scholarly journals The Outcomes of Epstein-Barr Virus Specific T Cells from Different Sources for EBV Infections in Recipients of Allogeneic Stem Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3330-3330
Author(s):  
Ren Lin ◽  
Fen Huang ◽  
Zhiping Fan ◽  
Xiaoyan Shao ◽  
Guoxian Dai ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Natural Science ◽  
Epstein Barr Virus ◽  
Third Party ◽  
Barr Virus ◽  
Ifn Γ ◽  
Epstein Barr

Abstract Background Epstein-Barr virus (EBV) specific T cells have been proven effective in prevention and treatment of EBV associated-diseases after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the optimal source of EBV specific T cells remains unclear. Here, we compared autologous and donor derived EBV specific T cells with respect to generation ex vivo and the efficacy on EBV infections in the recipients of allo-HSCT. Methods Thirty-eight patients with EBV infections were enrolled in this study, including 21 with EBV-emia and 17 with EBV associated post-transplant lymphoproliferative disease (PTLD). EBV specific T cells were generated by immunomagnetic isolation from all the recipients themselves and second-party (original HSCT donor, n=25) or third-party related donors (n=25). The donors were EBV seropositive. The percentages of IFN-γ+ EBV specific T cells in the products and cytotoxic capacity of EBV specific T cells were evaluated. Results The median time of EBV infections was 49 days (range, 24-1479 days) post-transplants. The generation of autologous EBV specific T cells failed within 14 days of culture in all the patients because the numbers of cells were insufficient for treatment. Donor derived EBV specific T cells were expanded in vitro for 14 days until the sufficient number (≥ 109) was generated. The percentages of IFN-γ+ EBV specific T cells were comparable in the products generated from second- and third-party donors, but both higher than autologous derived EBV specific T cells. Cytotoxic capacity of EBV specific T cells was lower in autologous EBV specific T cells than donor derived EBV specific T cells. Twenty-one patients with refractory EBV infections (12 with EBV-emia and 9 with PTLD) received EBV specific T cells treatment, including 13 receiving second-party and 8 third-party EBV specific T cells. After treatments, 20 patients exhibited EBV clearance in blood within 6 weeks without recurrence and 1 with PTLD died at 3 weeks after the first infusion of EBV specific T cells with the decline of EBV-DNA copies. Other 8 patients with PTLD received complete remission after treatment. The response rates were not different between the patients receiving second- and third-party donor derived EBV specific T cells. One of the 13 patients with second-party derived EBV specific T cells developed pre-existing chronic graft-versus-host disease (GVHD) exacerbation while 1 developed grade Ⅱ aGVHD in the 8 patients receiving third-party donor derived EBV specific T cells. Conclusion The efficacy of EBV-specific T cells derived from second- and third-party are comparable in treatment of EBV infections after allo-HSCT. Autologous derived EBV-specific T cells seems not suitable for treatment because of poor production in vitro. Disclosures Fan: National Natural Science Foundation of China (No. 81600141, No. 81770190) and Natural Science Foundation of Guangdong Province (No. 2016A030310390): Research Funding.

Rapid reconstitution of Epstein-Barr virus–specific T lymphocytes following allogeneic stem cell transplantation

Blood ◽  
2000 ◽  
Vol 96 (8) ◽  
pp. 2814-2821 ◽  
Author(s):  
Natalie A. Marshall ◽  
John Greg Howe ◽  
Richard Formica ◽  
Diane Krause ◽  
John E. Wagner ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cd8 T Cells ◽  
Epstein Barr Virus ◽  
Hla Class I ◽  
Barr Virus ◽  
Matched Sibling ◽  
Epstein Barr

Epstein-Barr virus (EBV)–specific CD8 T lymphocytes are present at remarkably high frequencies in healthy EBV+individuals and provide protection from EBV-associated lymphoproliferative diseases. Allogeneic peripheral blood stem cell transplantation (allo-PBSCT) is a commonly used therapy in which T-cell surveillance for EBV is temporarily disrupted. Herein, human leukocyte antigen (HLA) class I tetramers were used to investigate the reestablishment of the EBV-specific CD8 T-cell repertoire in patients following allo-PBSCT. CD8+ T cells specific for lytic and latent cycle–derived EBV peptides rapidly repopulate the periphery of matched sibling allo-PBSCT patients. The relative frequencies of T cells specific for different EBV peptides in transplantation recipients closely reflect those of their respective donors. Investigation of patients at monthly intervals following unmanipulated allo-PBSCT demonstrated that the frequency of EBV-specific T cells correlates with the number of EBV genome copies in the peripheral blood and that expansion of EBV-specific T-cell populations occurs even in the setting of immunosuppressive therapy. In contrast, patients undergoing T-cell–depleted or unrelated cord blood transplantation have undetectable EBV-specific T cells, even in the presence of Epstein-Barr viremia. The protective shield provided by EBV-specific CD8 T cells is rapidly established following unmanipulated matched sibling allo-PBSCT and demonstrates that HLA class I tetramers complexed with viral peptides can provide direct and rapid assessment of pathogen-specific immunity in this and other vulnerable patient populations.

scholarly journals Off-the-Shelf Virus-Specific T Cells to Treat BK Virus, Human Herpesvirus 6, Cytomegalovirus, Epstein-Barr Virus, and Adenovirus Infections After Allogeneic Hematopoietic Stem-Cell Transplantation

2017 ◽  
Vol 35 (31) ◽  
pp. 3547-3557 ◽  
Author(s):  
Ifigeneia Tzannou ◽  
Anastasia Papadopoulou ◽  
Swati Naik ◽  
Kathryn Leung ◽  
Caridad A. Martinez ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Epstein Barr Virus ◽  
Human Herpesvirus ◽  
Bk Virus ◽  
Third Party ◽  
Human Herpesvirus 6 ◽  
Hematopoietic Stem ◽  
Barr Virus ◽  
Epstein Barr

Purpose Improvement of cure rates for patients treated with allogeneic hematopoietic stem-cell transplantation (HSCT) will require efforts to decrease treatment-related mortality from severe viral infections. Adoptively transferred virus-specific T cells (VSTs) generated from eligible, third-party donors could provide broad antiviral protection to recipients of HSCT as an immediately available off-the-shelf product. Patient and Methods We generated a bank of VSTs that recognized five common viral pathogens: Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6). The VSTs were administered to 38 patients with 45 infections in a phase II clinical trial. Results A single infusion produced a cumulative complete or partial response rate of 92% (95% CI, 78.1% to 98.3%) overall and the following rates by virus: 100% for BKV (n = 16), 94% for CMV (n = 17), 71% for AdV (n = 7), 100% for EBV (n = 2), and 67% for HHV-6 (n = 3). Clinical benefit was achieved in 31 patients treated for one infection and in seven patients treated for multiple coincident infections. Thirteen of 14 patients treated for BKV-associated hemorrhagic cystitis experienced complete resolution of gross hematuria by week 6. Infusions were safe, and only two occurrences of de novo graft-versus host disease (grade 1) were observed. VST tracking by epitope profiling revealed persistence of functional VSTs of third-party origin for up to 12 weeks. Conclusion The use of banked VSTs is a feasible, safe, and effective approach to treat severe and drug-refractory infections after HSCT, including infections from two viruses (BKV and HHV-6) that had never been targeted previously with an off-the-shelf product. Furthermore, the multispecificity of the VSTs ensures extensive antiviral coverage, which facilitates the treatment of patients with multiple infections.

scholarly journals Expansion of T cells targeting multiple antigens of cytomegalovirus, Epstein–Barr virus and adenovirus to provide broad antiviral specificity after stem cell transplantation

Cytotherapy ◽  
2011 ◽  
Vol 13 (8) ◽  
pp. 976-986 ◽  
Author(s):  
Patrick J. Hanley ◽  
Donald R. Shaffer ◽  
Conrad R.Y. Cruz ◽  
Stephanie Ku ◽  
Benjamin Tzou ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Epstein Barr

Adoptive Transfer of Epstein-Barr Virus (EBV) Nuclear Antigen 1–Specific T Cells As Treatment for EBV Reactivation and Lymphoproliferative Disorders After Allogeneic Stem-Cell Transplantation

2013 ◽  
Vol 31 (1) ◽  
pp. 39-48 ◽  
Author(s):  
Vanya Icheva ◽  
Simone Kayser ◽  
Daniel Wolff ◽  
Sebastian Tuve ◽  
Christina Kyzirakos ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Adoptive Transfer ◽  
Epstein Barr Virus ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Epstein Barr

Purpose Reactivation of Epstein-Barr virus (EBV) after allogeneic stem-cell transplantation (SCT) can lead to severe life-threatening infections and trigger post-transplantation lymphoproliferative disease (PTLD). Since EBV-specific T cells could prevent PTLD, cellular immunotherapy has been a promising treatment option. However, generation of antigen-specific T-cell populations has been difficult within a short time frame. Patients and Methods To improve availability in urgent clinical conditions, we developed a rapid protocol for isolation of polyclonal EBV nuclear antigen 1 (EBNA-1) –specific T cells by using an interferon gamma (IFN-γ) capture technique. Results We report on the use of adoptive transfer of EBNA-1–specific T cells in 10 pediatric and adult patients with EBV viremia and/or PTLD after SCT. No acute toxicity or graft-versus-host disease (GVHD) of more than grade 2 occurred as a result of adoptive T-cell transfer. In vivo expansion of transferred EBNA-1–specific T cells was observed in eight of 10 patients after a median of 16 days following adoptive transfer that was associated with clinical and virologic response in seven of them (70%). None of the responders had EBV-associated mortality. Within clinical responders, three patients were disease free by the day of last follow-up (2 to 36 months), three patients died of other infectious complications, and one patient died as a result of relapse of malignancy. EBV-related mortality was observed in two of 10 patients, and another patient had ongoing viremia without clinical symptoms at last follow-up. Conclusion Adoptive ex vivo transfer of EBNA-1–specific T cells is a feasible and well-tolerated therapeutic option, representing a fast and efficient procedure to achieve reconstitution of antiviral T-cell immunity after SCT.

Rapid reconstitution of Epstein-Barr virus–specific T lymphocytes following allogeneic stem cell transplantation

Blood ◽  
2000 ◽  
Vol 96 (8) ◽  
pp. 2814-2821 ◽  
Author(s):  
Natalie A. Marshall ◽  
John Greg Howe ◽  
Richard Formica ◽  
Diane Krause ◽  
John E. Wagner ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cd8 T Cells ◽  
Epstein Barr Virus ◽  
Hla Class I ◽  
Barr Virus ◽  
Matched Sibling ◽  
Epstein Barr

Abstract Epstein-Barr virus (EBV)–specific CD8 T lymphocytes are present at remarkably high frequencies in healthy EBV+individuals and provide protection from EBV-associated lymphoproliferative diseases. Allogeneic peripheral blood stem cell transplantation (allo-PBSCT) is a commonly used therapy in which T-cell surveillance for EBV is temporarily disrupted. Herein, human leukocyte antigen (HLA) class I tetramers were used to investigate the reestablishment of the EBV-specific CD8 T-cell repertoire in patients following allo-PBSCT. CD8+ T cells specific for lytic and latent cycle–derived EBV peptides rapidly repopulate the periphery of matched sibling allo-PBSCT patients. The relative frequencies of T cells specific for different EBV peptides in transplantation recipients closely reflect those of their respective donors. Investigation of patients at monthly intervals following unmanipulated allo-PBSCT demonstrated that the frequency of EBV-specific T cells correlates with the number of EBV genome copies in the peripheral blood and that expansion of EBV-specific T-cell populations occurs even in the setting of immunosuppressive therapy. In contrast, patients undergoing T-cell–depleted or unrelated cord blood transplantation have undetectable EBV-specific T cells, even in the presence of Epstein-Barr viremia. The protective shield provided by EBV-specific CD8 T cells is rapidly established following unmanipulated matched sibling allo-PBSCT and demonstrates that HLA class I tetramers complexed with viral peptides can provide direct and rapid assessment of pathogen-specific immunity in this and other vulnerable patient populations.

scholarly journals Dendritic Cells Transduced with an Adenovirus Vector Encoding Epstein-Barr Virus Latent Membrane Protein 2B: a New Modality for Vaccination

1999 ◽  
Vol 73 (12) ◽  
pp. 10416-10425 ◽  
Author(s):  
E. Ranieri ◽  
W. Herr ◽  
A. Gambotto ◽  
W. Olson ◽  
D. Rowe ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Epstein Barr Virus ◽  
Recombinant Adenovirus ◽  
Adenovirus Vector ◽  
Latent Membrane Protein ◽  
Barr Virus ◽  
Ifn Γ ◽  
Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) is a herpesvirus commonly associated with several malignancies, particularly in immunocompromised hosts. As a strategy for stimulating immunity against EBV for the treatment of EBV-associated tumors, we have genetically engineered dendritic cells (DC) to express EBV antigens, such as latent membrane protein 2B (LMP2B), using recombinant adenovirus vectors. CD8+ T lymphocytes from HLA-A2.1+, EBV-seropositive healthy donors were cultured with autologous DC infected with recombinant adenovirus vector AdEGFP, encoding an enhanced green fluorescent protein (EGFP), or AdLMP2B at a multiplicity of infection of 250. After 48 h, >95% of the DC were positive for EGFP expression as assessed by fluorescence-activated cell sorting analysis, indicating efficient gene transfer. AdLMP2-transduced DC were used to stimulate CD8+T cells. Responder CD8+ T cells were tested for gamma interferon (IFN-γ) release by enzyme-linked spot (ELISPOT) assay and cytotoxic activity. Prior to in vitro stimulation, the frequencies of T-cells directed against two HLA-A2-presented LMP2 peptides (LMP2 329-337 and LMP2 426-434) were very low as assessed by IFN-γ spot formation (T-cell frequency, <0.003%). IFN-γ ELISPOT assays performed at day 14 showed a significant (2-log) increase of the day 0 frequency of T cells reactive against the LMP2 329-337 peptide, from 0.003 to 0.3 (P < 0.001). Moreover, specific cytolytic activity was observed against the autologous EBV B-lymphoblastoid cell lines after 21 days of stimulation of T-cell responders with AdLMP2-transduced DC (P < 0.01). In summary, autologous mature DC genetically modified with an adenovirus encoding EBV antigens stimulate the generation of EBV-specific CD8+ effector T cells in vitro, supporting the potential application of EBV-based adenovirus vector vaccination for the immunotherapy of the EBV-associated malignancies.

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