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

Icheva, Vanya; Kayser, Simone; Wolff, Daniel; Tuve, Sebastian; Kyzirakos, Christina; Bethge, Wolfgang; Greil, Johann; Albert, Michael H.; Schwinger, Wolfgang; Nathrath, Michaela; Schumm, Michael; Stevanović, Stefan; Handgretinger, Rupert; Lang, Peter; Feuchtinger, Tobias

doi:10.1200/jco.2011.39.8495

Cited by 244 publications

(185 citation statements)

References 40 publications

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“…The process to generate these EBNA1-specific EBV-CTLs is approximately 3 days. In a study of 10 patients with EBV-related refractory PTLD after allogeneic HSCT, the administration of EBNA1 specific EBV-CTLs was able to restore T-cell immunity against EBV and produced impressive clinical efficacy with a response rate of 70% [62]. In immunocompetent patients, generation of CTLs using this methodology did not yield the same efficacy when was administrated to EBVrelated Hodgkin lymphoma (HL) patients (latency type II) with a response rate of 30%, despite expressing the EBNA1 antigen, due to poor immunogenicity of latency II type EBV-HL cells (such as LMP1 and LMP2) [63].…”

Section: Ebv-specific Adoptive Cellular Immunotherapymentioning

confidence: 99%

EBV‐positive diffuse large B‐cell lymphoma of the elderly: 2016 update on diagnosis, risk‐stratification, and management

et al. 2016

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Epstein–Barr virus (EBV)‐positive diffuse large B‐cell lymphoma (DLBCL) of the elderly is a provisional entity included in the 2008 WHO classification of lymphoid neoplasms. It is a disease typically seen in the elderly and thought to be associated with chronic EBV infection and severe immunosuppression with a component of immunosenescence. Recent research, however, has suggested that EBV‐positive DLBCL can be seen in younger, immunocompetent patients.The diagnosis of EBV‐positive DLBCL of the elderly is made through a careful pathological evaluation. The differential diagnosis includes infectious mononucleosis (specifically in younger patients), lymphomatoid granulomatosis, Hodgkin lymphoma, and gray zone lymphoma, among others. Detection of EBV‐encoded RNA (EBER) is considered standard for diagnosis; however, a clear cutoff for positivity has not been defined.The International Prognostic Index (IPI), and the Oyama score can be used for risk‐stratification. The Oyama score includes age >70 years and presence of B symptoms. The expression of CD30 is emerging as a potential adverse, and targetable, prognostic factor.Patients with EBV‐positive DLBCL should be staged and managed following similar guidelines than patients with EBV‐negative DLBCL. It has been suggested, however, that EBV‐positive patients have a worse prognosis than EBV‐negative counterparts in the era of chemoimmunotherapy. There is an opportunity to study and develop targeted therapy in the management of patients with EBV‐positive DLBCL. Am. J. Hematol. 91:530–537, 2016. © 2016 Wiley Periodicals, Inc.

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Section: Ebv-specific Adoptive Cellular Immunotherapymentioning

confidence: 99%

EBV‐positive diffuse large B‐cell lymphoma of the elderly: 2016 update on diagnosis, risk‐stratification, and management

et al. 2016

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“…88,89 Rapid isolation strategies such as 'gamma catch' can be utilized when VSTs occur at high frequency in the donor's blood. This strategy has been successfully used in patients with CMV disease or viremia, with a response rate of 83%, 90 EBV, with a response rate of 50-70% 91,92 and ADV, with responses in 5 of 6 patients in a small study. 93 Adoptive transfer of VSTs from an adult stem cell donor is effective as prophylaxis and treatment for treatment-refractory EBV, CMV and ADV infections.…”

Section: Infectionmentioning

confidence: 99%

Umbilical cord blood graft engineering: challenges and opportunities

Thompson

Rezvani

Hosing

et al. 2015

Bone Marrow Transplant

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We are entering a very exciting era in umbilical cord blood transplantation (UCBT), where many of the associated formidable challenges may become treatable by ex vivo graft manipulation and/or adoptive immunotherapy utilizing specific cellular products. We envisage the use of double UCBT rather than single UCBT for most patients; this allows for greater ability to treat larger patients as well as to manipulate the graft. Ex vivo expansion and/or fucosylation of one cord will achieve more rapid engraftment, minimize the period of neutropenia and also give certainty that the other cord will provide long-term engraftment/immune reconstitution. The non-expanded (and future dominant) cord could be chosen for characteristics such as better HLA matching to minimize GvHD, or larger cell counts to enable part of the unit to be utilized for the development of specific cellular therapies such as the production of virus-specificT-cells or chimeric-antigen receptor T-cells which are reviewed in this study.

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“…Adoptive transfer of EBVspecific CD8 ϩ T cells has been successfully utilized to treat EBVassociated lymphoproliferative disease (4,5). In addition, CD8…”

Section: T He Gammaherpesvirus-directed Cd8mentioning

confidence: 99%

Type I Interferon Signaling Enhances CD8⁺T Cell Effector Function and Differentiation during Murine Gammaherpesvirus 68 Infection

Jennings

Grayson

Barton

2014

J Virol

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CD8؉ T cell responses are critical to the control of replication and reactivation associated with gammaherpesvirus infection. Type I interferons (IFNs) have been shown to have direct and indirect roles in supporting CD8؉ T cell development and function during viral infection; however, the role of type I interferons during latent viral infection has not been examined. Mice deficient in type I IFN signaling (IFNAR1 ؊/؊ mice) have high levels of reactivation during infection with murine gammaherpesvirus 68 (MHV68), a murine gammaherpesvirus model for Epstein-Barr virus. We hypothesized that type I IFNs function to enhance the anti-gammaherpesvirus CD8 ؉ T cell response. To test this, IFNAR1 ؊/؊ mice were infected with MHV68 and the CD8 ؉ T cell response was analyzed. In the absence of type I IFN signaling, there was a marked increase in short-lived effector CD8 ؉ T cells, and MHV68-specific CD8 ؉ T cells had upregulated expression of PD-1 and reduced tumor necrosis factor alpha (TNF-␣), gamma IFN (IFN-␥), and interleukin-2 (IL-2) production. Suppressing MHV68 replication early in infection using the antiviral cidofovir rescued CD8 ؉ T cell cytokine production and reduced PD-1 expression. However, suppressing high levels of reactivation in IFNAR1؊/؊ mice failed to improve CD8 ؉ T cell cytokine production during latency. T cell-specific abrogation of type I IFN signaling showed that the effects of type I IFNs on the CD8 ؉ T cell response during MHV68 infection are independent of direct type I IFN signaling on T cells. Our findings support a model in which type I IFNs likely suppress MHV68 replication, thus limiting viral antigen and facilitating an effective gammaherpesvirus-directed CD8 ؉ T cell response. IMPORTANCE The murine gammaherpesvirus MHV68 has both genetic and biologic homology to the human gammaherpesvirus Epstein-Barr virus (EBV), which infects over 90% of humans. Latent EBV infection and reactivation are associated with various life-threatening diseases and malignancies. Host suppression of gammaherpesvirus latency and reactivation requires both CD8 T he gammaherpesvirus-directed CD8ϩ T cell response is critical to the control of replication and reactivation associated with Epstein-Barr virus (EBV) infection, and individuals with either genetic or acquired immunodeficiencies are highly susceptible to EBV-associated diseases (1-3). Adoptive transfer of EBVspecific CD8 ϩ T cells has been successfully utilized to treat EBVassociated lymphoproliferative disease (4, 5). In addition, CD8 ϩ T cells prevent in vivo tumor outgrowth of B cell cancer lines immortalized by murine gammaherpesvirus 68 (MHV68), a wellcharacterized virus model for EBV (6). Thus, CD8ϩ T cells can suppress gammaherpesvirus-associated malignancies. The promise of immunotherapy and vaccine development relies on our understanding of factors that promote a highly effective gammaherpesvirus-directed CD8 ϩ T cell response. CD8 ϩ T cells responding to their cognate antigen require three signals for survival and differentiation: antige...

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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

Abstract: 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.

Cited by 244 publications

References 40 publications

EBV‐positive diffuse large B‐cell lymphoma of the elderly: 2016 update on diagnosis, risk‐stratification, and management

EBV‐positive diffuse large B‐cell lymphoma of the elderly: 2016 update on diagnosis, risk‐stratification, and management

Umbilical cord blood graft engineering: challenges and opportunities

Type I Interferon Signaling Enhances CD8⁺T Cell Effector Function and Differentiation during Murine Gammaherpesvirus 68 Infection

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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

Abstract: 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.

Cited by 244 publications

References 40 publications

EBV‐positive diffuse large B‐cell lymphoma of the elderly: 2016 update on diagnosis, risk‐stratification, and management

EBV‐positive diffuse large B‐cell lymphoma of the elderly: 2016 update on diagnosis, risk‐stratification, and management

Umbilical cord blood graft engineering: challenges and opportunities

Type I Interferon Signaling Enhances CD8+T Cell Effector Function and Differentiation during Murine Gammaherpesvirus 68 Infection

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Type I Interferon Signaling Enhances CD8⁺T Cell Effector Function and Differentiation during Murine Gammaherpesvirus 68 Infection