Virus-specific T-cells from third party or transplant donors for treatment of EBV lymphoproliferative diseases arising post hematopoietic cell or solid organ transplantation

O’Reilly, Richard J.; Prockop, Susan; Oved, Joseph H.

doi:10.3389/fimmu.2023.1290059

Cited by 3 publications

(1 citation statement)

References 119 publications

(313 reference statements)

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“…In addition, IL-15 and IL-21 enhance natural killer and CD8+ T cell cytotoxicity and antitumor effects [ 101 – 103 ]. An interesting approach could therefore be to combine HLA-matched, third party cytotoxic CD8+ T-cells [ 104 ] with IL-21, perhaps as an Fc-fusion to enhance [ 105 ]. Indeed, IL-21 therapy appears to generally be well tolerated [ 106 ].…”

Section: Discussionmentioning

confidence: 99%

Germinal center cytokine driven epigenetic control of Epstein-Barr virus latency gene expression

Liao,

Yan,

Beri

et al. 2024

PLoS Pathog

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Epstein-Barr virus (EBV) persistently infects 95% of adults worldwide and is associated with multiple human lymphomas that express characteristic EBV latency programs used by the virus to navigate the B-cell compartment. Upon primary infection, the EBV latency III program, comprised of six Epstein-Barr Nuclear Antigens (EBNA) and two Latent Membrane Protein (LMP) antigens, drives infected B-cells into germinal center (GC). By incompletely understood mechanisms, GC microenvironmental cues trigger the EBV genome to switch to the latency II program, comprised of EBNA1, LMP1 and LMP2A and observed in GC-derived Hodgkin lymphoma. To gain insights into pathways and epigenetic mechanisms that control EBV latency reprogramming as EBV-infected B-cells encounter microenvironmental cues, we characterized GC cytokine effects on EBV latency protein expression and on the EBV epigenome. We confirmed and extended prior studies highlighting GC cytokine effects in support of the latency II transition. The T-follicular helper cytokine interleukin 21 (IL-21), which is a major regulator of GC responses, and to a lesser extent IL-4 and IL-10, hyper-induced LMP1 expression, while repressing EBNA expression. However, follicular dendritic cell cytokines including IL-15 and IL-27 downmodulate EBNA but not LMP1 expression. CRISPR editing highlighted that STAT3 and STAT5 were necessary for cytokine mediated EBNA silencing via epigenetic effects at the EBV genomic C promoter. By contrast, STAT3 was instead necessary for LMP1 promoter epigenetic remodeling, including gain of activating histone chromatin marks and loss of repressive polycomb repressive complex silencing marks. Thus, EBV has evolved to coopt STAT signaling to oppositely regulate the epigenetic status of key viral genomic promoters in response to GC cytokine cues.

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Section: Discussionmentioning

confidence: 99%

Germinal center cytokine driven epigenetic control of Epstein-Barr virus latency gene expression

Liao,

Yan,

Beri

et al. 2024

PLoS Pathog

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Compassionate access to virus-specific T cells for adoptive immunotherapy over 15 years

Khanna,

Ambalathingal,

Hamad

et al. 2024

Preprint

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Adoptive T-cell immunotherapy holds great promise for the treatment of viral complications in immunocompromised patients resistant to standard anti-viral strategies. We present a retrospective analysis of 75 patients from 15 hospitals across Australia and New Zealand, treated over the last 15 years with “off-the-shelf” allogeneic T-cells directed to a combination of Epstein–Barr virus (EBV), cytomegalovirus (CMV), BK polyomavirus (BKV), John Cunningham virus (JCV) and/or adenovirus (AdV) under the Australian Therapeutic Goods Administration’s Special Access Scheme. Most patients had severe post-transplant viral complications, including drug-resistant end-organ CMV disease, BKV-associated haemorrhagic cystitis and EBV-driven post-transplant lymphoproliferative disorder. Adoptive immunotherapy was well tolerated with few adverse effects. Importantly, 50/75 (66.7%) patients showed definitive clinical improvement including reduction in viral load, clinical symptoms, complete resolution of end-organ disease and remained disease free. Based on this long-term encouraging clinical experience, we propose that a dedicated nationally funded centre for anti-viral cellular therapies should be established to provide T cell therapies for critically ill patients for compassionate use.

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EBV Reactivation and Disease in Allogeneic Hematopoietic Stem Cell Transplant (HSCT) Recipients and Its Impact on HSCT Outcomes

Law,

Logan,

Taplitz

2024

Viruses

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The acquisition or reactivation of Epstein–Barr virus (EBV) after allogeneic Hematopoietic Stem Cell Transplant (HSCT) can be associated with complications including the development of post-transplant lymphoproliferative disorder (PTLD), which is associated with significant morbidity and mortality. A number of risk factors for PTLD have been defined, including T-cell depletion, and approaches to monitoring EBV, especially in high-risk patients, with the use of preemptive therapy upon viral activation have been described. Newer therapies for the preemption or treatment of PTLD, such as EBV-specific cytotoxic T-cells, hold promise. Further studies to help define risks, diagnosis, and treatment of EBV-related complications are needed in this at-risk population.

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Virus-specific T-cells from third party or transplant donors for treatment of EBV lymphoproliferative diseases arising post hematopoietic cell or solid organ transplantation

Cited by 3 publications

References 119 publications

Germinal center cytokine driven epigenetic control of Epstein-Barr virus latency gene expression

Germinal center cytokine driven epigenetic control of Epstein-Barr virus latency gene expression

Compassionate access to virus-specific T cells for adoptive immunotherapy over 15 years

EBV Reactivation and Disease in Allogeneic Hematopoietic Stem Cell Transplant (HSCT) Recipients and Its Impact on HSCT Outcomes

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