17 results on '"E. Blyth"'
Search Results
2. Long-term outcomes of corticosteroid graft versus host disease prophylaxis in peripheral blood allogeneic haemopoietic stem cell transplant: a comparative cohort analysis.
- Author
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Blennerhassett R, Othman J, Biscoe A, Kliman D, Mills G, Blyth E, Micklethwaite K, Kwan J, Bilmon I, Bhattacharyya A, Panicker S, Fay K, Milliken S, Ma D, Hamad N, Stevenson W, Arthur C, Moore J, Greenwood M, Gottlieb D, and Kerridge I
- Subjects
- Humans, Neoplasm Recurrence, Local, Adrenal Cortex Hormones therapeutic use, Cohort Studies, Recurrence, Retrospective Studies, Hematopoietic Stem Cell Transplantation, Graft vs Host Disease prevention & control, Peripheral Blood Stem Cell Transplantation
- Abstract
Background: Corticosteroids (CSs) have previously been incorporated into graft versus host disease (GVHD) prophylaxis regimens for bone marrow (BM) and haemopoietic stem cell transplant (HSCT)., Aims: To assess the impact of prophylactic CS in HSCT using peripheral blood (PB) stem cells., Methods: Patients were identified from three HSCT centres receiving a first PB-HSCT between January 2011 and December 2015 from a fully human leukocyte antigen (HLA)-matched sibling or unrelated donor for acute myeloid leukaemia or acute lymphoblastic leukaemia. To enable meaningful comparison, patients were divided into two cohorts., Results: Cohort 1 included only myeloablative-matched sibling HSCT, where the only variation in GVHD prophylaxis was the addition of CS. In these 48 patients, there were no differences in GVHD, relapse, non-relapse mortality, overall survival or GVHD-relapse-free-survival (GRFS) at 4 years after transplant. Cohort 2 included the remaining HSCT recipients, where one group received CS-prophylaxis and the non-CS group received an antimetabolite, ciclosporin and anti-T-lymphocyte globulin. In these 147 patients, those receiving CS-prophylaxis experienced higher rates of chronic GVHD (71% vs 18.1%, P < 0.001) and lower rates of relapse (14.9% vs 33.9%, P = 0.02). Those receiving CS-prophylaxis had a lower 4-year GRFS (15.7% vs 40.3%, P = 0.002)., Conclusions: There does not appear to be a role for adding CS to standard GVHD prophylaxis regimens in PB-HSCT., (© 2023 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)
- Published
- 2023
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3. Australia and New Zealand Transplant and Cellular Therapies (ANZTCT) position statement: COVID-19 management in patients with haemopoietic stem cell transplant and chimeric antigen receptor T cell.
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Perram J, Purtill D, Bajel A, Butler J, O'Brien T, Teh B, Gilroy N, Ho PJ, Doocey R, Hills T, Perera T, Douglas G, Ramachandran S, Chee L, Trotman J, Weinkove R, Keogh S, Fraser C, Cochrane T, Watson AM, Diamond P, Latimer M, Irving I, Blyth E, Cheah C, Cole T, Milliken S, Yang H, Greenwood M, Bardy P, Kennedy G, Larsen S, Conyers R, and Hamad N
- Subjects
- Humans, New Zealand epidemiology, T-Lymphocytes, Receptors, Chimeric Antigen therapeutic use, COVID-19, Hematopoietic Stem Cell Transplantation
- Abstract
Patients with post-haemopoietic stem cell transplant or chimeric antigen receptor T -cell (CAR-T) therapy face a significant risk of morbidity and mortality from coronavirus disease 2019 because of their immunosuppressed state. As case numbers in Australia and New Zealand continue to rise, guidance on management in this high-risk population is needed. Whilst we have learned much from international colleagues who faced high infection rates early in the pandemic, guidance relevant to local health system structures, medication availability and emerging therapies is essential to equip physicians to manage our patients optimally., (© 2022 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)
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- 2023
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4. Combining CD34+ stem cell selection with prophylactic pathogen and leukemia directed T-cell immunotherapy to simultaneously reduce graft versus host disease, infection, and leukemia recurrence after allogeneic stem cell transplant.
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Gottlieb DJ, Sutrave G, Jiang W, Avdic S, Street JA, Simms R, Clancy LE, Antonenas V, Gloss BS, Bateman C, Bishop DC, Micklethwaite KP, and Blyth E
- Subjects
- Humans, T-Lymphocytes, Transplantation, Homologous, Treatment Outcome, Herpesvirus 4, Human, Stem Cell Transplantation, Immunotherapy, Epstein-Barr Virus Infections complications, Epstein-Barr Virus Infections therapy, Graft vs Host Disease etiology, Graft vs Host Disease prevention & control, Hematopoietic Stem Cell Transplantation, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy
- Abstract
We designed a trial to simultaneously address the problems of graft versus host disease (GVHD), infection, and recurrence of malignancy after allogeneic stem cell transplantation. CD34
+ stem cell isolation was used to minimize the development of acute and chronic GVHD. Two prophylactic infusions, one combining donor-derived cytomegalovirus, Epstein-Barr virus, and Aspergillus fumigatus specific T-cells and the other comprising donor-derived CD19 directed chimeric antigen receptor (CAR) bearing T-cells, were given 21-28 days after transplant. Two patients were transplanted for acute lymphoblastic leukemia from HLA identical siblings using standard doses of cyclophosphamide and total body irradiation without antilymphocyte globulin. Patients received no post-transplant immune suppression and were given no pre-CAR T-cell lymphodepletion. Neutrophil and platelet engraftment was prompt. Following adoptive T-cell infusions, there was rapid appearance of antigen-experienced CD8+ and to a lesser extent CD4+ T-cells. Tetramer-positive T-cells targeting CMV and EBV appeared rapidly after T-cell infusion and persisted for at least 1 year. CAR T-cell expansion occurred and persisted for up to 3 months. T-cell receptor tracking confirmed the presence of product-derived T-cell clones in blood targeting all three pathogens. Both patients are alive over 3 years post-transplant without evidence of GVHD or disease recurrence. Combining robust donor T-cell depletion with directed T-cell adoptive immunotherapy targeting infectious and malignant antigens permits independent modulation of GVHD, infection, and disease recurrence. The combination may separate GVHD from the graft versus tumor effect, accelerate immune reconstitution, and improve transplant tolerability., (© 2022 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)- Published
- 2023
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5. Third-party CMV- and EBV-specific T-cells for first viral reactivation after allogeneic stem cell transplant.
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Jiang W, Clancy LE, Avdic S, Sutrave G, Street J, Simms R, McGuire HM, Patrick E, Chan AS, McCaughan G, Myers N, Micklethwaite KP, Antonenas V, Selim AG, Ritchie D, Bateman CM, Shaw PJ, Blyth E, and Gottlieb DJ
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- Antiviral Agents, Australia, Cytomegalovirus, Herpesvirus 4, Human, Humans, Stem Cell Transplantation adverse effects, Transplantation, Homologous adverse effects, Cytomegalovirus Infections etiology, Cytomegalovirus Infections therapy, Epstein-Barr Virus Infections etiology, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Virus-specific T-cells (VSTs) from third-party donors mediate short- and long-term antiviral effects in allogeneic hematopoietic stem cell transplant (HSCT) recipients with relapsed or refractory viral infections. We investigated early administration of third-party VSTs, together with antiviral therapy in patients requiring treatment for first cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection. Thirty HSCT patients were treated with 1 to 4 VST infusions (2 × 107 cells/m2; CMV n=27, EBV n=3) at a median of 4 days after initiation of antiviral treatment. The overall viral response rate was 100%, with a complete response (CR) rate of 94%. Of the 28 patients who achieved a CR, 23 remained virus PCR negative (n=9) or below quantitation limit (n=14) for the duration of follow-up. Four patients had brief episodes of quantifiable reactivation not requiring additional therapy, and one required a second infusion after initial CR, remaining PCR negative thereafter. All 3 patients treated for EBV post-transplant lymphoproliferative disorder achieved sustained CR. Rates of aGVHD and cGVHD after infusion were 13% and 23%, respectively. There were no serious infusion-related adverse events. VST infusion was associated with rapid recovery of CD8+CD45RA-CD62L- and a slower recovery of CD4+CD45RA-CD62L- effector memory T-cells; CMV-specific T-cells comprised up to 13% of CD8+ cells. At 1 year post-transplant, non-relapse mortality was 10%, cumulative incidence of relapse was 7%, overall survival was 88% and 25 of 27 patients had ECOG status of 0 or 1. Early administration of third-party VSTs in conjunction with antiviral treatment appears safe and leads to excellent viral control and clinical outcomes. Registered on Australian New Zealand Clinical Trials Registry as #ACTRN12618000343202., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2022
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6. Immunoprofiling reveals cell subsets associated with the trajectory of cytomegalovirus reactivation post stem cell transplantation.
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Stern L, McGuire HM, Avdic S, Fazekas de St Groth B, Gottlieb D, Abendroth A, Blyth E, and Slobedman B
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- Cytomegalovirus immunology, Humans, Cytomegalovirus Infections, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Human cytomegalovirus reactivation is a major opportunistic infection after allogeneic haematopoietic stem cell transplantation and has a complex relationship with post-transplant immune reconstitution. Here, we use mass cytometry to define patterns of innate and adaptive immune cell reconstitution at key phases of human cytomegalovirus reactivation in the first 100 days post haematopoietic stem cell transplantation. Human cytomegalovirus reactivation is associated with the development of activated, memory T-cell profiles, with faster effector-memory CD4
+ T-cell recovery in patients with low-level versus high-level human cytomegalovirus DNAemia. Mucosal-associated invariant T cell levels at the initial detection of human cytomegalovirus DNAemia are significantly lower in patients who subsequently develop high-level versus low-level human cytomegalovirus reactivation. Our data describe distinct immune signatures that emerged with human cytomegalovirus reactivation after haematopoietic stem cell transplantation, and highlight Mucosal-associated invariant T cell levels at the first detection of reactivation as a marker that may be useful to anticipate the magnitude of human cytomegalovirus DNAemia., (© 2022. The Author(s).)- Published
- 2022
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7. An atypical case of Epstein-Barr virus-positive plasma cell post-transplant lymphoproliferative disorder successfully treated with adoptive cell therapy.
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Elliott J, Avdic S, Selim AG, Clancy L, Atkins E, Blyth E, Ritchie D, Gottlieb D, and Bajel A
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- Blood Viscosity, Clone Cells chemistry, Clone Cells virology, Combined Modality Therapy, Female, Herpesvirus 4, Human immunology, Herpesvirus 4, Human isolation & purification, Humans, Immunocompromised Host, Immunoglobulin M blood, Immunosuppressive Agents adverse effects, Lymphoproliferative Disorders etiology, Lymphoproliferative Disorders virology, Neoplastic Stem Cells chemistry, Neoplastic Stem Cells virology, Paraproteinemias etiology, Paraproteinemias virology, Paraproteins analysis, Plasma Cells chemistry, Plasma Cells virology, Plasmapheresis, Remission Induction, T-Cell Antigen Receptor Specificity, T-Lymphocytes, Cytotoxic immunology, Transplantation Conditioning adverse effects, Viremia etiology, Virus Activation, Young Adult, Epstein-Barr Virus Infections therapy, Hematopoietic Stem Cell Transplantation adverse effects, Immunotherapy, Adoptive, Lymphoproliferative Disorders therapy, Paraproteinemias therapy, Postoperative Complications therapy, T-Lymphocytes, Cytotoxic transplantation, Viremia therapy
- Published
- 2021
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8. Successful treatment of CMV, EBV, and adenovirus tissue infection following HLA-mismatched allogeneic stem cell transplant using infusion of third-party T cells from multiple donors in addition to antivirals, rituximab, and surgery.
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Di Ciaccio PR, Avdic S, Sutrave G, Clancy L, Withers B, Blyth E, McLeod D, and Gottlieb DJ
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- Adenoviridae immunology, Female, HLA Antigens, Herpesvirus 4, Human immunology, Humans, Middle Aged, Stem Cell Transplantation, Antiviral Agents therapeutic use, Cytomegalovirus Infections, Epstein-Barr Virus Infections, Hematopoietic Stem Cell Transplantation, Rituximab therapeutic use
- Abstract
Viral infections, principally cytomegalovirus, Epstein Barr virus (EBV) and adenovirus, are a leading cause of morbidity and mortality after allogeneic stem cell transplantation. The use of systemic antivirals is limited by limited efficacy and organ toxicities. Inability to clear infection is exacerbated by transplant-related immunosuppression and prophylaxis or treatment of acute graft versus host disease. We report the first patient to clear three serious viral infections after stem cell transplant using third-party donor partially human leukocyte antigen (HLA) matched virus-specific cytotoxic T cells. The patient, a 53 year old female with transplanted for relapsed leukemia, with severe graft versus host disease received five T cell infusions from three separate donors that ultimately cleared serious systemic infections with cytomegalovirus and adenovirus, and an EBV-driven lymphoma. Systemic antivirals had resulted in failed clinical responses. Use of repeated infusions of partially HLA matched virus-specific T cells from banks containing cryopreserved cells should be strongly considered in transplant recipients with single or multiple refractory viral infections., (© 2020 Wiley Periodicals LLC.)
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- 2021
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9. Profiling the Blood Compartment of Hematopoietic Stem Cell Transplant Patients During Human Cytomegalovirus Reactivation.
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Bernshtein B, Nachshon A, Shnayder M, Stern L, Avdic S, Blyth E, Gottlieb D, Abendroth A, Slobedman B, Stern-Ginossar N, and Schwartz M
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- DNA, Viral genetics, Humans, Immunocompromised Host, Leukocytes, Mononuclear, Cytomegalovirus genetics, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Human cytomegalovirus (HCMV) is a widespread pathogen establishing a latent infection in its host. HCMV reactivation is a major health burden in immunocompromised individuals, and is a major cause of morbidity and mortality following hematopoietic stem cell transplantation (HSCT). Here we determined HCMV genomic levels using droplet digital PCR in different peripheral blood mononuclear cell (PBMC) populations in HCMV reactivating HSCT patients. This high sensitivity approach revealed that all PBMC populations harbored extremely low levels of viral DNA at the peak of HCMV DNAemia. Transcriptomic analysis of PBMCs from high-DNAemia samples revealed elevated expression of genes typical of HCMV specific T cells, while regulatory T cell enhancers as well as additional genes related to immune response were downregulated. Viral transcript levels in these samples were extremely low, but remarkably, the detected transcripts were mainly immediate early viral genes. Overall, our data indicate that HCMV DNAemia is associated with distinct signatures of immune response in the blood compartment, however it is not necessarily accompanied by substantial infection of PBMCs and the residual infected PBMCs are not productively infected., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bernshtein, Nachshon, Shnayder, Stern, Avdic, Blyth, Gottlieb, Abendroth, Slobedman, Stern-Ginossar and Schwartz.)
- Published
- 2021
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10. Unrelated Donor Transplant Recipients Given Thymoglobuline Have Superior GRFS When Compared to Matched Related Donor Recipients Undergoing Transplantation without ATG.
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Othman J, Greenwood M, Moore J, Larsen S, Watson AM, Arthur C, Bhattacharyya A, Bilmon I, Blyth E, Bryant A, Bryant C, Dunlop L, Fay K, Gibson J, Hamad N, Kerridge I, Kwan J, Ma D, Micklethwaite K, Milliken S, Panicker S, Stevenson W, Withers B, Wilcox L, Tran S, and Gottlieb DJ
- Subjects
- Adult, Antilymphocyte Serum therapeutic use, Disease-Free Survival, Humans, Neoplasm Recurrence, Local, Prospective Studies, Retrospective Studies, Transplant Recipients, Transplantation Conditioning, Transplantation, Homologous, Unrelated Donors, Graft vs Host Disease prevention & control, Hematopoietic Stem Cell Transplantation
- Abstract
Recipients of allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated donors (URDs) and mismatched related donors (MMRDs) typically have a higher incidence of acute and chronic graft-versus-host disease (GVHD) compared with matched related donors (MRDs). Anti-T-cell globulins (ATGs) are often used to reduce GVHD in these recipients. We report the outcomes of 211 adult peripheral blood stem cell transplant recipients with myeloid malignancies who received a standardized transplant protocol, in which ATG (Thymoglobuline 4.5 mg/kg) was administered to recipients of URD and MMRD (n = 147) but not MRD (n = 64) transplant. For all patients, incidence of acute GVHD grades 2 to 4 was 21.4%, and chronic GVHD was 35.0%. Two-year overall survival was 63.2% (95% confidence interval, 55.8% to 71.5%), relapse-free survival was 55.3% (47.4% to 64.6%), and GVHD-free, relapse-free survival (GRFS) was 30.7% (23.2% to 40.8%). There were no differences between recipients of MRDs and other donors in relapse, nonrelapse mortality, and overall and relapse-free survival. However, compared with MRD, recipients from URDs and MMRDs had reduced moderate to severe chronic GVHD (10.4% versus 30.1%, P= .002), less chronic GVHD requiring systemic therapy (19.4% versus 38.9%, P = .006), and superior 2-year GRFS (35.5% versus 20.0%, P = .003). In this retrospective review of nonrandomized transplant groups, outcomes of HSCT performed using an URD with ATG during conditioning were superior to transplant from an MRD without ATG. The addition of Thymoglobuline to conditioning in HSCT from MRD should be further examined in prospective trials., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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11. Cellular therapy for multiple pathogen infections after hematopoietic stem cell transplant.
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Sutrave G, Blyth E, and Gottlieb DJ
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- Cytomegalovirus Infections immunology, Cytomegalovirus Infections therapy, Epstein-Barr Virus Infections therapy, Hematologic Diseases therapy, Hematopoietic Stem Cell Transplantation methods, Herpesvirus 4, Human immunology, Herpesvirus 4, Human pathogenicity, Humans, Immunocompromised Host, Immunotherapy, Adoptive methods, Infections etiology, Infections virology, T-Lymphocytes immunology, Tissue Donors, Cell Transplantation methods, Hematopoietic Stem Cell Transplantation adverse effects, Infections therapy, T-Lymphocytes transplantation
- Abstract
Hematopoietic stem cell transplantation (HSCT) represents the only crative treatment option for many hematological conditions but results in a profound T-cell deficiency in the post-HSCT period. Infections account for a significant proportion of non-relapse morbidity and mortality, and infections with multiple organisms either simultaneously or at different times after transplant are common. Adoptive cellular therapy (ACT) with prophylactic or therapeutic infusion of donor derived or third-party, pathogen-specific T-cells represents a novel methodology to rapidly reconstitute T-cell mediated immunity in this context. For cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infection, clear evidence of efficacy with limited toxicity has been observed, with response rates up to 90%. Infusion of third-party, partially human leukocyte antigen-matched pathogen-specific T-cells have also demonstrated remarkable efficacy with responses seen in up to 70% of patients with resistant CMV, EBV and adenoviral infection. This review addresses the nature of post-HSCT immune deficiency, the common infections that occur in the post-HSCT period and how advances in ACT manufacturing methodologies is allowing for wider implementation of T-cell therapies targeting multiple pathogens in HSCT recipients., (Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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12. CMV-specific immune reconstitution following allogeneic stem cell transplantation.
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Blyth E, Withers B, Clancy L, and Gottlieb D
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- Adoptive Transfer, Adult, Antiviral Agents therapeutic use, Cytomegalovirus physiology, Female, Graft vs Host Disease immunology, Graft vs Host Disease virology, Humans, Immunocompromised Host, Male, Vaccination, Virus Replication, Cytomegalovirus immunology, Cytomegalovirus Infections immunology, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Cytomegalovirus (CMV) remains a major contributor to morbidity and mortality following allogeneic haemopoietic stem cell transplant (HSCT) despite widespread use of viraemia monitoring and pre-emptive antiviral therapy. Uncontrolled viral replication occurs primarily in the first 100 d post transplant but this high risk period can extend to many months if immune recovery is delayed. The re-establishment of a functional population of cellular effectors is essential for control of virus replication and depends on recipient and donor serostatus, the stem cell source, degree of HLA matching and post-transplant factors such as CMV antigen exposure, presence of GVHD and ongoing use of immune suppression. A number of immune monitoring assays exist but have not yet become widely accessible for routine clinical use. Vaccination, adoptive transfer of CMV specific T cells and a number of graft engineering processes are being evaluated to enhance of CMV specific immune recovery post HSCT.
- Published
- 2016
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13. Addition of varicella zoster virus-specific T cells to cytomegalovirus, Epstein-Barr virus and adenovirus tri-specific T cells as adoptive immunotherapy in patients undergoing allogeneic hematopoietic stem cell transplantation.
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Ma CK, Blyth E, Clancy L, Simms R, Burgess J, Brown R, Deo S, Micklethwaite KP, and Gottlieb DJ
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- Adenovirus Infections, Human prevention & control, Adenoviruses, Human immunology, Adult, Female, Graft vs Host Disease virology, Herpes Zoster immunology, Herpes Zoster prevention & control, Humans, Interferon-gamma immunology, Male, Middle Aged, T-Lymphocytes immunology, Transplantation, Homologous, Virus Activation, Young Adult, Cytomegalovirus immunology, Graft vs Host Disease prevention & control, Hematopoietic Stem Cell Transplantation adverse effects, Herpesvirus 3, Human immunology, Herpesvirus 4, Human immunology, Immunotherapy, Adoptive methods, T-Lymphocytes transplantation, Virus Diseases prevention & control
- Abstract
Background Aims: Virus-specific T-cell immunotherapy is emerging as a promising management strategy for virus infections in patients after hematopoietic stem cell transplant (HSCT). Here we present outcomes of 10 adult patients who received multi-virus-specific T cells prophylactically after HSCT., Methods: Donor-derived cytomegalovirus (CMV)-, Epstein-Barr virus (EBV)-, adenoviral- and varicella zoster virus (VZV)-specific T cells were generated in a single culture and administered to HSCT patients at a dose of 2 × 10(7)/m(2) virus-specific T cells at a median of 63 days post-transplant. Patients were monitored for 12 months for evidence of viral reactivation and graft-versus-host disease., Results: There was no acute infusion-related toxicity. Six patients developed CMV reactivation after T-cell infusion with a median peak CMV DNA titer of 600 copies per milliliter, and 1 received CMV-specific pharmacotherapy post-infusion. No EBV, adenoviral or VZV reactivation or disease was reported. Using interferon-γ Elispot analysis on post-infusion samples, we identified anti-viral immunity against all viruses including VZV. Three patients (30%) developed grade II-IV acute graft-versus-host disease., Conclusions: This is the first description of the use of a multi-virus-specific T-cell product containing cells specific for VZV after allogeneic HSCT. The T-cell product appears safe in the setting of HSCT and confirms our previous findings regarding CMV control and treatment. A larger study with longer follow-up is required to determine the efficacy of VZV-specific T cells given prophylactically in controlling episodes of herpes zoster and disseminated varicella infection after cessation of prophylactic anti-viral treatment., (Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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14. Donor-derived CMV-specific T cells reduce the requirement for CMV-directed pharmacotherapy after allogeneic stem cell transplantation.
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Blyth E, Clancy L, Simms R, Ma CK, Burgess J, Deo S, Byth K, Dubosq MC, Shaw PJ, Micklethwaite KP, and Gottlieb DJ
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- Adolescent, Adult, Aged, Case-Control Studies, Child, Child, Preschool, Clinical Trials, Phase II as Topic statistics & numerical data, Cohort Studies, Cytomegalovirus Infections blood, Cytomegalovirus Infections drug therapy, Female, Follow-Up Studies, Hematologic Neoplasms blood, Hematologic Neoplasms complications, Hematologic Neoplasms mortality, Humans, Immunotherapy, Adoptive, Male, Middle Aged, T-Lymphocytes immunology, Transplantation, Homologous, Virus Activation immunology, Young Adult, Antiviral Agents therapeutic use, Cytomegalovirus immunology, Cytomegalovirus Infections immunology, Cytomegalovirus Infections prevention & control, Hematologic Neoplasms therapy, Hematopoietic Stem Cell Transplantation adverse effects, T-Lymphocytes transplantation, Tissue Donors
- Abstract
We investigated the use of adoptively transferred donor-derived cytomegalovirus (CMV) specific cytotoxic T lymphocytes (CTL) as immune reconstitution postallogeneic transplant in a phase 2 study. Fifty patients were infused with a single dose of 2 × 10(7)cells/m(2) after day 28 post-transplant. Twenty-six patients reactivated CMV posttransplant (only 5 post-CTL infusion) and 9 required therapy with ganciclovir or foscarnet (only 1 post-CTL infusion). There was 1 case of fatal CMV disease, attributable to high levels of antithymocyte globulin at the time of T cell infusion. We compared the patients in the phase 2 study with a group of contemporaneous controls also treated at the trial centers. There was no increase in acute or chronic graft-versus-host disease attributable to CTL infusion; overall and progression-free survival were similar in both groups. There was a reduction in the percentage of patients who required CMV directed antiviral therapy (17% vs 36%, P = .01) and in the total number of treatment days in the cohort receiving CTL (3.4 days vs 8.9 days, P = .03) without a reduction in CMV reactivation rates. We postulate that adoptively transferred cells are able to expand in response to viral antigen, limit viral replication, and prevent progression to tissue infection. This study was registered on the Australian Clinical Trial Registry as #ACTRN12605000213640 and #ACTRN12607000224426.
- Published
- 2013
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15. Cytomegalovirus-specific cytotoxic T lymphocytes can be efficiently expanded from granulocyte colony-stimulating factor-mobilized hemopoietic progenitor cell products ex vivo and safely transferred to stem cell transplantation recipients to facilitate immune reconstitution.
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Clancy LE, Blyth E, Simms RM, Micklethwaite KP, Ma CK, Burgess JS, Antonenas V, Shaw PJ, and Gottlieb DJ
- Subjects
- Adult, Aged, Clinical Trials, Phase I as Topic, Clinical Trials, Phase II as Topic, Cytomegalovirus genetics, Cytomegalovirus Infections etiology, Cytomegalovirus Infections immunology, Cytotoxicity, Immunologic, Female, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells immunology, Humans, Male, Middle Aged, T-Lymphocytes, Cytotoxic cytology, T-Lymphocytes, Cytotoxic virology, Cytomegalovirus immunology, Granulocyte Colony-Stimulating Factor therapeutic use, Hematopoietic Stem Cell Transplantation methods, Hematopoietic Stem Cells drug effects, Immunotherapy, Adoptive methods, T-Lymphocytes, Cytotoxic immunology
- Abstract
Uncontrolled cytomegalovirus (CMV) reactivation after allogeneic hematopoietic stem cell transplantation causes significant morbidity and mortality. Adoptive transfer of CMV-specific cytotoxic T lymphocytes (CTLs) is a promising therapy to treat reactivation and prevent viral disease. In this article, we describe the generation of clinical-grade CMV-specific CTLs directly from granulocyte colony-stimulating factor-mobilized hemopoietic progenitor cell (G-HPC) products collected for transplantation. This method requires less than 2.5% of a typical G-HPC product to reproducibly expand CMV-specific CTLs ex vivo. Comparison of 11 CMV CTL lines generated from G-HPC products with 52 CMV CTL lines generated from nonmobilized peripheral blood revealed similar expansion kinetics and phenotype. G-HPC-derived CTLs produced IFN-γ after reexposure to CMVpp65 antigen and exhibited CMV-directed cytotoxicity but no alloreactivity against transplantation recipient-derived cells. Seven patients received CMV-specific CTL lines expanded from G-HPC products in a prophylactic adoptive immunotherapy phase I/II clinical trial. Use of G-HPC products will facilitate integration of CTL generation into established quality systems of transplantation centers and more rapid inclusion of T cell therapies into routine clinical care., (Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2013
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16. Clinical-grade varicella zoster virus-specific T cells produced for adoptive immunotherapy in hemopoietic stem cell transplant recipients.
- Author
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Blyth E, Gaundar SS, Clancy L, Simms RM, Bilmon I, Micklethwaite KP, and Gottlieb DJ
- Subjects
- Cell Proliferation, Cytotoxicity, Immunologic, Epitopes immunology, Herpes Zoster immunology, Herpesvirus 3, Human pathogenicity, Humans, Phenotype, Receptors, Antigen, T-Cell, alpha-beta immunology, Species Specificity, Hematopoietic Stem Cell Transplantation, Herpesvirus 3, Human immunology, Immunotherapy, Adoptive methods, T-Lymphocytes, Cytotoxic immunology
- Abstract
Background Aims: Varicella zoster virus (VZV) causes life-long latent infection in healthy individuals, which reactivates in 10-68% of stem cell transplant patients. Reconstituting immunity through adoptive transfer of T cells specific for VZV may aid in the prophylaxis and treatment of VZV infections. The potential for generating T cells specific for VZV using a clinically approved VZV vaccine strain was investigated., Methods: The Varivax® vaccine was used to stimulate peripheral blood mononuclear cells from healthy donors. Only reagents approved for clinical manufacture were used. Monocyte-derived dendritic cells pulsed with Varivax (R) were used to stimulate autologous mononuclear cells at a responder to stimulator ratio of 10:1. On day 7, a second stimulation was performed; 20 U/mL interleukin (IL)-2 were added from day 7 and 50 U/mL IL-2 from day 14 onwards. Cell phenotype and functionality were assessed after 21 days of culture., Results: A mean increase of 11-fold in cell number was observed (n= 18). Cultures were mainly T cells (mean CD3 (+) 89.7%, CD4 (+) 54.2%, CD8 (+) 28.7%) with effector and central memory phenotypes. Cells produced one or more T helper (Th)1 cytokine (interferon-γ, tumor necrosis factor-α and IL-2), and CD4 (+) (but not CD8 (+) ) cells expressed the cytoxicity marker CD107 when restimulated with VZV antigens., Conclusions: We have demonstrated a clinically applicable method that yields high numbers of highly reactive T cells specific for VZV. We propose that reconstructing host immunity through adoptive transfer of VZV-specific T cells will reduce the frequency of clinical VZV infection in the period of severe immune suppression that follows allogeneic stem cell transplantation.
- Published
- 2012
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17. Prophylactic infusion of cytomegalovirus-specific cytotoxic T lymphocytes stimulated with Ad5f35pp65 gene-modified dendritic cells after allogeneic hemopoietic stem cell transplantation.
- Author
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Micklethwaite KP, Clancy L, Sandher U, Hansen AM, Blyth E, Antonenas V, Sartor MM, Bradstock KF, and Gottlieb DJ
- Subjects
- Adenoviridae genetics, Adenoviridae immunology, Adolescent, Adult, Coculture Techniques, Cytomegalovirus genetics, Cytomegalovirus Infections genetics, Cytomegalovirus Infections immunology, Cytomegalovirus Infections mortality, Female, Graft vs Host Disease genetics, Graft vs Host Disease immunology, Graft vs Host Disease mortality, Graft vs Host Disease prevention & control, Humans, Male, Middle Aged, Phosphoproteins genetics, T-Lymphocytes immunology, Transduction, Genetic, Transplantation, Homologous, Viral Matrix Proteins genetics, Adoptive Transfer, Cytomegalovirus immunology, Cytomegalovirus Infections prevention & control, Dendritic Cells immunology, Hematopoietic Stem Cell Transplantation, Phosphoproteins immunology, T-Lymphocytes transplantation, Viral Matrix Proteins immunology
- Abstract
Cytomegalovirus (CMV) and its therapy continue to contribute to morbidity and mortality in hemopoietic stem cell transplantation (HSCT). Many studies have demonstrated the feasibility of in vitro generation of CMV-specific T cells for adoptive immunotherapy of CMV. Few clinical trials have been performed showing the safety and efficacy of this approach in vivo. In this study, donor-derived, CMV-specific T cells were generated for 12 adult HSCT patients by stimulation with dendritic cells transduced with an adenoviral vector encoding the CMV-pp65 protein. Patients received a prophylactic infusion of T cells after day 28 after HSCT. There were no infusion related adverse events. CMV DNAemia was detected in 4 patients after infusion but was of low level. No patient required CMV-specific pharmacotherapy. Immune reconstitution to CMV was demonstrated by enzyme linked immunospot assay in all recipients with rapid increases in predominantly CMV-pp65 directed immunity in 5. Rates of graft-versus-host disease, infection, and death were not increased compared with expected. These results add to the growing evidence of the safety and efficacy of immunotherapy of CMV in HSCT, supporting its more widespread use. This study was registered at www.anzctr.org.au as #ACTRN12605000213640.
- Published
- 2008
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