therapies have gained renewed interest in the field of immunotherapy following the advent of chimeric antigen receptor (CAR) technology. This immunological breakthrough requires immune cell engineering with an artificial surface protein receptor for antigen-specific recognition coupled to an intracellular protein domain for cell activating functions. CAR-based ACT has successfully solved some hematological malignancies, and it is expected that other tumors may soon benefit from this approach. However, the potential of CAR technology is such that other immune-mediated disorders are beginning to profit from it. This review will focus on CAR-based ACT therapeutic areas other than oncology such as infection, allergy, autoimmunity, transplantation, and fibrotic repair. Herein, we discuss the results and limitations of preclinical and clinical studies in that regard.
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Affiliation(s)
| | - Guillermo Muñoz-Sánchez
- Servei d'Immunologia, Centre de Diagnòstic Biomèdic, Hospital Clínic de Barcelona, Barcelona, Spain
| | | | | | - Cristina Català
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Marcos Isamat
- Sepsia Therapeutics S.L., L'Hospitalet de Llobregat, Spain
| | - Francisco Lozano
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Servei d'Immunologia, Centre de Diagnòstic Biomèdic, Hospital Clínic de Barcelona, Barcelona, Spain
- Departament de Biomedicina, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain
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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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20
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Infection and Immunity. Clin Immunol 2023. [DOI: 10.1016/b978-0-12-818006-8.00007-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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Woodring T, Deepe GS, Levitz SM, Wuethrich M, Klein BS. They shall not grow mold: Soldiers of innate and adaptive immunity to fungi. Semin Immunol 2023; 65:101673. [PMID: 36459927 PMCID: PMC10311222 DOI: 10.1016/j.smim.2022.101673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Indexed: 11/30/2022]
Abstract
Fungi are ubiquitous commensals, seasoned predators, and important agents of emerging infectious diseases [1 ]. The immune system assumes the essential responsibility for responding intelligently to the presence of known and novel fungi to maintain host health. In this Review, we describe the immune responses to pathogenic fungi and the varied array of fungal agents confronting the vertebrate host within the broader context of fungal and animal evolution. We provide an overview of the mechanistic details of innate and adaptive antifungal immune responses, as well as ways in which these basic mechanisms support the development of vaccines and immunotherapies.
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Affiliation(s)
- Therese Woodring
- Departments of Pediatrics, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison WI, USA
| | - George S Deepe
- Department of Medicine, Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Stuart M Levitz
- Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Marcel Wuethrich
- Departments of Pediatrics, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison WI, USA
| | - Bruce S Klein
- Departments of Pediatrics, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison WI, USA; Departments of Internal Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison WI, USA; Departments of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison WI, USA.
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Chechi JL, da Costa FAC, Figueiredo JM, de Souza CM, Valdez AF, Zamith-Miranda D, Camara AC, Taborda CP, Nosanchuk JD. Vaccine development for pathogenic fungi: current status and future directions. Expert Rev Vaccines 2023; 22:1136-1153. [PMID: 37936254 PMCID: PMC11500455 DOI: 10.1080/14760584.2023.2279570] [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: 08/01/2023] [Accepted: 11/01/2023] [Indexed: 11/09/2023]
Abstract
INTRODUCTION Fungal infections are caused by a broad range of pathogenic fungi that are found worldwide with different geographic distributions, incidences, and mortality rates. Considering that there are relatively few approved medications available for combating fungal diseases and no vaccine formulation commercially available, multiple groups are searching for new antifungal drugs, examining drugs for repurposing and developing antifungal vaccines, in order to control deaths, sequels, and the spread of these complex infections. AREAS COVERED This review provides a summary of advances in fungal vaccine studies and the different approaches under development, such as subunit vaccines, whole organism vaccines, and DNA vaccines, as well as studies that optimize the use of adjuvants. We conducted a literature search of the PubMed with terms: fungal vaccines and genus of fungal pathogens (Cryptococcus spp. Candida spp. Coccidioides spp. Aspergillus spp. Sporothrix spp. Histoplasma spp. Paracoccidioides spp. Pneumocystis spp. and the Mucorales order), a total of 177 articles were collected from database. EXPERT OPINION Problems regarding the immune response development in an immunocompromised organism, the similarity between fungal and mammalian cells, and the lack of attention by health organizations to fungal infections are closely related to the fact that, at present, there are no fungal vaccines available for clinical use.
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Affiliation(s)
- Jéssica L. Chechi
- Laboratório de Fungos Dimórficos Patogênicos, Departamento de Microbiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brasil
| | - Felipe A. C. da Costa
- Laboratório de Fungos Dimórficos Patogênicos, Departamento de Microbiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brasil
- Laboratório de Micologia Médica (LIM-53), Departamento de Dermatologia, Instituto de Medicina Tropical, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brasil
| | - Julia M. Figueiredo
- Laboratório de Fungos Dimórficos Patogênicos, Departamento de Microbiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brasil
| | - Cássia M. de Souza
- Laboratório de Fisiologia e Biologia Molecular de Fungos, Departamento de Microbiologia, Universidade Estadual de Londrina, Londrina, Brasil
- Instituto Carlos Chagas, Fundação Oswaldo Cruz (Fiocruz), Curitiba, Brasil
| | - Alessandro F. Valdez
- Departments of Medicine (Division of Infectious Diseases) and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States
| | - Daniel Zamith-Miranda
- Departments of Medicine (Division of Infectious Diseases) and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States
| | - Aline C. Camara
- Laboratório de Fungos Dimórficos Patogênicos, Departamento de Microbiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brasil
- Laboratório de Micologia Médica (LIM-53), Departamento de Dermatologia, Instituto de Medicina Tropical, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brasil
| | - Carlos P. Taborda
- Laboratório de Fungos Dimórficos Patogênicos, Departamento de Microbiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brasil
- Laboratório de Micologia Médica (LIM-53), Departamento de Dermatologia, Instituto de Medicina Tropical, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brasil
| | - Joshua D. Nosanchuk
- Departments of Medicine (Division of Infectious Diseases) and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States
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23
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Puerta-Alcalde P, Garcia-Vidal C. Non- Aspergillus mould lung infections. Eur Respir Rev 2022; 31:31/166/220104. [PMID: 36261156 DOI: 10.1183/16000617.0104-2022] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 07/24/2022] [Indexed: 12/20/2022] Open
Abstract
Non-Aspergillus filamentous fungi causing invasive mould infections have increased over the last years due to the widespread use of anti-Aspergillus prophylaxis and increased complexity and survival of immunosuppressed patients. In the few studies that have reported on invasive mould infection epidemiology, Mucorales are the most frequently isolated group, followed by either Fusarium spp. or Scedosporium spp. The overall incidence is low, but related mortality is exceedingly high. Patients with haematological malignancies and haematopoietic stem cell transplant recipients comprise the classical groups at risk of infection for non-Aspergillus moulds due to profound immunosuppression and the vast use of anti-Aspergillus prophylaxis. Solid organ transplant recipients also face a high risk, especially those receiving lung transplants, due to direct exposure of the graft to mould spores with altered mechanical and immunological elimination, and intense, associated immunosuppression. Diagnosing non-Aspergillus moulds is challenging due to unspecific symptoms and radiological findings, lack of specific biomarkers, and low sensitivity of cultures. However, the advent of molecular techniques may prove helpful. Mucormycosis, fusariosis and scedosporiosis hold some differences regarding clinical paradigmatic presentations and preferred antifungal therapy. Surgery might be an option, especially in mucormycosis. Finally, various promising strategies to restore or enhance the host immune response are under current evaluation.
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24
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Ouellette CP. Adoptive Immunotherapy for Prophylaxis and Treatment of Cytomegalovirus Infection. Viruses 2022; 14:v14112370. [PMID: 36366468 PMCID: PMC9694397 DOI: 10.3390/v14112370] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 10/22/2022] [Accepted: 10/25/2022] [Indexed: 01/31/2023] Open
Abstract
Cytomegalovirus (CMV), a member of the Herpesviridae family, is frequent among hematopoietic cell transplant (HCT) and solid organ transplant (SOT) recipients in absence of antiviral prophylaxis, and is a major cause of morbidity and mortality in these vulnerable populations. Antivirals such ganciclovir, valganciclovir, and foscarnet are the backbone therapies, however drug toxicity and antiviral resistance may render these agents suboptimal in treatment. Newer therapies such as letermovir and maribavir have offered additional approaches for antiviral prophylaxis as well as treatment of drug resistant CMV infection, though may be limited by cost, drug intolerance, or toxicity. Adoptive immunotherapy, the transfer of viral specific T-cells (VSTs), offers a new approach in treatment of drug-resistant or refractory viral infections, with early clinical trials showing promise with respect to efficacy and safety. In this review, we will discuss some of the encouraging results and challenges of widespread adoption of VSTs in care of immunocompromised patients, with an emphasis on the clinical outcomes for treatment and prophylaxis of CMV infection among high-risk patient populations.
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Affiliation(s)
- Christopher P Ouellette
- Division of Pediatric Infectious Diseases and Host Defense Program, Nationwide Children's Hospital, Columbus, OH 43205, USA
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25
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Seif M, Kakoschke TK, Ebel F, Bellet MM, Trinks N, Renga G, Pariano M, Romani L, Tappe B, Espie D, Donnadieu E, Hünniger K, Häder A, Sauer M, Damotte D, Alifano M, White PL, Backx M, Nerreter T, Machwirth M, Kurzai O, Prommersberger S, Einsele H, Hudecek M, Löffler J. CAR T cells targeting Aspergillus fumigatus are effective at treating invasive pulmonary aspergillosis in preclinical models. Sci Transl Med 2022; 14:eabh1209. [PMID: 36170447 DOI: 10.1126/scitranslmed.abh1209] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Aspergillus fumigatus is a ubiquitous mold that can cause severe infections in immunocompromised patients, typically manifesting as invasive pulmonary aspergillosis (IPA). Adaptive and innate immune cells that respond to A. fumigatus are present in the endogenous repertoire of patients with IPA but are infrequent and cannot be consistently isolated and expanded for adoptive immunotherapy. Therefore, we gene-engineered A. fumigatus-specific chimeric antigen receptor (Af-CAR) T cells and demonstrate their ability to confer antifungal reactivity in preclinical models in vitro and in vivo. We generated a CAR targeting domain AB90-E8 that recognizes a conserved protein antigen in the cell wall of A. fumigatus hyphae. T cells expressing the Af-CAR recognized A. fumigatus strains and clinical isolates and exerted a direct antifungal effect against A. fumigatus hyphae. In particular, CD8+ Af-CAR T cells released perforin and granzyme B and damaged A. fumigatus hyphae. CD8+ and CD4+ Af-CAR T cells produced cytokines that activated macrophages to potentiate the antifungal effect. In an in vivo model of IPA in immunodeficient mice, CD8+ Af-CAR T cells localized to the site of infection, engaged innate immune cells, and reduced fungal burden in the lung. Adoptive transfer of CD8+ Af-CAR T cells conferred greater antifungal efficacy compared to CD4+ Af-CAR T cells and an improvement in overall survival. Together, our study illustrates the potential of gene-engineered T cells to treat aggressive infectious diseases that are difficult to control with conventional antimicrobial therapy and support the clinical development of Af-CAR T cell therapy to treat IPA.
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Affiliation(s)
- Michelle Seif
- Medizinische Klinik und Poliklinik II und Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, 97080 Würzburg, Germany
| | - Tamara Katharina Kakoschke
- Klinik und Poliklinik für Mund-, Kiefer- und Gesichtschirurgie, Klinikum der Universität München, LMU, 80337 München, Germany.,Institut für Infektionsmedizin und Zoonosen, Medizinische Fakultät, LMU, 80539 München, Germany
| | - Frank Ebel
- Institut für Infektionsmedizin und Zoonosen, Medizinische Fakultät, LMU, 80539 München, Germany
| | - Marina Maria Bellet
- Dipartimento di Medicina e Chirurgia, Università degli Studi di Perugia, 06132 Perugia, Italy
| | - Nora Trinks
- Lehrstuhl für Biotechnologie und Biophysik, Biozentrum und RVZ - Center for Integrative and Translational Bioimaging, Julius-Maximilians-Universität Würzburg, 97074 Würzburg, Germany
| | - Giorgia Renga
- Dipartimento di Medicina e Chirurgia, Università degli Studi di Perugia, 06132 Perugia, Italy
| | - Marilena Pariano
- Dipartimento di Medicina e Chirurgia, Università degli Studi di Perugia, 06132 Perugia, Italy
| | - Luigina Romani
- Dipartimento di Medicina e Chirurgia, Università degli Studi di Perugia, 06132 Perugia, Italy
| | - Beeke Tappe
- Medizinische Klinik und Poliklinik II und Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, 97080 Würzburg, Germany
| | - David Espie
- Université de Paris, Institut Cochin, INSERM, CNRS, 75014 Paris, France.,CAR-T Cells Department, Invectys, 75013 Paris, France
| | - Emmanuel Donnadieu
- Université de Paris, Institut Cochin, INSERM, CNRS, 75014 Paris, France.,Equipe labellisée Ligue Contre le Cancer, 75014 Paris, France
| | - Kerstin Hünniger
- Institut für Hygiene und Mikrobiologie, Julius-Maximilians-Universität Würzburg, 97080 Würzburg, Germany.,Fungal Septomics Research Group, Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie - Hans-Knöll-Institut (HKI), 07743 Jena, Germany
| | - Antje Häder
- Fungal Septomics Research Group, Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie - Hans-Knöll-Institut (HKI), 07743 Jena, Germany
| | - Markus Sauer
- Lehrstuhl für Biotechnologie und Biophysik, Biozentrum und RVZ - Center for Integrative and Translational Bioimaging, Julius-Maximilians-Universität Würzburg, 97074 Würzburg, Germany
| | - Diane Damotte
- Department of Pathology, Paris Centre University Hospitals, AP-HP, 75014 Paris, France.,INSERM U1138, Cordeliers Research Center, Team Cancer, Immune Control and Escape, Paris, France; University Pierre and Marie Curie, 75006 Paris, France
| | - Marco Alifano
- Department of Thoracic Surgery, Paris Centre University Hospitals, AP-HP, Paris, France; University Paris Descartes, 75014 Paris, France
| | - P Lewis White
- Public Health Wales, Microbiology Cardiff, UHW, CF14 4XW Cardiff, UK
| | - Matthijs Backx
- Public Health Wales, Microbiology Cardiff, UHW, CF14 4XW Cardiff, UK
| | - Thomas Nerreter
- Medizinische Klinik und Poliklinik II und Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, 97080 Würzburg, Germany
| | - Markus Machwirth
- Medizinische Klinik und Poliklinik II und Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, 97080 Würzburg, Germany
| | - Oliver Kurzai
- Institut für Hygiene und Mikrobiologie, Julius-Maximilians-Universität Würzburg, 97080 Würzburg, Germany.,Fungal Septomics Research Group, Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie - Hans-Knöll-Institut (HKI), 07743 Jena, Germany
| | - Sabrina Prommersberger
- Medizinische Klinik und Poliklinik II und Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, 97080 Würzburg, Germany
| | - Hermann Einsele
- Medizinische Klinik und Poliklinik II und Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, 97080 Würzburg, Germany
| | - Michael Hudecek
- Medizinische Klinik und Poliklinik II und Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, 97080 Würzburg, Germany
| | - Jürgen Löffler
- Medizinische Klinik und Poliklinik II und Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, 97080 Würzburg, Germany
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26
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Viral infection in hematopoietic stem cell transplantation: an International Society for Cell & Gene Therapy Stem Cell Engineering Committee review on the role of cellular therapy in prevention and treatment. Cytotherapy 2022; 24:884-891. [PMID: 35705447 DOI: 10.1016/j.jcyt.2022.05.010] [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: 12/30/2021] [Revised: 04/13/2022] [Accepted: 05/22/2022] [Indexed: 11/20/2022]
Abstract
Despite recent advances in the field of HSCT, viral infections remain a frequent causeof morbidity and mortality among HSCT recipients. Adoptive transfer of viral specific T cells has been successfully used both as prophylaxis and treatment of viral infections in immunocompromised HSCT recipients. Increasingly, precise risk stratification of HSCT recipients with infectious complications should incorporate not only pretransplant clinical criteria, but milestones of immune reconstitution as well. These factors can better identify those at highest risk of morbidity and mortality and identify a population of HSCT recipients in whom adoptive therapy with viral specific T cells should be considered for either prophylaxis or second line treatment early after inadequate response to first line antiviral therapy. Broadening these approaches to improve outcomes for transplant recipients in countries with limited resources is a major challenge. While the principles of risk stratification can be applied, early detection of viral reactivation as well as treatment is challenging in regions where commercial PCR assays and antiviral agents are not readily available.
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27
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Rosichini M, Catanoso M, Screpanti I, Felli MP, Locatelli F, Velardi E. Signaling Crosstalks Drive Generation and Regeneration of the Thymus. Front Immunol 2022; 13:920306. [PMID: 35734178 PMCID: PMC9207182 DOI: 10.3389/fimmu.2022.920306] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 05/17/2022] [Indexed: 12/19/2022] Open
Abstract
Optimal recovery of immune competence after periods of hematopoietic insults or stress is crucial to re-establish patient response to vaccines, pathogens and tumor antigens. This is particularly relevant for patients receiving high doses of chemotherapy or radiotherapy, who experience prolonged periods of lymphopenia, which can be associated with an increased risk of infections, malignant relapse, and adverse clinical outcome. While the thymus represents the primary organ responsible for the generation of a diverse pool of T cells, its function is profoundly impaired by a range of acute insults (including those caused by cytoreductive chemo/radiation therapy, infections and graft-versus-host disease) and by the chronic physiological deterioration associated with aging. Impaired thymic function increases the risk of infections and tumor antigen escape due to a restriction in T-cell receptor diversity and suboptimal immune response. Therapeutic approaches that can promote the renewal of the thymus have the potential to restore immune competence in patients. Previous work has documented the importance of the crosstalk between thymocytes and thymic epithelial cells in establishing correct architecture and function of thymic epithelium. This crosstalk is relevant not only during thymus organogenesis, but also to promote the recovery of its function after injuries. In this review, we will analyze the signals involved in the crosstalk between TECs and hematopoietic cells. We will focus in particular on how signals from T-cells can regulate TEC function and discuss the relevance of these pathways in restoring thymic function and T-cell immunity in experimental models, as well as in the clinical setting.
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Affiliation(s)
- Marco Rosichini
- Department of Pediatric Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Marialuigia Catanoso
- Department of Pediatric Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Isabella Screpanti
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Maria Pia Felli
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Franco Locatelli
- Department of Pediatric Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Department of Maternal and Child Health, Sapienza University of Rome, Rome, Italy
| | - Enrico Velardi
- Department of Pediatric Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- *Correspondence: Enrico Velardi,
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Wang Y, Xu H, Chen N, Yang J, Zhou H. LncRNA: A Potential Target for Host-Directed Therapy of Candida Infection. Pharmaceutics 2022; 14:pharmaceutics14030621. [PMID: 35335994 PMCID: PMC8954347 DOI: 10.3390/pharmaceutics14030621] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 02/25/2022] [Accepted: 03/09/2022] [Indexed: 02/01/2023] Open
Abstract
Despite various drugs work against Candida, candidiasis represents clinical management challenges worldwide due to the rising incidence and recurrence rate, as well as epidemics, of new drug-resistant pathogens. Recent insights into interactions between Candida and hosts contribute to exploring novel therapeutic strategies, termed host-directed therapies (HDTs). HDTs are viable adjuncts with good efficacy for the existing standard antifungal regimens. However, HDTs induce other response unintendedly, thus requiring molecular targets with highly specificity. Long noncoding RNAs (lncRNAs) with highly specific expression patterns could affect biological processes, including the immune response. Herein, this review will summarize recent advances of HDTs based on the Candida–host interaction. Especially, the findings and application strategies of lncRNAs related to the host response are emphasized. We propose it is feasible to target lncRNAs to modulate the host defense during Candida infection, which provides a new perspective in identifying options of HDTs for candidiasis.
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Ye Y, Yang L, Yuan X, Huang H, Luo Y. Optimization of Donor Lymphocyte Infusion for AML Relapse After Allo-HCT in the Era of New Drugs and Cell Engineering. Front Oncol 2022; 11:790299. [PMID: 35155192 PMCID: PMC8829143 DOI: 10.3389/fonc.2021.790299] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 12/28/2021] [Indexed: 12/19/2022] Open
Abstract
Donor lymphocyte infusion (DLI) is a key strategy for the treatment of AML relapse after allogeneic hematopoietic cell transplantation (allo-HCT) and has been used for either prophylactic, pre-emptive, or therapeutic purposes. However, the prognosis of these patients remains dismal even after DLI infusion (2-year overall survival, ~25%), and the efficacy is achieved at the cost of toxicities such as graft-versus-host (GVH) disease. Attempts to optimize DLI efficacy and safety, such as dose/timing modification and the use of cytoreduction, before DLI have been performed previously. Recently, a great number of novel targeted and immunomodulatory agents have emerged. Some of them, such as hypomethylating agents, FLT3 and Bcl-2 inhibitors, have been used in combination with DLI, aiming to enhance the graft-versus-leukemia effect. Moreover, manipulation of the DLI graft through cell selection (e.g., donor NK cells) or cell engineering (donor CAR-T cells) has shown potentially superior anti-tumor effects but less GVH effect than conventional DLI in clinical trials. This review summarizes the recent advances on the use of DLI for the prophylaxis/treatment of AML relapse and discusses future strategies which may further improve the treatment efficacy.
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Affiliation(s)
- Yishan Ye
- First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Luxin Yang
- First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Xiaolin Yuan
- First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China
| | - He Huang
- First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Yi Luo
- First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Institute of Hematology, Zhejiang University, Hangzhou, China
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Füchsl F, Krackhardt AM. Adoptive Cellular Therapy for Multiple Myeloma Using CAR- and TCR-Transgenic T Cells: Response and Resistance. Cells 2022; 11:410. [PMID: 35159220 PMCID: PMC8834324 DOI: 10.3390/cells11030410] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/17/2022] [Accepted: 01/21/2022] [Indexed: 12/15/2022] Open
Abstract
Despite the substantial improvement of therapeutic approaches, multiple myeloma (MM) remains mostly incurable. However, immunotherapeutic and especially T cell-based approaches pioneered the therapeutic landscape for relapsed and refractory disease recently. Targeting B-cell maturation antigen (BCMA) on myeloma cells has been demonstrated to be highly effective not only by antibody-derived constructs but also by adoptive cellular therapies. Chimeric antigen receptor (CAR)-transgenic T cells lead to deep, albeit mostly not durable responses with manageable side-effects in intensively pretreated patients. The spectrum of adoptive T cell-transfer covers synthetic CARs with diverse specificities as well as currently less well-established T cell receptor (TCR)-based personalized strategies. In this review, we want to focus on treatment characteristics including efficacy and safety of CAR- and TCR-transgenic T cells in MM as well as the future potential these novel therapies may have. ACT with transgenic T cells has only entered clinical trials and various engineering strategies for optimization of T cell responses are necessary to overcome therapy resistance mechanisms. We want to outline the current success in engineering CAR- and TCR-T cells, but also discuss challenges including resistance mechanisms of MM for evading T cell therapy and point out possible novel strategies.
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Affiliation(s)
- Franziska Füchsl
- School of Medicine, Klinik und Poliklinik für Innere Medizin III, Klinikum rechts der Isar, Technische Universität München, Ismaningerstraße 22, 81675 Munich, Germany;
| | - Angela M. Krackhardt
- School of Medicine, Klinik und Poliklinik für Innere Medizin III, Klinikum rechts der Isar, Technische Universität München, Ismaningerstraße 22, 81675 Munich, Germany;
- German Cancer Consortium (DKTK), Partner-Site Munich, and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Einsteinstraße 25, 81675 Munich, Germany
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31
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Cytomegalovirus and other herpesviruses after hematopoietic cell and solid organ transplantation: From antiviral drugs to virus-specific T cells. Transpl Immunol 2022; 71:101539. [PMID: 35051589 DOI: 10.1016/j.trim.2022.101539] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 01/11/2022] [Accepted: 01/11/2022] [Indexed: 12/13/2022]
Abstract
Herpesviruses can either cause primary infection or may get reactivated after both hematopoietic cell and solid organ transplantations. In general, viral infections increase post-transplant morbidity and mortality. Prophylactic, preemptive, or therapeutically administered antiviral drugs may be associated with serious side effects and may induce viral resistance. Virus-specific T cells represent a valuable addition to antiviral treatment, with high rates of response and minimal side effects. Even low numbers of virus-specific T cells manufactured by direct selection methods can reconstitute virus-specific immunity after transplantation and control viral replication. Virus-specific T cells belong to the advanced therapy medicinal products, and their production is regulated by appropriate legislation; also, strict safety regulations are required to minimize their side effects.
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32
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Takahashi T, Prockop SE. T-cell depleted haploidentical hematopoietic cell transplantation for pediatric malignancy. Front Pediatr 2022; 10:987220. [PMID: 36313879 PMCID: PMC9614427 DOI: 10.3389/fped.2022.987220] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 09/20/2022] [Indexed: 11/13/2022] Open
Abstract
Access to allogenic hematopoietic cell transplantation (HCT), a potentially curative treatment for chemotherapy-resistant hematologic malignancies, can be limited if no human leukocyte antigen (HLA) identical related or unrelated donor is available. Alternative donors include Cord Blood as well as HLA-mismatched unrelated or related donors. If the goal is to minimize the number of HLA disparities, partially matched unrelated donors are more likely to share 8 or 9 of 10 HLA alleles with the recipient. However, over the last decade, there has been success with haploidentical HCT performed using the stem cells from HLA half-matched related donors. As the majority of patients have at least one eligible and motivated haploidentical donor, recruitment of haploidentical related donors is frequently more rapid than of unrelated donors. This advantage in the accessibility has historically been offset by the increased risks of graft rejection, graft-versus-host disease and delayed immune reconstitution. Various ex vivo T-cell depletion (TCD) methods have been investigated to overcome the immunological barrier and facilitate immune reconstitution after a haploidentical HCT. This review summarizes historical and contemporary clinical trials of haploidentical TCD-HCT, mainly in pediatric malignancy, and describes the evolution of these approaches with a focus on serial improvements in the kinetics of immune reconstitution. Methods of TCD discussed include in vivo as well as ex vivo positive and negative selection. In addition, haploidentical TCD as a platform for post-HCT cellular therapies is discussed. The present review highlights that, as a result of the remarkable progress over half a century, haploidentical TCD-HCT can now be considered as a preferred alternative donor option for children with hematological malignancy in need of allogeneic HCT.
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Affiliation(s)
- Takuto Takahashi
- Pediatric Stem Cell Transplantation, Boston Children's Hospital/Dana-Farber Cancer Institute, Boston, MA, United States.,Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, Minneapolis, MN, United States
| | - Susan E Prockop
- Pediatric Stem Cell Transplantation, Boston Children's Hospital/Dana-Farber Cancer Institute, Boston, MA, United States
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33
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Luberto L, Neroni B, Gandini O, Fiscarelli EV, Salvatori G, Roscilli G, Marra E. Genetic Vaccination as a Flexible Tool to Overcome the Immunological Complexity of Invasive Fungal Infections. Front Microbiol 2021; 12:789774. [PMID: 34975811 PMCID: PMC8715041 DOI: 10.3389/fmicb.2021.789774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 11/25/2021] [Indexed: 11/13/2022] Open
Abstract
The COVID-19 pandemic has highlighted genetic vaccination as a powerful and cost-effective tool to counteract infectious diseases. Invasive fungal infections (IFI) remain a major challenge among immune compromised patients, particularly those undergoing allogeneic hematopoietic bone marrow transplantation (HSCT) or solid organ transplant (SOT) both presenting high morbidity and mortality rates. Candidiasis and Aspergillosis are the major fungal infections among these patients and the failure of current antifungal therapies call for new therapeutic aids. Vaccination represents a valid alternative, and proof of concept of the efficacy of this approach has been provided at clinical level. This review will analyze current understanding of antifungal immunology, with a particular focus on genetic vaccination as a suitable strategy to counteract these diseases.
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Affiliation(s)
- Laura Luberto
- Takis s.r.l., Rome, Italy
- *Correspondence: Laura Luberto,
| | - Bruna Neroni
- Cystic Fibrosis Diagnostic Section, U.O. Microbiology and Immunology Diagnostic, Department of Immunology and Laboratory Medicine, Children’s Hospital Bambino Gesù Organization IRCCS, Rome, Italy
| | - Orietta Gandini
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Ersilia Vita Fiscarelli
- Cystic Fibrosis Diagnostic Section, U.O. Microbiology and Immunology Diagnostic, Department of Immunology and Laboratory Medicine, Children’s Hospital Bambino Gesù Organization IRCCS, Rome, Italy
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Hansen BT, Bacher P, Eiz-Vesper B, Heckl SM, Klapper W, Koch K, Maecker-Kolhoff B, Baldus CD, Fransecky L. Adoptive Cell Transfer of Allogeneic Epstein–Barr Virus-Specific T Lymphocytes for Treatment of Refractory EBV-Associated Posttransplant Smooth Muscle Tumors: A Case Report. Front Immunol 2021; 12:727814. [PMID: 34925312 PMCID: PMC8677671 DOI: 10.3389/fimmu.2021.727814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Accepted: 11/01/2021] [Indexed: 11/13/2022] Open
Abstract
Posttransplant smooth muscle tumors (PTSMTs) are rare Epstein–Barr virus (EBV)-associated neoplasms, mostly occurring after solid organ transplantation. Current therapeutic strategies include surgery and reduction of immunosuppressive medication. We describe for the first time a novel treatment approach for PTSMT by adoptive cell transfer (ACT) of EBV-specific T cells to a 20-year-old patient with a medical history of cardiac transplantation, posttransplant lymphoproliferative disease, and multilocular PTSMT. During ACT, mild cytokine release syndrome occurred, while no unexpected safety signals were recorded. We observed in vivo expansion of EBV-specific T cells and reduction of EBV viremia. Best response was stable disease after 4 months with reduction of EBV viremia and normalization of lactate dehydrogenase levels. ACT with EBV-specific T cells may be a safe and efficacious therapeutic option for PTSMT that warrants further exploration.
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Affiliation(s)
- Bjoern-Thore Hansen
- Medical Department II – Hematology and Oncology, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Petra Bacher
- Institute of Immunology, Christian-Albrechts-University of Kiel, Kiel, Germany
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Britta Eiz-Vesper
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
| | - Steffen M. Heckl
- Medical Department II – Hematology and Oncology, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Wolfram Klapper
- Section for Hematopathology and Lymph Node Registry, Department of Pathology, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Karoline Koch
- Section for Hematopathology and Lymph Node Registry, Department of Pathology, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Britta Maecker-Kolhoff
- Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
| | - Claudia D. Baldus
- Medical Department II – Hematology and Oncology, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Lars Fransecky
- Medical Department II – Hematology and Oncology, University Hospital Schleswig-Holstein, Kiel, Germany
- *Correspondence: Lars Fransecky,
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Karavalakis G, Yannaki E, Papadopoulou A. Reinforcing the Immunocompromised Host Defense against Fungi: Progress beyond the Current State of the Art. J Fungi (Basel) 2021; 7:jof7060451. [PMID: 34204025 PMCID: PMC8228486 DOI: 10.3390/jof7060451] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 05/31/2021] [Accepted: 06/02/2021] [Indexed: 12/11/2022] Open
Abstract
Despite the availability of a variety of antifungal drugs, opportunistic fungal infections still remain life-threatening for immunocompromised patients, such as those undergoing allogeneic hematopoietic cell transplantation or solid organ transplantation. Suboptimal efficacy, toxicity, development of resistant variants and recurrent episodes are limitations associated with current antifungal drug therapy. Adjunctive immunotherapies reinforcing the host defense against fungi and aiding in clearance of opportunistic pathogens are continuously gaining ground in this battle. Here, we review alternative approaches for the management of fungal infections going beyond the state of the art and placing an emphasis on fungus-specific T cell immunotherapy. Harnessing the power of T cells in the form of adoptive immunotherapy represents the strenuous protagonist of the current immunotherapeutic approaches towards combating invasive fungal infections. The progress that has been made over the last years in this field and remaining challenges as well, will be discussed.
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Affiliation(s)
- Georgios Karavalakis
- Hematology Department-Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center, “George Papanikolaou” Hospital, 57010 Thessaloniki, Greece; (G.K.); (E.Y.)
| | - Evangelia Yannaki
- Hematology Department-Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center, “George Papanikolaou” Hospital, 57010 Thessaloniki, Greece; (G.K.); (E.Y.)
- Department of Medicine, University of Washington, Seattle, WA 98195, USA
| | - Anastasia Papadopoulou
- Hematology Department-Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center, “George Papanikolaou” Hospital, 57010 Thessaloniki, Greece; (G.K.); (E.Y.)
- Correspondence: ; Tel.: +30-2313-307-693; Fax: +30-2313-307-521
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36
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Parajuli S, Jorgenson M, Meyers RO, Djamali A, Galipeau J. Role of Virus-Specific T Cell Therapy for Cytomegalovirus and BK Infections in Kidney Transplant Recipients. KIDNEY360 2021; 2:905-915. [PMID: 35373059 PMCID: PMC8791350 DOI: 10.34067/kid.0001572021] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 03/24/2021] [Indexed: 02/04/2023]
Abstract
Cytomegalovirus (CMV) and BK virus (BKV) are common viral infections after kidney transplant. Their negative effects on patient and graft outcomes have been well described. However, despite improvement in screening and prophylaxis strategies, CMV and BKV continue to negatively affect both short- and long-term graft survival. Adequate cell-mediated immunity is essential for the control and prevention of opportunistic viral infections, such as CMV and BKV. Therefore, immune reconstitution, in particular T cell recovery, is a key factor in antiviral control after kidney transplantation. Cell-based immunotherapy offers an attractive alternative approach to traditional interventions. Adoptive T cell transfer, via infusions of allogeneic virus-specific T lymphocytes is capable of restoring virus-specific T cell immunity, and are safe and effective in the treatment of viral infections after hematopoietic stem cell transplantation. In this article, we review the emerging role of virus-specific T cell therapy in the management of CMV and BKV after kidney transplantation. On the basis of the available data, virus-specific T cell therapy may be a promising addition to the antiviral treatment armamentarium after kidney transplantation. Future studies are needed to more clearly define the efficacy and risks of virus-specific T cell therapy in the kidney transplant population.
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Affiliation(s)
- Sandesh Parajuli
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Margaret Jorgenson
- Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, Wisconsin
| | - Ross O. Meyers
- Division of Pharmacy Professional Development, University of Wisconsin-Madison School of Pharmacy, Madison, Wisconsin
- Program for Advanced Cell Therapy, University of Wisconsin Hospital and Clinics and School of Medicine and Public Health, Madison Wisconsin
| | - Arjang Djamali
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Jacques Galipeau
- Program for Advanced Cell Therapy, University of Wisconsin Hospital and Clinics and School of Medicine and Public Health, Madison Wisconsin
- Division of Hematology and Oncology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
- University of Wisconsin Carbone Cancer Center, Madison, Wisconsin
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Koukoulias K, Papadopoulou A, Kouimtzidis A, Papayanni PG, Papaloizou A, Sotiropoulos D, Yiangou M, Costeas P, Anagnostopoulos A, Yannaki E, Kaloyannidis P. Non-transplantable cord blood units as a source for adoptive immunotherapy of leukaemia and a paradigm of circular economy in medicine. Br J Haematol 2021; 194:158-167. [PMID: 34036576 DOI: 10.1111/bjh.17464] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 03/15/2021] [Indexed: 12/17/2022]
Abstract
Advances in immunotherapy with T cells armed with chimeric antigen receptors (CAR-Ts), opened up new horizons for the treatment of B-cell lymphoid malignancies. However, the lack of appropriate targetable antigens on the malignant myeloid cell deprives patients with refractory acute myeloid leukaemia of effective CAR-T therapies. Although non-engineered T cells targeting multiple leukaemia-associated antigens [i.e. leukaemia-specific T cells (Leuk-STs)] represent an alternative approach, the prerequisite challenge to obtain high numbers of dendritic cells (DCs) for large-scale Leuk-ST generation, limits their clinical implementation. We explored the feasibility of generating bivalent-Leuk-STs directed against Wilms tumour 1 (WT1) and preferentially expressed antigen in melanoma (PRAME) from umbilical cord blood units (UCBUs) disqualified for allogeneic haematopoietic stem cell transplantation. By repurposing non-transplantable UCBUs and optimising culture conditions, we consistently produced at clinical scale, both cluster of differentiation (CD)34+ cell-derived myeloid DCs and subsequently polyclonal bivalent-Leuk-STs. Those bivalent-Leuk-STs contained CD8+ and CD4+ T cell subsets predominantly of effector memory phenotype and presented high specificity and cytotoxicity against both WT1 and PRAME. In the present study, we provide a paradigm of circular economy by repurposing unusable UCBUs and a platform for future banking of Leuk-STs, as a 'third-party', 'off-the-shelf' T-cell product for the treatment of acute leukaemias.
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Affiliation(s)
- Kiriakos Koukoulias
- Gene and Cell Therapy Center, Hematology Department-HCT Unit, George Papanikolaou Hospital, Thessaloniki, Greece.,Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Anastasia Papadopoulou
- Gene and Cell Therapy Center, Hematology Department-HCT Unit, George Papanikolaou Hospital, Thessaloniki, Greece
| | - Anastasios Kouimtzidis
- Gene and Cell Therapy Center, Hematology Department-HCT Unit, George Papanikolaou Hospital, Thessaloniki, Greece.,Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Penelope-Georgia Papayanni
- Gene and Cell Therapy Center, Hematology Department-HCT Unit, George Papanikolaou Hospital, Thessaloniki, Greece.,Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | | | - Damianos Sotiropoulos
- Gene and Cell Therapy Center, Hematology Department-HCT Unit, George Papanikolaou Hospital, Thessaloniki, Greece
| | - Minas Yiangou
- Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | | | - Achilles Anagnostopoulos
- Gene and Cell Therapy Center, Hematology Department-HCT Unit, George Papanikolaou Hospital, Thessaloniki, Greece
| | - Evangelia Yannaki
- Gene and Cell Therapy Center, Hematology Department-HCT Unit, George Papanikolaou Hospital, Thessaloniki, Greece
| | - Panayotis Kaloyannidis
- Adult Hematology and Stem cell Transplantation Department, King Fahad Specialist Hospital Dammam, Dammam, Saudi Arabia
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38
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Rapidly expanded partially HLA DRB1-matched fungus-specific T cells mediate in vitro and in vivo antifungal activity. Blood Adv 2021; 4:3443-3456. [PMID: 32722785 DOI: 10.1182/bloodadvances.2020001565] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 06/24/2020] [Indexed: 01/23/2023] Open
Abstract
Invasive fungal infections are a major cause of disease and death in immunocompromised hosts, including patients undergoing allogeneic hematopoietic stem cell transplant (HSCT). Recovery of adaptive immunity after HSCT correlates strongly with recovery from fungal infection. Using initial selection of lymphocytes expressing the activation marker CD137 after fungal stimulation, we rapidly expanded a population of mainly CD4+ T cells with potent antifungal characteristics, including production of tumor necrosis factor α, interferon γ, interleukin-17, and granulocyte-macrophage colony stimulating factor. Cells were manufactured using a fully good manufacturing practice-compliant process. In vitro, the T cells responded to fungal antigens presented on fully and partially HLA-DRB1 antigen-matched presenting cells, including when the single common DRB1 antigen was allelically mismatched. Administration of antifungal T cells lead to reduction in the severity of pulmonary and cerebral infection in an experimental mouse model of Aspergillus. These data support the establishment of a bank of cryopreserved fungus-specific T cells using normal donors with common HLA DRB1 molecules and testing of partially HLA-matched third-party donor fungus-specific T cells as a potential therapeutic in patients with invasive fungal infection after HSCT.
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Gottlieb DJ, Clancy LE, Withers B, McGuire HM, Luciani F, Singh M, Hughes B, Gloss B, Kliman D, Ma CKK, Panicker S, Bishop D, Dubosq MC, Li Z, Avdic S, Micklethwaite K, Blyth E. Prophylactic antigen-specific T-cells targeting seven viral and fungal pathogens after allogeneic haemopoietic stem cell transplant. Clin Transl Immunology 2021; 10:e1249. [PMID: 33747509 PMCID: PMC7960021 DOI: 10.1002/cti2.1249] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 12/18/2020] [Accepted: 01/12/2021] [Indexed: 01/16/2023] Open
Abstract
Objectives Adoptive immunotherapy using donor-derived antigen-specific T-cells can prevent and treat infection after allogeneic haemopoietic stem cell transplant (HSCT). Methods We treated 11 patients with a prophylactic infusion of 2 × 107 cells per square metre donor-derived T-cells targeting seven infections (six viral and one fungal) following HSCT. Targeted pathogens were cytomegalovirus (CMV), Epstein-Barr virus (EBV), adenovirus, varicella zoster virus, influenza, BK virus (BKV) and Aspergillus fumigatus. Results T-cell products were successfully generated in all patients with 10 products responsive to 6 or 7 infections. T-cell infusions were associated with increases in antigen-experienced activated CD8+ T-cells by day 30. CMV, EBV and BKV reactivation occurred in the majority of patients and was well controlled except where glucocorticoids were administered soon after T-cell infusion. Three patients in that circumstance developed CMV tissue infection. No patient required treatment for invasive fungal infection. The most common CMV and EBV TCR clonotypes in the infusion product became the most common clonotypes seen at day 30 post-T-cell infusion. Donors and their recipients were recruited to the study prior to transplant. Grade III/IV graft-versus-host disease developed in four patients. At a median follow-up of 390 days post-transplant, six patients had died, 5 of relapse, and 1 of multi-organ failure. Infection did not contribute to death in any patient. Conclusion Rapid reconstitution of immunity to a broad range of viral and fungal infections can be achieved using a multi-pathogen-specific T-cell product. The development of GVHD after T-cell infusion suggests that infection-specific T-cell therapy after allogeneic stem cell transplant should be combined with other strategies to reduce graft-versus-host disease.
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Affiliation(s)
- David Jonathan Gottlieb
- Sydney Medical School University of Sydney Sydney NSW Australia.,Blood Transplant and Cell Therapies Program Westmead Hospital Sydney NSW Australia.,Westmead Institute for Medical Research at the University of Sydney Westmead NSW Australia
| | - Leighton Edward Clancy
- Blood Transplant and Cell Therapies Program Westmead Hospital Sydney NSW Australia.,Sydney Cellular Therapies Laboratory NSW Health Pathology ICPMR Sydney NSW Australia
| | - Barbara Withers
- Sydney Medical School University of Sydney Sydney NSW Australia.,Westmead Institute for Medical Research at the University of Sydney Westmead NSW Australia
| | - Helen Marie McGuire
- Ramaciotti Facility for Human Systems Biology The University of Sydney Sydney NSW Australia.,Charles Perkins Centre University of Sydney Sydney NSW Australia.,Discipline of Pathology Faculty of Medicine and Health The University of Sydney Camperdown NSW Australia
| | - Fabio Luciani
- Kirby Institute University of New South Wales Sydney NSW Australia
| | - Mandeep Singh
- The Garvan Institute of Medical Research Darlinghurst NSW Australia.,Faculty of Medicine St. Vincent's Clinical School UNSW Sydney NSW Australia
| | - Brendan Hughes
- Kirby Institute University of New South Wales Sydney NSW Australia
| | - Brian Gloss
- Westmead Institute for Medical Research at the University of Sydney Westmead NSW Australia
| | - David Kliman
- Blood Transplant and Cell Therapies Program Westmead Hospital Sydney NSW Australia
| | - Chun Kei Kris Ma
- Blood Transplant and Cell Therapies Program Westmead Hospital Sydney NSW Australia
| | - Shyam Panicker
- Blood Transplant and Cell Therapies Program Westmead Hospital Sydney NSW Australia
| | - David Bishop
- Sydney Medical School University of Sydney Sydney NSW Australia.,Blood Transplant and Cell Therapies Program Westmead Hospital Sydney NSW Australia.,Westmead Institute for Medical Research at the University of Sydney Westmead NSW Australia
| | - Ming-Celine Dubosq
- Sydney Medical School University of Sydney Sydney NSW Australia.,Blood Transplant and Cell Therapies Program Westmead Hospital Sydney NSW Australia.,Westmead Institute for Medical Research at the University of Sydney Westmead NSW Australia
| | - Ziduo Li
- Westmead Institute for Medical Research at the University of Sydney Westmead NSW Australia
| | - Selmir Avdic
- Sydney Medical School University of Sydney Sydney NSW Australia.,Westmead Institute for Medical Research at the University of Sydney Westmead NSW Australia
| | - Kenneth Micklethwaite
- Sydney Medical School University of Sydney Sydney NSW Australia.,Blood Transplant and Cell Therapies Program Westmead Hospital Sydney NSW Australia.,Westmead Institute for Medical Research at the University of Sydney Westmead NSW Australia.,Sydney Cellular Therapies Laboratory NSW Health Pathology ICPMR Sydney NSW Australia
| | - Emily Blyth
- Sydney Medical School University of Sydney Sydney NSW Australia.,Blood Transplant and Cell Therapies Program Westmead Hospital Sydney NSW Australia.,Westmead Institute for Medical Research at the University of Sydney Westmead NSW Australia.,Sydney Cellular Therapies Laboratory NSW Health Pathology ICPMR Sydney NSW Australia
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40
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Oliveira LVN, Wang R, Specht CA, Levitz SM. Vaccines for human fungal diseases: close but still a long way to go. NPJ Vaccines 2021; 6:33. [PMID: 33658522 PMCID: PMC7930017 DOI: 10.1038/s41541-021-00294-8] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Accepted: 01/27/2021] [Indexed: 01/31/2023] Open
Abstract
Despite the substantial global burden of human fungal infections, there are no approved fungal vaccines to protect at risk individuals. Here, we review the progress that has been made and the challenges that lie ahead in the quest towards efficacious fungal vaccines. In mouse studies, protection has been achieved with vaccines directed against fungal pathogens, including species of Candida, Cryptococcus, and Aspergillus, that most commonly cause life-threatening human disease. Encouraging results have been obtained with vaccines composed of live-attenuated and killed fungi, crude extracts, recombinant subunit formulations, and nucleic acid vaccines. Novel adjuvants that instruct the immune system to mount the types of protective responses needed to fight mycotic infections are under development. Candidate vaccines include those that target common antigens expressed on multiple genera of fungi thereby protecting against a broad range of mycoses. Encouragingly, three vaccines have reached human clinical trials. Still, formidable obstacles must be overcome before we will have fungal vaccines licensed for human use.
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Affiliation(s)
- Lorena V N Oliveira
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Ruiying Wang
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Charles A Specht
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Stuart M Levitz
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
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41
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Zhou X, Jin N, Chen B. Human cytomegalovirus infection: A considerable issue following allogeneic hematopoietic stem cell transplantation. Oncol Lett 2021; 21:318. [PMID: 33692850 PMCID: PMC7933754 DOI: 10.3892/ol.2021.12579] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 12/23/2020] [Indexed: 12/11/2022] Open
Abstract
Cytomegalovirus (CMV) is an opportunistic virus, whereby recipients are most susceptible following allogeneic hematopoietic stem cell transplantation (allo-HSCT). With the development of novel immunosuppressive agents and antiviral drugs, accompanied with the widespread application of prophylaxis and preemptive treatment, significant developments have been made in transplant recipients with human (H)CMV infection. However, HCMV remains an important cause of short- and long-term morbidity and mortality in transplant recipients. The present review summarizes the molecular mechanism and risk factors of HCMV reactivation following allo-HSCT, the diagnosis of CMV infection following allo-HSCT, prophylaxis and treatment of HCMV infection, and future perspectives. All relevant literature were retrieved from PubMed and have been reviewed.
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Affiliation(s)
- Xinyi Zhou
- Department of Hematology and Oncology, Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Nan Jin
- Department of Hematology and Oncology, Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Baoan Chen
- Department of Hematology and Oncology, Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu 210009, P.R. China
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42
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Chaves AFA, Xander P, Romera LMD, Fonseca FLA, Batista WL. What is the elephant in the room when considering new therapies for fungal diseases? Crit Rev Microbiol 2021; 47:275-289. [PMID: 33513315 DOI: 10.1080/1040841x.2021.1876632] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The global scenario of antimicrobial resistance is alarming, and the development of new drugs has not appeared to make substantial progress. The constraints on drug discovery are due to difficulties in finding new targets for therapy, the high cost of development, and the mismatch between the time of drug introduction in a clinic and microorganism adaptation to a drug. Policies to address neglected diseases miss the broad spectrum of mycosis. Society is not aware of the actual threat represented by fungi to human health, food security, and biodiversity. The evidence discussed here is critical for warning governments to establish effective surveillance policies for fungi.HIGHLIGHTSFungal diseases are ignored even among neglected disease classifications.There are few options to treat mycoses, which is an increasing concern regarding fungal resistance to drugs, as evidenced by the spread of Candida auris.Fungal diseases represent a real threat to human health and food security.Investment in research to investigate the potential of repurposing drugs already in use could obtain results in the short term.
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Affiliation(s)
| | - Patricia Xander
- Department of Pharmaceutical Sciences, Federal University of São Paulo, São Paulo, Brazil
| | | | | | - Wagner Luiz Batista
- Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo, São Paulo, Brazil.,Department of Pharmaceutical Sciences, Federal University of São Paulo, São Paulo, Brazil
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43
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Elmariah H, Brunstein CG, Bejanyan N. Immune Reconstitution after Haploidentical Donor and Umbilical Cord Blood Allogeneic Hematopoietic Cell Transplantation. Life (Basel) 2021; 11:102. [PMID: 33572932 PMCID: PMC7911120 DOI: 10.3390/life11020102] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/19/2021] [Accepted: 01/25/2021] [Indexed: 02/07/2023] Open
Abstract
Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy for a variety of hematologic diseases. However, this therapeutic platform is limited by an initial period when patients are profoundly immunocompromised. There is gradual immune recovery over time, that varies by transplant platform. Here, we review immune reconstitution after allogeneic HCT with a specific focus on two alternative donor platforms that have dramatically improved access to allogeneic HCT for patients who lack an HLA-matched related or unrelated donor: haploidentical and umbilical cord blood HCT. Despite challenges, interventions are available to mitigate the risks during the immunocompromised period including antimicrobial prophylaxis, modified immune suppression strategies, graft manipulation, and emerging adoptive cell therapies. Such interventions can improve the potential for long-term overall survival after allogeneic HCT.
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Affiliation(s)
- Hany Elmariah
- Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL 33612, USA;
| | - Claudio G. Brunstein
- Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN 55455, USA;
| | - Nelli Bejanyan
- Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL 33612, USA;
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Koukoulias K, Papayanni PG, Georgakopoulou A, Alvanou M, Laidou S, Kouimtzidis A, Pantazi C, Gkoliou G, Vyzantiadis TA, Spyridonidis A, Makris A, Chatzidimitriou A, Psatha N, Anagnostopoulos A, Yannaki E, Papadopoulou A. "Cerberus" T Cells: A Glucocorticoid-Resistant, Multi-Pathogen Specific T Cell Product to Fight Infections in Severely Immunocompromised Patients. Front Immunol 2021; 11:608701. [PMID: 33537032 PMCID: PMC7848034 DOI: 10.3389/fimmu.2020.608701] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 11/27/2020] [Indexed: 12/27/2022] Open
Abstract
Adoptive immunotherapy (AI) with pathogen-specific T cells is a promising alternative to pharmacotherapy for the treatment of opportunistic infections after allogeneic hematopoietic cell transplantation or solid organ transplantation. However, clinical implementation of AI is limited to patients not receiving high-dose steroids, a prerequisite for optimal T-cell function, practically excluding the most susceptible to infections patients from the benefits of AI. To address this issue, we here rapidly generated, clinical doses of a steroid-resistant T-cell product, simultaneously targeting four viruses (adenovirus, cytomegalovirus, Epstein Barr virus, and BK virus) and the fungus Aspergillus fumigatus, by genetic disruption of the glucocorticoid receptor (GR) gene using CRISPR/CAS9 ribonucleoprotein delivery. The product, “Cerberus” T cells (Cb-STs), was called after the monstrous three-headed dog of Greek mythology, due to its triple potential; specificity against viruses, specificity against fungi and resistance to glucocorticoids. Following efficient on-target GR disruption and minimal off-target editing, the generated Cb-STs maintained the characteristics of pentavalent-STs, their unedited counterparts, including polyclonality, memory immunophenotype, specificity, and cytotoxicity while they presented functional resistance to dexamethasone. Cb-STs may become a powerful, one-time treatment for severely immunosuppressed patients under glucocorticoids who suffer from multiple, life-threatening infections post-transplant, and for whom therapeutic choices are limited.
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Affiliation(s)
- Kiriakos Koukoulias
- Hematology Department, Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center, "George Papanikolaou" Hospital, Thessaloniki, Greece.,Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Penelope-Georgia Papayanni
- Hematology Department, Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center, "George Papanikolaou" Hospital, Thessaloniki, Greece.,Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Aphrodite Georgakopoulou
- Hematology Department, Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center, "George Papanikolaou" Hospital, Thessaloniki, Greece.,Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Maria Alvanou
- Hematology Department, Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center, "George Papanikolaou" Hospital, Thessaloniki, Greece.,Department of Internal Medicine, BMT Unit, University of Patras, Patras, Greece
| | - Stamatia Laidou
- Institute of Applied Biosciences (INAB), Centre for Research and Technology Hellas (CERTH), Thessaloniki, Greece
| | - Anastasios Kouimtzidis
- Hematology Department, Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center, "George Papanikolaou" Hospital, Thessaloniki, Greece.,Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Chrysoula Pantazi
- Hematology Department, Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center, "George Papanikolaou" Hospital, Thessaloniki, Greece
| | - Glykeria Gkoliou
- Institute of Applied Biosciences (INAB), Centre for Research and Technology Hellas (CERTH), Thessaloniki, Greece
| | | | | | - Antonios Makris
- Institute of Applied Biosciences (INAB), Centre for Research and Technology Hellas (CERTH), Thessaloniki, Greece
| | - Anastasia Chatzidimitriou
- Institute of Applied Biosciences (INAB), Centre for Research and Technology Hellas (CERTH), Thessaloniki, Greece
| | - Nikoletta Psatha
- Altius Institute for Biomedical Sciences, Seattle, WA, United States
| | - Achilles Anagnostopoulos
- Hematology Department, Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center, "George Papanikolaou" Hospital, Thessaloniki, Greece
| | - Evangelia Yannaki
- Hematology Department, Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center, "George Papanikolaou" Hospital, Thessaloniki, Greece.,Department of Medicine, University of Washington, Seattle, WA, United States
| | - Anastasia Papadopoulou
- Hematology Department, Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center, "George Papanikolaou" Hospital, Thessaloniki, Greece
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45
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Multipathogen-specific T cells against viral and fungal infections. Bone Marrow Transplant 2021; 56:1445-1448. [PMID: 33420391 DOI: 10.1038/s41409-020-01210-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 11/25/2020] [Accepted: 12/17/2020] [Indexed: 12/19/2022]
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Biswas PS. Vaccine-Induced Immunological Memory in Invasive Fungal Infections - A Dream so Close yet so Far. Front Immunol 2021; 12:671068. [PMID: 33968079 PMCID: PMC8096976 DOI: 10.3389/fimmu.2021.671068] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 04/01/2021] [Indexed: 12/21/2022] Open
Abstract
The invasive fungal infections (IFIs) are a major cause of mortality due to infectious disease worldwide. Majority of the IFIs are caused by opportunistic fungi including Candida, Aspergillus and Cryptococcus species. Lack of approved antifungal vaccines and the emergence of antifungal drug-resistant strains pose major constraints in controlling IFIs. A comprehensive understanding of the host immune response is required to develop novel fungal vaccines to prevent death from IFIs. In this review, we have discussed the challenges associated with the development of antifungal vaccines. We mentioned how host-pathogen interactions shape immunological memory and development of long-term protective immunity to IFIs. Furthermore, we underscored the contribution of long-lived innate and adaptive memory cells in protection against IFIs and summarized the current vaccine strategies.
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Abstract
INTRODUCTION Cytomegalovirus (CMV) infection is widely prevalent but mostly harmless in immunocompetent individuals. In the post hematopoietic stem cell transplant (HSCT) setting unrestricted viral replication can cause end-organ damage (CMV disease) and, in a small proportion, mortality. Current management strategies are based on sensitive surveillance programmes, with the more recent introduction of an effective prophylactic antiviral drug, letermovir, but all aim to bridge patients until reconstitution of endogenous immunity is sufficient to constrain viral replication. AREAS COVERED Over the past 25 years, the adoptive transfer of CMV-specific T-cells has developed from the first proof of concept transfer of CD 8 + T-cell clones, to the development of 'off the shelf' third party derived Viral-Specific T-cells (VSTs). In this review, we cover the current management of CMV, and discuss the developments in CMV adoptive cellular therapy. EXPERT OPINION Due to the adoption of letermovir as a prophylaxis in standard therapy, the incidence of CMV reactivation is likely to decrease, and any widely adopted cellular therapy needs to be economically competitive. Current clinical trials will help to identify the patients most likely to gain the maximum benefit from any form of cell therapy.
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Affiliation(s)
- Lorna Neill
- Department of Haematology, University College London Hospitals NHS Foundation Trust, London, UK
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48
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Ciccocioppo R, Comoli P, Astori G, Del Bufalo F, Prapa M, Dominici M, Locatelli F. Developing cell therapies as drug products. Br J Pharmacol 2020; 178:262-279. [PMID: 33140850 DOI: 10.1111/bph.15305] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 10/22/2020] [Accepted: 10/23/2020] [Indexed: 02/06/2023] Open
Abstract
In the last 20 years, the global regulatory frameworks for drug assessment have been managing the challenges posed by using cellular products as new therapeutic tools. Currently, they are defined as "Advanced Therapy Medicinal Products", comprising a large group of cellular types that either alone or in combination with gene and tissue engineering technology. They have the potential to change the natural course of still lethal or highly debilitating diseases, including cancers, opportunistic infections and chronic inflammatory conditions. Globally, more than 50 cell-based products have obtained market authorization. This overview describes the advantages and unsolved challenges on developing cells as innovative therapeutic vehicles. The main cell therapy players and the legal framework are discussed, starting from chimeric antigen receptor T-cells for leukaemia and solid tumours, dealing then with lymphocytes as potent anti-microbiological tools and then focusing on mesenchymal stem/stromal cells whose role covers regenerative medicine, immunology and anti-tumour therapy.
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Affiliation(s)
- Rachele Ciccocioppo
- Gastroenterology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy
| | - Patrizia Comoli
- Cell Factory and Paediatric Haematology/Oncology Unit, Fondazione I.R.C.C.S. Policlinico San Matteo, Pavia, Italy
| | - Giuseppe Astori
- Laboratory of Advanced Cellular Therapies, Haematology Unit, San Bortolo Hospital, A.U.L.S.S. 8 "Berica", Vicenza, Italy
| | - Francesca Del Bufalo
- Department of Paediatric Haematology and Oncology and Cell and Gene Therapy, I.R.C.C.S. Bambino Gesù Children's Hospital, Rome, Italy
| | - Malvina Prapa
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Massimo Dominici
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Franco Locatelli
- Department of Paediatric Haematology and Oncology and Cell and Gene Therapy, I.R.C.C.S. Bambino Gesù Children's Hospital, Rome, Italy.,Department of Paediatrics, Sapienza University of Rome, Rome, Italy
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Williams TJ, Harvey S, Armstrong-James D. Immunotherapeutic approaches for fungal infections. Curr Opin Microbiol 2020; 58:130-137. [PMID: 33147544 DOI: 10.1016/j.mib.2020.09.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 08/25/2020] [Accepted: 09/15/2020] [Indexed: 12/18/2022]
Abstract
Despite the availability of antifungal treatments, fungal infections are still causing morbidity all around the globe with unacceptably high mortality rates. A major driver for the rising incidence of serious fungal infections is due to a substantial increase in immunocompromised individuals with autoimmune diseases, cancers and transplants. Because of growing resistance in fungus to frontline triazole antifungals and the association of fungal disease with the immunocompromised host, adjunctive host-directed therapy is seen as a promising choice to improve patient outcomes. Immunotherapeutic treatments being explored as adjunct therapies to existing antifungal treatments include cytokine therapy, monoclonal antibodies and cellular immunotherapy. In this review, we give a brief overview of potential immunotherapies and recent developments in the field, which are needed to tackle the growing problem of fungal diseases.
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Affiliation(s)
- Thomas J Williams
- MRC Centre for Molecular Bacteriology and Infection, Imperial College London, 14 Armstrong Rd, South Kensington, London SW7 2DD, United Kingdom
| | - Sunshine Harvey
- MRC Centre for Molecular Bacteriology and Infection, Imperial College London, 14 Armstrong Rd, South Kensington, London SW7 2DD, United Kingdom
| | - Darius Armstrong-James
- MRC Centre for Molecular Bacteriology and Infection, Imperial College London, 14 Armstrong Rd, South Kensington, London SW7 2DD, United Kingdom.
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50
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From bench to bedside - translational approaches in anti-fungal immunology. Curr Opin Microbiol 2020; 58:153-159. [PMID: 33190074 DOI: 10.1016/j.mib.2020.10.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 10/14/2020] [Accepted: 10/15/2020] [Indexed: 11/24/2022]
Abstract
Invasive fungal infections mainly occur in patients suffering from impaired immunity. Their associated mortality is high despite antifungal treatment. Thus, several efforts have been made to translate our knowledge on protective antifungal immunity into clinical application. Since the first attempts with transfusion of neutrophilic granulocytes, these approaches have become more refined and include administration of cytokines to booster antifungal immune responses or selective stimulation of pattern recognition receptors. Recently, novel tools that have proven effective in the treatment of cancer have offered new options for enhancing antifungal immunity. These approaches include checkpoint inhibitors as well as T-cell based therapies, including chimeric antigen receptor T-cells.
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