Exploring the Impact of Humoral Immunogenicity with Tabelecleucel for the Treatment of EBV⁺ PTLD Following HCT and SOT

Background: Tabelecleucel is a non-genetically modified, allogeneic Epstein-Barr virus (EBV)-T-cell immunotherapy which targets and eliminates EBV-expressing cells in an HLA-restricted manner to treat patients (pts) with EBV⁺ post-transplant lymphoproliferative disease (PTLD) following hematopoietic stem cell transplantation (HCT) or solid organ transplantation (SOT). The theoretical risk of invoking a humoral or cell-mediated immune response against tabelecleucel is limited to the partially mismatched HLA allele. Tabelecleucel has proven to be safe and effective, with no confirmed evidence for clinical manifestation of immunogenicity in association with tabelecleucel. However, the theoretical consequences of eliciting an immune reaction against the mismatched HLA range from transient appearance of anti-HLA antibodies without any manifestation of clinically significant effects to the development of severe life-threatening conditions, which may include the potential for organ rejection. Therefore, evaluating the potential risk of immunogenicity against an allogeneic cell therapy like tabelecleucel is an important step in assessing the safety profile of the therapeutic agent. In this study we will assess the potential impact of humoral immunogenicity against tabelecleucel in pts with EBV⁺ PTLD after failure of rituximab or rituximab and chemotherapy enrolled in the ALLELE (NCT03394365) clinical study.

Methods: Humoral immunogenicity was assessed through two methods of anti-HLA antibody detection that evaluated a total of 28 pts on study. The primary approach evaluated 9 pts by a pan anti-HLA detection method that provides a positive or negative result. In this approach evaluable pts must have a negative result in pre-treatment measurement and have at least one post-treatment measurement. Results are coupled with the pt's clinical safety profile to assess treatment related immunogenicity. The secondary approach evaluated 24 pts in a single-antigen bead method that provides not just a positive or negative result but also defines the specificity and strength of the positive result. Cross referencing the allele specificity of the Class I or Class II anti-HLA antibodies with the HLA type of the pt, the transplant and the infusion product aids in elucidating the source of the anti-HLA antibodies in these pts.

Results: Two of the nine pts tested using the pan anti-HLA antibody detection approach had detection of anti-HLA antibodies in their pre-treatment sample. The remaining 7 evaluable pts had a median of 1 post-treatment measurement (min, max: 1, 3) and the median time post-treatment evaluated was 113 days (min, max: 40, 179). Six out of the 7 evaluable pts did not develop any anti-HLA antibodies post-treatment. One pt in the SOT cohort did develop anti-HLA antibodies 40 days after initial dosing on cycle 2 day 1. No treatment-emergent serious adverse events were reported for this pt, and only one adverse event of grade 1 fever was assessed as possibly related per investigator. The pt received additional doses of tabelecleucel yet did not manifest any subsequent events of fever or any signs of organ rejection. The second, single-antigen bead-based approach evaluated 24 pts. Four had anti-HLA antibodies present prior to tabelecleucel infusion. None of the pts evaluated had any incidence of de novo anti-HLA antibodies emerging post-treatment. For the 4 pts with pre-existing anti-HLA antibodies, evaluation of their safety profile and comparison to the total HLA immune profile of the pt is currently underway and will be reported at the time of presentation.

Conclusions: To date, there has been no confirmed evidence for clinical manifestation of immunogenicity in association with tabelecleucel. Only 1 pt (tested using the pan anti-HLA method) out of 28 pts (tested using either method) had de novo emergence of anti-HLA antibodies post-infusion. This pt did not experience any severe events potentially reflecting immunogenicity such as hypersensitivity or SOT rejection. Taken together, these results reaffirm the low potential risk of developing humoral immunogenicity following tabelecleucel administration in HCT or SOT recipients with EBV⁺ PTLD after failure of rituximab or rituximab and chemotherapy.

Spindler:Atara Biotherapeutics: Current Employment, Current holder of stock options in a privately-held company. Ruiz:Atara Biotherapeutics: Current Employment, Current holder of stock options in a privately-held company. Jehng:Atara Biotherapeutics: Current Employment, Current holder of stock options in a privately-held company. Ding:Atara Biotherapeutics: Current Employment, Current holder of stock options in a privately-held company. Guzman-Becerra:Atara Biotherapeutics: Current Employment, Current holder of stock options in a privately-held company. Khanzadeh:Atara Biotherapeutics: Current Employment, Current holder of stock options in a privately-held company. Li:Atara Biotherapeutics: Current Employment, Current holder of stock options in a privately-held company. Gamelin:Atara Biotherapeutics: Current Employment, Current holder of stock options in a privately-held company. Dubovsky:Atara Biotherapeutics: Current holder of stock options in a privately-held company, Ended employment in the past 24 months. Nguyen:Atara Biotherapeutics: Current Employment, Current holder of stock options in a privately-held company.