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 allogeneic, off‑the‑shelf Epstein–Barr virus (EBV)–specific T‑cell immunotherapy for EBV‑positive post‑transplant lymphoproliferative disease (EBV+ PTLD) after failure of at least one prior therapy. It received EU marketing authorization under exceptional circumstances on December 16, 2022, for adults and children ≥2 years; the Summary of Product Characteristics was last updated February 18, 2025. As of September 2, 2025, it has FDA Priority Review in the United States with a PDUFA target action date of January 10, 2026, following a January 16, 2025 Complete Response Letter related to third‑party manufacturing inspection issues (not efficacy/safety), and subsequent resubmission; clinical holds linked to those issues were lifted in May 2025. (ema.europa.eu, reuters.com, onclive.com, investors.atarabio.com)

Mechanism of action

Tabelecleucel consists of partially HLA‑matched, EBV‑specific cytotoxic T lymphocytes derived from healthy donors, expanded ex vivo by stimulation with donor EBV‑infected B‑cell lines. After infusion, these T cells recognize EBV antigens (for example, latent proteins such as EBNA and LMP family antigens) presented in an HLA‑restricted manner on malignant or infected B cells, and eliminate them. Dosing is 2 × 10^6 cells/kg intravenously on days 1, 8, and 15 of 35‑day cycles, with response‑guided continuation. (ema.europa.eu, pmc.ncbi.nlm.nih.gov)

Efficacy

• Phase 3, multicenter, open‑label ALLELE trial (Lancet Oncology 2024): Among 43 treated patients (14 HSCT, 29 SOT) with EBV+ PTLD after failure of rituximab ± chemotherapy, objective response rate (ORR) was 50% in HSCT and 52% in SOT. Responses were durable in a subset (durable responses ≥6 months reported), with ongoing follow‑up. (pubmed.ncbi.nlm.nih.gov)

• Updated ALLELE results (ASH 2024 abstract; ASTCT journal 2025 in‑press abstract): In 75 treated patients (49 SOT, 26 HCT), ORR was 50.7% overall (CR 28.0%, PR 22.7%), median time to response 1.1 months, and median duration of response 23.0 months. Median overall survival (OS) was 18.4 months; 1‑year OS was 78.7% for responders vs 28.2% for non‑responders. (ash.confex.com, astctjournal.org)

• Multicenter expanded‑access cohort (Blood Advances 2024): In 26 patients (14 HCT, 12 SOT) with relapsed/refractory EBV+ PTLD after rituximab ± chemotherapy, investigator‑assessed ORR was 65% overall (50% HCT; 83% SOT). Estimated 1‑ and 2‑year OS were both 70% overall; responders had markedly higher OS than non‑responders. (pmc.ncbi.nlm.nih.gov)

These findings support clinically meaningful and often durable responses in a population with historically poor outcomes after failure of initial therapy. (pubmed.ncbi.nlm.nih.gov, pmc.ncbi.nlm.nih.gov)

Safety

Across studies, tabelecleucel was generally well tolerated. In ALLELE (n=43), serious TEAEs occurred in 53% and fatal TEAEs in 12%, but none of the fatal events were considered treatment‑related. Notably, no cytokine release syndrome, ICANS, infusion reactions, marrow rejection, graft‑versus‑host disease, or solid‑organ graft rejection were reported as related to tabelecleucel. In the 75‑patient update, serious and fatal TEAEs occurred in approximately 61–65% and 18–19% by cohort, with no fatal treatment‑related TEAEs and no GVHD or organ rejection attributed to therapy. The EMA product information lists common adverse reactions (e.g., pyrexia, diarrhea, fatigue, cytopenias, liver enzyme elevations) and notes authorization under exceptional circumstances with ongoing data collection. (pubmed.ncbi.nlm.nih.gov, astctjournal.org, ema.europa.eu)

Further reading

• Lancet Oncology 2024: Phase 3 ALLELE primary results. (pubmed.ncbi.nlm.nih.gov)
• ASH 2024 abstract: Updated ALLELE outcomes (n=75). (ash.confex.com)
• ASTCT Journal 2025 abstract: Updated ALLELE results with longer follow‑up. (astctjournal.org)
• Blood Advances 2024: Multicenter expanded‑access experience. (pmc.ncbi.nlm.nih.gov)
• J Clin Invest 2020: Foundational “off‑the‑shelf” EBV‑specific CTL approach underlying tabelecleucel. (pmc.ncbi.nlm.nih.gov)
• EMA EPAR (Ebvallo): Indication, dosing, authorization details, and safety. (ema.europa.eu)

Notes on U.S. regulatory status: FDA issued a CRL on January 16, 2025, due to third‑party manufacturing inspection findings; clinical holds tied to those issues were lifted May 8, 2025. The resubmitted BLA has Priority Review with a PDUFA target action date of January 10, 2026. (reuters.com, onclive.com, investors.atarabio.com)

Last updated: Sep 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.