Adoptive Transfer of EBNA1-Specific T-Cells as a Treatment of Epstein-Barr-Virus Reactivation Following Allogeneic Stem Cell Transplantation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2342-2342
Author(s):  
Vanya Icheva ◽  
Kathrin Opherk ◽  
Wolfgang A. Bethge ◽  
Simone Kayser ◽  
Johann Greil ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Epstein Barr Virus ◽  
Cell Transfer ◽  
Adoptive T Cell Transfer ◽  
Barr Virus ◽  
Cell Responses ◽  
Epstein Barr ◽  
T Cell Transfer

Abstract Abstract 2342 Reactivation of Epstein-Barr-Virus (EBV) after allogeneic stem cell transplantation (SCT) is responsible for significant morbidity and mortality. EBV is also assotiated with the development of some malingancies, such as Burkitt-Lymphoma or nasopharyngeal carcinoma (NPC). In particular, the EBV-induced lymphoproliferative disorder (PTLD) is a rare but severe condition after SCT. PTLD is often associated with insufficient immune responses against EBV in transplant recipients. There is no effective antiviral drug treatment against EBV by now. Given that T-cell immunity is crucial for protection against infection or reactivation of EBV, cellular immunotherapy is a promising therapeutic option. The Epstein-Barr-Virus Nuclear Antigen 1 (EBNA-1) has been shown to contain immunodominant T-cell epitopes with T-cell responses in the majority of the healthy population. Here we report adoptive EBNA-1-specific T-cell transfer in seven pediatric and adult patients with chemorefractory EBV-reactivation after allogenic SCT. Four patients had PTLD and one had metastatic relapse of a NPC. EBNA-1-specific T-cells were isolated from the SCT-donor by using an IFNγ-capture technique. These small T-cell populations were immediately infused to the patient without in vitro expansion steps. The adoptive T-cell transfer contained both, CD4+ T-helper cells and CD8+ cytotoxic T-cells. The patients with a mean age of 20 years were treated with antigen specific T-cells from haploidentical, matched unrelated or matched sibling donor SCT between day 72 and 410 post SCT. The T-cell dose varied from 150–7750 T-cells/ kg. No acute toxicity was observed. In vivo T-cell responses before adoptive T-cell transfer were absent and were detectable in all of the patients within the first weeks after adoptive transfer, associated with a partial clinical and/or virological response to the adoptive T-cell transfer. In three of the patients a second specific T-cell administration was needed to achieve an improvement of the EBV-related condition. PTLD or EBV-infection was not a cause of death in any of the other six patients. In conclusion we could show that adoptive T-cell-immunotherapy is safe, feasible and a promising therapeutic option in patients with EBV- infection and/or PTLD, having the advantage of not being immunosuppressive compared to chemotherapy against PTLD. Infusion of small IFNγ producing EBNA-1-specific T-cell populations resulted in an in vivo expansion of specific T-cells. Emergence of in vivo T-cell responses was closely associated with a clearance or reduction of the viral load. Disclosures: No relevant conflicts of interest to declare.

Adoptive Transfer of Hexon-Specific T-Cells as a Treatment of Adenovirus Reactivation Following Allogeneic Stem Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 796-796
Author(s):  
Kathrin Opherk ◽  
Friedhelm R Schuster ◽  
Wolfgang Andreas Bethge ◽  
Peter Bader ◽  
Johann Greil ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adoptive Immunotherapy ◽  
Therapeutic Option ◽  
T Cell Responses ◽  
Cell Transfer ◽  
Adoptive T Cell Transfer ◽  
Cell Responses ◽  
T Cell Transfer

Abstract Abstract 796 In pediatric patients human adenovirus (HAdV) was identified as a common viral pathogen responsible for significant morbidity and mortality post allo SCT. Antiviral chemotherapy is often insufficient. Given that T-cell immunity is crucial for protection against adenoviral infection/reactivation, cellular immunotherapy is a promising therapeutic option. The capsid protein Hexon has been shown to contain immunodominant T-cell epitopes, with T-cell responses in the majority of the healthy population. Therefore a prospective phase I/II clinical study was performed analysing safety and feasibility of adoptive Hexon-specific T-cell transfer in patients after allogeneic SCT and HAdV infection refractory to Cidofovir treatment. Hexon-specific T-cells were isolated from the SCT-donor by using the IFNγ secretion system and small T-cell populations were immediately infused, without in vitro expansion steps. Fourty pediatric and adult patients with a mean age of 15 years were treated according to the study protocol after haploidentical, matched unrelated and matched sibling donor SCT between day 11 and 327 post SCT. The T-cell dose varied from 300-25000 T-cells/kg. No acute toxicitiy was observed. In two patients GvHD °I-°II of the skin occured within two weeks after administration of specific T-cells, one patient also developed GvHD of the gut. In vivo T-cell responses were absent in all patients before adoptive T-cell transfer and detectable in 70% of evaluable patients within the first weeks after adoptive transfer, associated with a clinical and/or virological response to the adoptive T-cell transfer. However, in patients with adenoviral disease response rate was lower and 6 of 14 evaluable patients succumbed with the infection within few days, in spite of adoptive immunotherapy. This lead to the assumption, that adoptive treatment in patients with severe infection related morbidity was to late during the course of infection. In conclusion we could show that adoptive immunotherapy is safe, feasible and a promising therapeutic option in patients with HAdV infection. Infusion of small IFNγ producing Hexon-specific T-cells populations resulted in an in vivo expansion of specific T-cells in the majority of cases. Emergence of in vivo T-cell responses was closely associated with a clearance or reduction of the viral load. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Epstein-Barr virus (EBV)-carrying and -expressing T-cell lines established from severe chronic active EBV infection

Blood ◽  
1996 ◽  
Vol 87 (4) ◽  
pp. 1446-1457 ◽  
Author(s):  
S Imai ◽  
M Sugiura ◽  
O Oikawa ◽  
S Koizumi ◽  
M Hirao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lines ◽  
Epstein Barr Virus ◽  
Gene Rearrangement ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr ◽  
T Cell Lines

Four novel Epstein-Barr virus (EBV)-carrying T-cell lines, designated SIS, AIK-T8, AIK-T4, and SKN, were established from peripheral blood lymphocytes (PBL) of patients with severe chronic active EBV infection, in the presence of interleukin-2 and 4-deoxyphorbol ester. AIK-T8 and - T4 were derived from a single patient. Cell marker and genotype analyses showed that SIS, AIK-T8, and AIK-T4 had mature T-cell phenotypes with clonally rearranged T-cell receptor (TCR) genes, whereas SKN had an immature T-cell phenotype without TCR gene rearrangement. None of the cell lines expressed B, natural killer, or myeloid antigens or had Ig gene rearrangement. All lines carried EBV genomes in a single episomal form. SIS, AIK-T8, and SKN showed the same phenotype, TCR gene configuration, and/or EBV clonotype as their source or biopsied materials; therefore, they represented EBV-infected T cells proliferating in the patients. TCR gene and EBV episomal structures similar to those of AIK-T4 were not found in its source PBL, probably due to the few parental clones in vivo. All lines expressed EBV-encoded small RNA (EBER) 1, nuclear antigen (EBNA) 1, and latent membrane protein (LMP) 1, -2A, and -2B, but not other EBNAs that could be recognized by EBV-specific immune T cells. EBV replicative antigens were rarely expressed or induced. Such EBV latency reflects the in vivo situation, in which the T cells may evade immune surveillance and be insensitive to antiherpesvirus drugs. Collectively, the data suggest that EBV can target and latently infect T cells at any stage of differentiation in vivo, thus potentially causing uncontrolled T-cell proliferation. These cell lines will facilitate further analyses of possible EBV-induced oncogenicity in T cells.

scholarly journals Activated Human γδ T Cells as Stimulators of Specific CD8+ T-cell Responses to Subdominant Epstein Barr Virus Epitopes

2009 ◽  
Vol 32 (3) ◽  
pp. 310-321 ◽  
Author(s):  
Silke Landmeier ◽  
Bianca Altvater ◽  
Sibylle Pscherer ◽  
Heribert Juergens ◽  
Lena Varnholt ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Epstein Barr Virus ◽  
Γδ T Cells ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Barr Virus ◽  
Cell Responses ◽  
Epstein Barr

Hexon Specific T-Cells for Adoptive T-Cell Transfer as a Treatment of Adenovirus Infection after Allogeneic Stem Cell Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2853-2853
Author(s):  
Tobias Feuchtinger ◽  
Celine Richard ◽  
Rupert Handgretinger ◽  
Christiane Braun ◽  
Michael Schumm ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
Adenovirus Infection ◽  
Cell Transfer ◽  
Adoptive T Cell Transfer ◽  
Cell Responses ◽  
Hexon Protein ◽  
T Cell Transfer

Abstract Adenovirus infection (ADV) after allogeneic hematopoietic stem cell transplantation (HSCT) is an emerging pathogen causing relevant morbidity and mortality, with preponderance in children. Since a sufficient host T-cell response has been shown essential to clear the virus, diagnostic procedures for detection of virus-specific T-cells have recently developed to asses the specific cellular immune response. Furthermore adoptive immunotherapy is a new treatment option for patients with absent specific T-cell response and present systemic adenoviral infection. The possibility of an adoptive T-cell transfer depends on the availability of GMP compatible protocols and reagents. The adenoviral hexon protein was shown a immunodominant T-cell target within the viral capsid. In the present study we investigate the presence of Hexon-specific T-cell responses in HSCT donors, i.e. the availability of donors for an adoptive T-cell transfer. Secondly, the emergence of Hexon-specific T-cells in recipients post HSCT was analyzed. Thirdly, a protocol was established under GMP-conditions for adoptive T-cell immunotherapy through isolation of IFN-γ secreting T-cells after ex-vivo stimulation with the adenoviral Hexon protein. This procedure resulted in a mixed population of CD4 and CD8 positive T-cells with an effector memory phenotype and Th1 cytokine pattern (n=8). Isolated Hexon-specific T-cells show a strong expansion potential in vitro as well as specific cytotoxic activity. The availability of a donor was evaluated in 76 HSCT donors. Only 17.1% of donors had no ADV-specific T-cell response and 72.4% of donors were eligible for an adoptive T-cell transfer using the presented approach. The Hexon protein was responsible for almost the complete response to ADV, since no significant difference was seen against ADV lysate and the Hexon protein. In 76% HSCT recipients Hexon directed T-cell responses were evaluated and were shown to be responsible for clearance of the viral infection. In conclusion feasibility of an adoptive T-cell transfer for the treatment of ADV infection post HSCT is shown in accordance to current GMP regulations.

scholarly journals MicroRNAs of Epstein-Barr Virus Attenuate T-Cell-Mediated Immune ControlIn Vivo

mBio ◽  
2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Anita Murer ◽  
Julia Rühl ◽  
Andrea Zbinden ◽  
Riccarda Capaul ◽  
Wolfgang Hammerschmidt ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Immune Responses ◽  
Epstein Barr Virus ◽  
Tumor Formation ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

ABSTRACTThe human persistent and oncogenic Epstein-Barr virus (EBV) was one of the first viruses that were described to express viral microRNAs (miRNAs). These have been proposed to modulate many host and viral functions, but their predominant rolein vivohas remained unclear. We compared recombinant EBVs expressing or lacking miRNAs duringin vivoinfection of mice with reconstituted human immune system components and found that miRNA-deficient EBV replicates to lower viral titers with decreased frequencies of proliferating EBV-infected B cells. In response, activated cytotoxic EBV-specific T cells expand to lower frequencies than during infection with miRNA-expressing EBV. However, when we depleted CD8+T cells the miRNA-deficient virus reached similar viral loads as wild-type EBV, increasing by more than 200-fold in the spleens of infected animals. Furthermore, CD8+T cell depletion resulted in lymphoma formation in the majority of animals after miRNA-deficient EBV infection, while no tumors emerged when CD8+T cells were present. Thus, miRNAs mainly serve the purpose of immune evasion from T cellsin vivoand could become a therapeutic target to render EBV-associated malignancies more immunogenic.IMPORTANCEEpstein-Barr virus (EBV) infects the majority of the human population and usually persists asymptomatically within its host. Nevertheless, EBV is the causative agent for infectious mononucleosis (IM) and for lymphoproliferative disorders, including Burkitt and Hodgkin lymphomas. The immune system of the infected host is thought to prevent tumor formation in healthy virus carriers. EBV was one of the first viruses described to express miRNAs, and many host and viral targets were identified for thesein vitro. However, their role during EBV infectionin vivoremained unclear. This work is the first to describe that EBV miRNAs mainly increase viremia and virus-associated lymphomas through dampening antigen recognition by adaptive immune responses in mice with reconstituted immune responses. Currently, there is no prophylactic or therapeutic treatment to restrict IM or EBV-associated malignancies; thus, targeting EBV miRNAs could promote immune responses and limit EBV-associated pathologies.

scholarly journals Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8+T cells

2016 ◽  
Vol 113 (42) ◽  
pp. E6467-E6475 ◽  
Author(s):  
Manuel Albanese ◽  
Takanobu Tagawa ◽  
Mickaël Bouvet ◽  
Liridona Maliqi ◽  
Dominik Lutter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Mhc Class Ii ◽  
Epstein Barr Virus ◽  
T Cell Responses ◽  
Peptide Transporter ◽  
Barr Virus ◽  
Cell Responses ◽  
Epstein Barr

Infection with Epstein–Barr virus (EBV) affects most humans worldwide and persists life-long in the presence of robust virus-specific T-cell responses. In both immunocompromised and some immunocompetent people, EBV causes several cancers and lymphoproliferative diseases. EBV transforms B cells in vitro and encodes at least 44 microRNAs (miRNAs), most of which are expressed in EBV-transformed B cells, but their functions are largely unknown. Recently, we showed that EBV miRNAs inhibit CD4+T-cell responses to infected B cells by targeting IL-12, MHC class II, and lysosomal proteases. Here we investigated whether EBV miRNAs also counteract surveillance by CD8+T cells. We have found that EBV miRNAs strongly inhibit recognition and killing of infected B cells by EBV-specific CD8+T cells through multiple mechanisms. EBV miRNAs directly target the peptide transporter subunit TAP2 and reduce levels of the TAP1 subunit, MHC class I molecules, and EBNA1, a protein expressed in most forms of EBV latency and a target of EBV-specific CD8+T cells. Moreover, miRNA-mediated down-regulation of the cytokine IL-12 decreases the recognition of infected cells by EBV-specific CD8+T cells. Thus, EBV miRNAs use multiple, distinct pathways, allowing the virus to evade surveillance not only by CD4+but also by antiviral CD8+T cells.

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