An Open-label, Single-arm, Multicohort, Phase 2 Study to Assess the Efficacy and Safety of Tabelecleucel in Subjects With Epstein-Barr Virus-associated Diseases (EBVision)

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Overview

Tabelecleucel (Ebvallo) is an off‑the‑shelf, allogeneic, Epstein–Barr virus (EBV)–specific T‑cell therapy for EBV‑positive post‑transplant lymphoproliferative disease (EBV+ PTLD). It received EU marketing authorization on December 16, 2022, for adults and children ≥2 years with relapsed/refractory EBV+ PTLD after at least one prior therapy (for solid‑organ transplant, prior therapy includes chemotherapy unless inappropriate). In the United States, FDA issued a Complete Response Letter in January 2025 related to third‑party manufacturing; the resubmitted BLA received Priority Review in July 2025 with a PDUFA target action date of January 10, 2026. (ema.europa.eu)

Mechanism of action

Tabelecleucel consists of EBV‑specific cytotoxic T cells derived from seropositive third‑party donors. Donor T cells are primed ex vivo against EBV‑infected B cells from the same donor and expanded without genetic modification. After infusion, these HLA‑restricted T cells recognize and eliminate EBV‑infected cells in the recipient. (ema.europa.eu)

Efficacy

• Pivotal single‑arm phase 3 (ALLELE; multicenter, open‑label) in relapsed/refractory EBV+ PTLD after HCT or SOT: among the first 43 treated patients, objective response rate (ORR) was 51.2% (CR 26%, PR 25%); median duration of response (DOR) 23.0 months; median overall survival (OS) 18.4 months; 1‑year OS 84.4% for responders vs 34.8% for non‑responders. (sciencedirect.com)
• Updated ALLELE cohort (conference update; n=75): ORR 50.7% overall (SOT 51.0%, HCT 50.0%); median DOR 23 months; median OS 18.4 months. (ashpublications.org)
• EU EPAR summary of the 43‑patient dataset: responses in 15/29 SOT and 7/14 HCT; several responses >6 months. (ema.europa.eu)
• Multicenter Expanded Access Protocol (Blood Advances 2024; n=26 treated: 14 HCT, 12 SOT): investigator‑assessed ORR 65.4% overall (HCT 50%, SOT 83.3%); estimated 1‑ and 2‑year OS 70% overall; responses associated with markedly higher survival. (scholars.duke.edu)
• CNS‑involved EBV+ PTLD pooled analysis (Transplantation and Cellular Therapy 2023; n=18): ORR 77.8%; 1‑ and 2‑year OS 70.6% and 54.9%. (astctjournal.org)

Context: EBV+ PTLD after failure of initial therapy has historically poor survival measured in weeks to a few months, underscoring the unmet need. (ashpublications.org)

Safety

• In ALLELE (Lancet Oncology) and subsequent ASH update, no cytokine release syndrome, tumor flare reaction, immune‑effector neurotoxicity, or graft‑versus‑host disease/organ rejection events were reported as related to tabelecleucel; serious TEAEs occurred but fatal events were not considered treatment‑related. (sciencedirect.com)
• EU product information lists common adverse reactions (e.g., pyrexia, diarrhea, fatigue, anemia) and identifies tumor flare reaction and graft‑versus‑host disease as important risks warranting monitoring. (ema.europa.eu)
• Expanded‑access reports describe good tolerability with absence of CRS, ICANS, tumor flare, or transplant rejection attributed to therapy. (scholars.duke.edu)

Further reading

• Lancet Oncology (phase 3 ALLELE primary report). (sciencedirect.com)
• EMA EPAR for Ebvallo (regulatory overview, dosing, safety). (ema.europa.eu)
• Blood Advances 2024 (multicenter expanded access experience). (scholars.duke.edu)
• ASH 2024 abstract (updated ALLELE results, n=75). (ashpublications.org)
• Transplantation and Cellular Therapy 2023 (CNS EBV+ PTLD analysis). (astctjournal.org)
• Blood 2023 “How I treat PTLD” (treatment landscape context). (ashpublications.org)

Notes on status (United States): FDA issued a CRL in January 2025 related to manufacturing; the resubmitted BLA was accepted with Priority Review in July 2025 (PDUFA target January 10, 2026). As of October 7, 2025, tabelecleucel remains EU‑approved and investigational in the U.S. pending that action date. (reuters.com)

Last updated: Oct 2025

Inclusion Criteria:

* Diagnosis of EBV+ disorder.

* Eastern Cooperative Oncology Group performance status ≤ 3 for participants aged ≥ 16 years; Lansky score ≥ 20 for participants from ≥ 1 year to \< 16 years.

* Adequate organ function test results, unless organ dysfunction is considered to be due to the underlying EBV-associated disease by the investigator.

Cohort-specific Inclusion Criteria:

* For participants with PID LPD:

* R/R or newly diagnosed PID LPD for whom. the standard first-line therapy is inappropriate, as determined by investigator. The LPD is confirmed by at least biopsy-proven EBV+ LPD or positive cerebrospinal fluid (CSF) cytology with or without radiographically measurable intracranial disease with EBV detected in CSF.

* Participants with R/R disease must have had at least one prior line of systemic therapy and one of the following: radiographic disease progression per Lugano Classification (Cheson BD, et al. J Clin Oncol. 2014;27:3059) during or after treatment or failure to achieve a complete response (CR) or partial response (PR) (defined by Lugano radiographic criteria) after standard first-line therapy.

* Participant may have systemic disease only, systemic and CNS disease, or CNS disease only.

* For participants with AID LPD:

* R/R or newly diagnosed AID LPD for whom the standard first line therapy is inappropriate, as determined by the investigator. The LPD is confirmed by at least biopsy-proven EBV+ LPD or positive CSF cytology, with or without radiographically measurable intracranial disease, with EBV detected in CSF.

* Participants with R/R disease must have had at least one prior line of systemic therapy and one of the following: radiographic disease progression per Lugano Classification during or after treatment or failure to achieve a CR or PR (defined by Lugano radiographic criteria) after standard first-line therapy.

* Participant may have systemic disease only, systemic and CNS disease, or CNS disease only.

* For participants with AID etiology or AID attributable to immunosenescence, objective laboratory evidence of immunodeficiency.

* For participants with CNS PTLD:

* R/R or newly diagnosed EBV+ CNS PTLD for whom the standard. first-line therapy is inappropriate, as determined by the investigator. The CNS PTLD is histologically confirmed by at least biopsy-proven EBV+ CNS PTLD or positive CSF cytology with or without radiographically measurable intracranial disease with EBV detected in CSF.

* Participants with R/R disease must have had at least one prior line of systemic therapy and one of the following: radiographic disease progression per Lugano Classification during or after treatment or failure to achieve a CR or PR (defined by Lugano radiographic criteria) after standard first-line therapy.

* Participant may have systemic and CNS disease or CNS disease only.

* For participants with EBV+ 1L PTLD, including CD20-negative disease:

* Biopsy-proven EBV+ PTLD for whom standard first-line therapy (rituximab and/or chemotherapy) is inappropriate, as determined by the investigator.

* Participants must have systemic disease measurable per Lugano Classification criteria, except when contraindicated or mandated by local practice, then MRI may be used.

* For participants with sarcoma, including LMS, or smooth muscle tumors:

* EBV+ sarcoma or smooth muscle tumor with rapidly progressive disease defined as progressive disease per RECIST 1.1 criteria as documented radiographically within a 6-month interval prior to enrollment.

* Participants with newly diagnosed EBV+ sarcoma for whom the standard first-line therapy is inappropriate, as determined by the investigator.

* Biopsy-proven EBV+ sarcoma meeting one of the criteria's of pathologically confirmed EBV+ Leiomyosarcoma or EBV+ sarcoma or smooth muscle tumor.

* Measurable disease using diagnostic CT and/or MRI following RECIST 1.1 criteria (Eisenhauer et al. 2009. Eur J Cancer 45\[2\]:228-247).

Exclusion Criteria:

* Currently active Burkitt, T-cell, natural killer/T-cell lymphoma/LPD, Hodgkin, plasmablastic, transformed lymphoma, active hemophagocytic lymphohistiocytosis, or other malignancies requiring systemic therapy.

* Serious known active infections, defined as ongoing uncontrolled adenovirus infection or infections requiring systemic therapy at the time of enrollment, or known history of human immunodeficiency virus (HIV) infection.

* Suspected or confirmed Grade ≥ 2 acute graft-versus-host disease (GvHD) per the Center for International Blood and Marrow Transplant Research (CIBMTR) consensus grading system or extensive chronic GvHD per National Institutes of Health (NIH) consensus criteria at the time of the enrollment.

* Need for vasopressor or ventilatory support at the time of enrollment.

* Prior therapy (in order of increasing washout period) prior to enrollment as follows:

* Within 4 weeks or 5 half-lives (whichever is shorter) for any investigational product and/ or any chemotherapy (systemic or intrathecal), targeted small molecule therapy, or antibody/biologic therapy. Note: prior anti-CD20 antibody use is permitted within the washout period if a subsequent disease response assessment indicates disease progression.

* Within 8 weeks: prior tabelecleucel (\> 8 weeks prior to enrollment) is permitted if response was obtained or if usual protocol-directed therapeutic options were not exhausted, for cellular therapies (chimeric antigen receptor therapies directed at T-cells or T-cell subsets, donor lymphocyte infusion, other CTLs or virus-specific T-cells); and/or therapies which could impact tabelecleucel function (anti-thymocyte globulin, alemtuzumab).

* Any prior treatment with EBV-CTLs with the exception of tabelecleucel as above

* Women who are breastfeeding or pregnant.

* Unwilling to comply with protocol specified contraceptive/reproductive restrictions from enrollment through 90 days after the last treatment.

* Ongoing need for daily steroids of \> 0.5 mg/kg prednisone or glucocorticoid equivalent, ongoing methotrexate, or extracorporeal photopheresis (for participants with CNS disease, protocol-specified dexamethasone is permitted and concludes by the time of enrollment).

* Any conditions that may put the study outcomes at undue risk (life expectancy \< 60 days or any life-threatening illness, medical condition, or organ system dysfunction).

* For participants with PID LPD or AID LPD: history of prior allogeneic HCT or solid organ transplant.

* For participants with EBV+ 1L PTLD: prior systemic therapy for PTLD.