Generation of Epstein-Barr Virus Antigen-Specific T Cell Receptors Recognizing Immunodominant Epitopes of LMP1, LMP2A, and EBNA3C for Immunotherapy

Dudaniec, Krystyna; Westendorf, Kerstin; Nößner, Elfriede; Uckert, Wolfgang

doi:10.1089/hum.2020.283

Cited by 8 publications

(7 citation statements)

References 42 publications

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“…Each row represents one specific TCR rearrangement. Identified public TCR sequences (P1 and P2) published [ 28 , 30 ] are highlighted in grey boxes. The most dominant clones (D 1–3) within each specificity are highlighted in pink boxes.…”

Section: Supporting Informationmentioning

confidence: 99%

Reconstitution of EBV-directed T cell immunity by adoptive transfer of peptide-stimulated T cells in a patient after allogeneic stem cell transplantation for AITL

et al. 2022

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Reconstitution of the T cell repertoire after allogeneic stem cell transplantation is a long and often incomplete process. As a result, reactivation of Epstein-Barr virus (EBV) is a frequent complication that may be treated by adoptive transfer of donor-derived EBV-specific T cells. We generated donor-derived EBV-specific T cells by stimulation with peptides representing defined epitopes covering multiple HLA restrictions. T cells were adoptively transferred to a patient who had developed persisting high titers of EBV after allogeneic stem cell transplantation for angioimmunoblastic T-cell lymphoma (AITL). T cell receptor beta (TCRβ) deep sequencing showed that the T cell repertoire of the patient early after transplantation (day 60) was strongly reduced and only very low numbers of EBV-specific T cells were detectable. Manufacturing and in vitro expansion of donor-derived EBV-specific T cells resulted in enrichment of EBV epitope-specific, HLA-restricted T cells. Monitoring of T cell clonotypes at a molecular level after adoptive transfer revealed that the dominant TCR sequences from peptide-stimulated T cells persisted long-term and established an EBV-specific TCR clonotype repertoire in the host, with many of the EBV-specific TCRs present in the donor. This reconstituted repertoire was associated with immunological control of EBV and with lack of further AITL relapse.

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Section: Supporting Informationmentioning

confidence: 99%

Reconstitution of EBV-directed T cell immunity by adoptive transfer of peptide-stimulated T cells in a patient after allogeneic stem cell transplantation for AITL

et al. 2022

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“…Subsequent sequencing of their TCR CDR3 genes has led to identification of variable numbers of TCR clonotypes specific for individual epitopes. Examples include TCRs specifics for epitopes of LMP-1 presented by prevalent HLA alleles such as HLA A*0201 ( 108 , 109 ) and HLA A*1101 ( 110 , 111 ) as well as rarer alleles such as HLA B*5701 and HLA C*1502 ( 112 ). Using a similar approach, TCRs specific for both latency 3 and lytic EBV antigens have also been sequenced ( 112 – 117 ).…”

Section: Current Approaches To Address Those Hct and Sot Patients Wit...mentioning

confidence: 99%

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,

Prockop,

Oved

2024

Front. Immunol.

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EBV+ lymphomas constitute a significant cause of morbidity and mortality in recipients of allogeneic hematopoietic cell (HCT) and solid organ transplants (SOT). Phase I and II trials have shown that in HCT recipients, adoptive transfer of EBV-specific T-cells from the HCT donor can safely induce durable remissions of EBV+ lymphomas including 70->90% of patients who have failed to respond to treatment with Rituximab. More recently, EBV-specific T-cells generated from allogeneic 3rd party donors have also been shown to induce durable remission of EBV+ lymphomas in Rituximab refractory HCT and SOT recipients. In this review, we compare results of phase I and II trials of 3rd party and donor derived EBV-specific T-cells. We focus on the attributes and limitations of each product in terms of access, safety, responses achieved and durability. The limited data available regarding donor and host factors contributing to T cell persistence is also described. We examine factors contributing to treatment failures and approaches to prevent or salvage relapse. Lastly, we summarize strategies to further improve results for virus-specific immunotherapies for post-transplant EBV lymphomas.

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“…Genetically modified T cells expressing virus-specific transgenic TCRs, may be an option in the future for patients in whom no suitable T-cell donors are available or the donors are seronegative for the respective virus [72 ▪ ,73 ▪ ,74–75].…”

Section: Text Of Reviewmentioning

confidence: 99%

Immunocompromised host section: Adoptive T-cell therapy for dsDNA viruses in allogeneic hematopoietic cell transplant recipients

Walti

Stuehler

Palianina

et al. 2022

Current Opinion in Infectious Diseases

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Purpose of review Double-stranded DNA (dsDNA) viruses remain important causes of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). As treatment options are limited, adoptive therapy with virusspecific T cells (VST) is promising in restoring immunity and thereby preventing and treating virus infections. Here we review current evidence and recent advances in the field of VST for dsDNA viruses in allogeneic HCT recipients. Recent findingsFour different protocols for VST generation are currently used in clinical trials, and various products including multivirus-specific and off-the-shelf products are under investigation for prophylaxis, preemptive therapy or treatment. Data from nearly 1400 dsDNA-VST applications in allogeneic HCT patients have been published and demonstrated its safety. Although Epstein--Barr virus, cytomegalovirus, and adenovirusspecific T-cell therapy studies have predominated over the past 25 years, additional human herpes viruses were added to multivirus-specific T cells over the last decade and clinical evidence for polyomavirus-specific VST has just recently emerged. Response rates of around 70--80% have been reported, but cautious interpretation is warranted as data are predominantly from phase 1/2 studies and clinical efficacy needs to be confirmed in phase 3 studies.

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Generation of Epstein-Barr Virus Antigen-Specific T Cell Receptors Recognizing Immunodominant Epitopes of LMP1, LMP2A, and EBNA3C for Immunotherapy

Cited by 8 publications

References 42 publications

Reconstitution of EBV-directed T cell immunity by adoptive transfer of peptide-stimulated T cells in a patient after allogeneic stem cell transplantation for AITL

Reconstitution of EBV-directed T cell immunity by adoptive transfer of peptide-stimulated T cells in a patient after allogeneic stem cell transplantation for AITL

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

Immunocompromised host section: Adoptive T-cell therapy for dsDNA viruses in allogeneic hematopoietic cell transplant recipients

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