Rapid single-cell identification of Epstein–Barr virus-specific T-cell receptors for cellular therapy

Cobo, María Fernanda Lammoglia; Welters, Carlotta; Rosenberger, Leonie; Leisegang, Matthias; Dietze, Kerstin; Pircher, Christian; Penter, Livius; Gary, Regina; Bullinger, Lars; Takvorian, Anna; Moosmann, Andreas; Dornmair, Klaus; Blankenstein, Thomas; Kammertöns, Thomas; Gerbitz, Armin; Hansmann, Leo

doi:10.1016/j.jcyt.2022.03.005

Cited by 8 publications

(10 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, we have previously shown by T cell receptor (TCR) sequencing in a patient receiving TPD-derived EBV-CTLs that both persistence and expansion of transferred cells — as well as induction of endogenous EBV-specific T cell responses, thereby broadening the antigenic repertoire — can occur ( 31 ). Single-cell sequencing studies are starting to elucidate TCR sequences that confer therapeutic efficacy and protective anti-EBV immunity ( 44 ). Future studies, including immune monitoring prior to EBV-CTL infusion as well as discrimination between donor- and recipient-derived T cells after transfer, are required to elucidate the mechanism as well as the therapeutic efficacy of adoptive T cell transfer.…”

Section: Discussionmentioning

confidence: 99%

Patient-tailored adoptive immunotherapy with EBV-specific T cells from related and unrelated donors

Bonifacius¹,

Lamottke²,

Tischer-Zimmermann³

et al. 2023

Journal of Clinical Investigation

Self Cite

View full text Add to dashboard Cite

BACKGROUND Adoptive transfer of EBV-specific T cells can restore specific immunity in immunocompromised patients with EBV-associated complications. METHODS We provide results of a personalized T cell manufacturing program evaluating donor, patient, T cell product, and outcome data. Patient-tailored clinical-grade EBV-specific cytotoxic T lymphocyte (EBV-CTL) products from stem cell donors (SCDs), related third-party donors (TPDs), or unrelated TPDs from the allogeneic T cell donor registry (alloCELL) at Hannover Medical School were manufactured by immunomagnetic selection using a CliniMACS Plus or Prodigy device and the EBV PepTivators EBNA-1 and Select. Consecutive manufacturing processes were evaluated, and patient outcome and side effects were retrieved by retrospective chart analysis. RESULTS Forty clinical-grade EBV-CTL products from SCDs, related TPDs, or unrelated TPDs were generated for 37 patients with refractory EBV infections or EBV-associated malignancies with and without a history of transplantation, within 5 days (median) after donor identification. Thirty-four patients received 1–14 EBV-CTL products (fresh and cryopreserved). EBV-CTL transfer led to a complete response in 20 of 29 patients who were evaluated for clinical response. No infusion-related toxicity was reported. EBV-specific T cells in patients’ blood were detectable in 16 of 18 monitored patients (89%) after transfer, and their presence correlated with clinical response. CONCLUSION Personalized clinical-grade manufacture of EBV-CTL products via immunomagnetic selection from SCDs, related TPDs, or unrelated TPDs in a timely manner is feasible. Overall, EBV-CTLs were clinically effective and well tolerated. Our data suggest EBV-CTL transfer as a promising therapeutic approach for immunocompromised patients with refractory EBV-associated diseases beyond HSCT, as well as patients with preexisting organ dysfunction. TRIAL REGISTRATION Not applicable. FUNDING This study was funded in part by the German Research Foundation (DFG, 158989968/SFB 900), the Deutsche Kinderkrebsstiftung (DKS 2013.09), Wilhelm-Sander-Stiftung (reference 2015.097.1), Ellen-Schmidt-Program of Hannover Medical School, and German Federal Ministry of Education and Research (reference 01EO0802).

show abstract

Section: Discussionmentioning

confidence: 99%

Patient-tailored adoptive immunotherapy with EBV-specific T cells from related and unrelated donors

Bonifacius¹,

Lamottke²,

Tischer-Zimmermann³

et al. 2023

Journal of Clinical Investigation

Self Cite

View full text Add to dashboard Cite

show abstract

“…For target peptide screening and coincubation with multiple myeloma cells, TCRs specific for cytomegalovirus-derived peptides (TPR, amino acid sequence: TPRVTGGGAM; or VTE, amino acid sequence: VTEHDTLLY), and an Epstein–Barr virus-derived peptide (GLC, amino acid sequence: GLCTLVAML) were used as positive controls. The sequences of the TPR-specific TCR are derived from MM008 15E10, and the VTE-specific TCR from MM139 10F7 (Supplementary Table S3); the GLC-specific TCR was previously published ( 30 ). CDR3 amino acid sequences of all TCRs detailed in Supplementary Table S3 were screened for potential target epitopes using VDJdb ( https://vdjdb.cdr3.net ).…”

Section: Methodsmentioning

confidence: 99%

Immune Phenotypes and Target Antigens of Clonally Expanded Bone Marrow T Cells in Treatment-Naïve Multiple Myeloma

Welters

Cobo

Stein

et al. 2022

Cancer Immunology Research

Self Cite

View full text Add to dashboard Cite

Multiple myeloma is a hematologic malignancy of monoclonal plasma cells that accumulate in the bone marrow. Despite their clinical and pathophysiological relevance, the roles of bone marrow infiltrating T cells in treatment-naïve patients are incompletely understood. We investigated whether clonally expanded T cells i) were detectable in multiple myeloma bone marrow, ii) showed characteristic immune phenotypes, and iii) whether dominant clones recognized antigens selectively presented on multiple myeloma cells. Single-cell index sorting and T-cell receptor (TCR)αβ sequencing of bone marrow T cells from 13 treatment-naïve patients showed dominant clonal expansion within CD8+ cytolytic effector compartments, and only a minority of expanded T-cell clones expressed the classical immune checkpoint molecules PD 1, CTLA 4, or TIM 3. To identify their molecular targets, TCRs of 68 dominant bone marrow clones from five selected patients were re-expressed and incubated with multiple myeloma and non multiple myeloma cells from corresponding patients. Only one out of 68 TCRs recognized antigen presented on multiple myeloma cells. This TCR was HLA-C-restricted, self-peptide-specific, and could be activated by multiple myeloma cells of multiple patients. The remaining dominant T-cell clones did not recognize multiple myeloma cells and were, in part, specific for antigens associated with chronic viral infections. In conclusion, we showed that dominant bone marrow T-cell clones in treatment naïve patients rarely recognize antigens presented on multiple myeloma cells and exhibit low expression of classical immune checkpoint molecules. Our data provide experimental context for experiences from clinical immune checkpoint inhibition trials and will inform future T cell-dependent therapeutic strategies.

show abstract

“…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 ). In sequential analyses of HCT-donor-derived epitope-specific T-cell clonotypes following transplant ( 40 ) Lommoglia Cobo et al.…”

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

confidence: 99%

“…Recently, several groups have developed novel retroviral-based constructs for transducing adult or cord blood T-cells to express activatable TCRs specific for immunodominant epitopes of selected EBV proteins and have begun pre-clinical assessments of their activity against EBV+ malignancies ( 109 – 112 , 117 – 119 ). However, while techniques securing efficiently transduced T-cells that highly express a correctly paired, activatable, high affinity TCR that can induce epitope-specific HLA restricted lysis of EBV+ tumor cells in vitro are increasingly effective, selection of one or a set of epitope-specific TCRs that, when expressed by autologous or an allogeneic donor’s T-cells will ensure therapeutic efficacy is a major challenge.…”

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.

View full text Add to dashboard Cite

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.

show abstract

Rapid single-cell identification of Epstein–Barr virus-specific T-cell receptors for cellular therapy

Cited by 8 publications

References 58 publications

Patient-tailored adoptive immunotherapy with EBV-specific T cells from related and unrelated donors

Patient-tailored adoptive immunotherapy with EBV-specific T cells from related and unrelated donors

Immune Phenotypes and Target Antigens of Clonally Expanded Bone Marrow T Cells in Treatment-Naïve Multiple Myeloma

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

Contact Info

Product

Resources

About