Tabelecleucel Advances in EBV+ PTLD With Phase 3 Trial and FDA Resubmission

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  • Pierre Fabre Laboratories has assumed global responsibility for clinical development and manufacturing of tabelecleucel (tab-cel; Ebvallo), including oversight of 2 active clinical trials in Epstein-Barr virus–associated (EBV+) posttransplant lymphoproliferative disorder (PTLD) and EBV-associated diseases.
  • Enrollment continues for the pivotal phase 3 ALLELE study (NCT03394365) evaluating tab-cel in patients with relapsed or refractory EBV+ PTLD after solid organ or hematopoietic cell transplantation.
  • Atara Biotherapeutics has resubmitted the biologics license application (BLA) for tab-cel following FDA feedback, with potential US approval pending.

Pierre Fabre Pharmaceuticals has officially assumed global clinical development responsibility for tab-cel, an off-the-shelf allogeneic T-cell therapy targeting EBV-infected cells.1 The company’s new role follows the transfer of the investigational new drug (IND) application from partner Atara Biotherapeutics on July 14, 2025, advancing tab-cel’s development for EBV+ PTLD and related EBV-driven malignancies.

This follows Atara Biotherapeutics’ resubmission of the BLA for tab-cel to the FDA on July 11, 2025. The initial application had received a complete response letter (CRL) in January 2025 due to issues with a third-party manufacturing facility.2 There were no issues with regard to efficacy or safety data in the CRL. Further, no additional clinical studies were requested to support the resubmission of the BLA.

“The BLA resubmission for tab-cel represents the collaborative efforts with our partner, Pierre Fabre Laboratories, to address the third-party manufacturing facility observations outlined in the January 2025 CRL,” said Cokey Nguyen, PhD, president and chief executive officer of Atara Biotherapeutics, stated in a press release.1 “We look forward to continued engagement with the FDA throughout its review and with Pierre Fabre Laboratories as they actively prepare for the potential launch of this innovative therapy in the US.”

3d rendered medically accurate illustration of too many white blood cells due to leukemia: © Sebastian Kaulitzki – stock.adobe.com

EBV+ PTLD is a rare but often fatal complication that arises in patients with compromised immune surveillance due to immunosuppression following transplant. It is marked by unchecked proliferation of EBV-infected B-cells and carries poor outcomes in patients who fail standard therapies. Median survival is reported at approximately 3 weeks in patients who underwent hematopoietic stem cell transplant (HSCT) and just over 4 months in solid organ transplant (SOT) patients after failing rituximab (Rituxan)-based treatment, highlighting the critical need for novel therapies.

Tab-cel is a donor-derived, EBV-specific, cytotoxic T-cell therapy designed to recognize and eliminate EBV-infected cells in immunocompromised patients. Unlike autologous chimeric antigen receptor (CAR) T-cell therapies, tab-cel is an allogeneic therapy produced from healthy donors, avoiding the lengthy and complex manufacturing timeline of patient-specific treatments.

Enrollment is ongoing in the pivotal phase 3 ALLELE trial. The study is evaluating tab-cel in patients with EBV+ PTLD following failure of rituximab or rituximab-based chemotherapy.2 This multicenter study includes patients who have undergone either SOT or allogeneic HSCT.

Patients must have biopsy-proven, measurable, FDG-avid EBV+ PTLD with prior failure of rituximab monotherapy or rituximab plus chemotherapy. Key eligibility criteria include adequate organ function, performance status of ≤3 for adults or Lansky score ≥20 for pediatric patients, and confirmed availability of a suitable HLA-partially matched tab-cel product. Central nervous system involvement is permitted if appropriately treated and monitored using Lugano Classification criteria.

The trial’s primary end point is objective response rate (ORR), with secondary end points including duration of response (DOR), complete and partial response rates, time to response, overall survival (OS), and graft-related outcomes in SOT recipients.

Prior results from the phase 3 ALLELE trial support the BLA.4 Updated data presented at the 2024 American Society of Hematology Annual Meeting highlighted an ORR of 50.7% among 75 evaluable patients (95% CI, 38.9%–62.4%). Among subgroups, the ORR was 51.0% for SOT recipients and 50.0% for those who had undergone HSCT. The median DOR across the overall cohort was 23 months, with a median OS of 18.4 months.

Importantly, no treatment-related deaths were reported. Serious treatment-emergent adverse events (TEAEs) occurred in 65.4% of HSCT patients and 61.2% of SOT patients, with fatal TEAEs seen in 19.2% and 18.4%, respectively. However, no cases of cytokine release syndrome, infusion reactions, or graft-vs-host disease were observed, underscoring the favorable safety profile of this off-the-shelf therapy.

An additional trial (NCT04554914) is also actively enrolling patients with a broader spectrum of EBV-associated diseases, such as EBV-positive lymphomas beyond PTLD. This multicenter, multicohort, open-label phase 2 study aims to expand the therapeutic potential of tab-cel across various EBV-driven conditions.1

With both the phase 3 ALLELE and phase 2 EBV-associated disease studies open for enrollment, and a regulatory review process underway in the US, tab-cel is poised to become a key therapeutic option in the management of EBV+ malignancies. Should FDA approval follow the European Commission’s authorization in 2022, oncologists in the US may soon gain access to the first allogeneic T-cell therapy for this ultra-rare and aggressive disease.

REFERENCES
  1. Perre Fabre Pharmaceuticals, Inc. announces transfer of investigational new drug application for tabelecleucel from Atara Biotherapeutics, Inc. News release. July 15, 2025. Accessed July 15, 2025. https://tinyurl.com/ynhf9c7a
  2. Atara Biotherapeutics provides regulatory and business update on Ebvallo (tabelecleucel). News release. Atara Bihttps://tinyurl.com/ynhf9c7aotherapeutics. January 16, 2025. Accessed July 15, 2025. https://tinyurl.com/yuc4d6jy
  3. Tabelecleucel for solid organ or allogeneic hematopoietic cell transplant participants With Epstein-Barr virus-associated post-transplant lymphoproliferative disease (EBV+ PTLD) after failure of rituximab or rituximab and chemotherapy (ALLELE). ClinicalTrials.gov. Updated July 14, 2025. Accessed July 15, 2025. https://clinicaltrials.gov/study/NCT03394365
  4. Updated results of phase 3 ALLELE study presented at 66th American Society of Hematology Annual Meeting confirm efficacy, safety and durability of novel allogeneic cell therapy tabelecleucel in relapsed or refractory Epstein-Barr virus positive post-transplant lymphoproliferative disease (EBV+ PTLD). News release. Pierre Fabre Pharmaceuticals. December 7, 2024. Accessed July 15, 2025. https://tinyurl.com/2mauhuw7

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