What question did this study set out to answer?

This research aims to evaluate if blinatumomab can maintain antileukemic efficacy during CD28 blockade by abatacept in B-ALL.

June 14, 2026Open Access

Blinatumomab bypasses CD28 blockade to sustain T-cell cytotoxicity and improve survival in a xenograft B-ALL model

Key Points

This research aims to evaluate if blinatumomab can maintain antileukemic efficacy during CD28 blockade by abatacept in B-ALL.
In vitro assays tested T-cell responses in the presence and absence of abatacept.
Humanized NSG-IL-15 mouse models were used to assess in vivo antileukemic efficacy.
Animal models were treated with BLINA, ABATA, or combination therapy to analyze leukemia burden and survival.
ABATA did not reduce BLINA-induced cytotoxicity or activation of T-cells.
BLINA significantly decreased leukemia burden but caused early mortality due to severe GvHD.
The combination therapy of BLINA and ABATA extended median survival by 35 days compared to controls (p<0.0001).

Abstract

Background Relapse and graft-versus-host disease (GvHD) remain primary causes of treatment failure in patients with B-cell acute lymphoblastic leukemia (B-ALL) undergoing allogeneic hematopoietic cell transplantation (allo-HCT). While abatacept (ABATA) effectively mitigates GvHD via CD28-costimulation blockade, there is significant concern that it concurrently diminishes graft-versus-leukemia (GvL) effects, potentially leading to higher relapse rates. We investigated whether blinatumomab (BLINA) retains antileukemic efficacy in the presence of ABATA using in vitro assays and humanized NOD.Cg-Prkdc scid Il2rg tm1Wjl Tg(IL15)1Sz/SzJ (NSG-IL15) and NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ (NSG) mouse models. Methods In vitro and ex vivo flow cytometry-based cytotoxicity, degranulation (CD107a), cytokine production (interferon (IFN)-γ), and activation-marker (CD25, CD69, CD137, OX40) assays were performed using healthy donor peripheral blood mononuclear cells (PBMCs) (pretreated±ABATA) against leukemia or lymphoma cell lines (RS4;11, NALM-6, and JEKO-1) in the presence or not of BLINA. In vivo human PBMC-reconstituted NSG-IL-15 mice bearing RS4;11 B-ALL xenografts were treated with vehicle, monotherapy (BLINA or ABATA), or combination therapy. Leukemia burden and immune reconstitution were assessed through week 4; GvHD scores and overall survival were monitored longitudinally. Results ABATA did not impair BLINA-mediated cytotoxicity across multiple effector-to-target ratios against any of the cell lines, nor did it reduce BLINA-induced degranulation, IFN-γ production, or activation marker expression. In vivo, BLINA monotherapy significantly reduced leukemia burden, but resulted in early mortality due to severe GvHD. Conversely, ABATA markedly reduced GvHD severity. The combination of BLINA and ABATA preserved potent antileukemic efficacy while significantly extending median survival by 35 days compared with tumor controls (p<0.0001). Although ABATA attenuated T-cell expansion and differentiation, BLINA-driven cytotoxic function was maintained, even after prolonged in vivo exposure to cytotoxic T-lymphocyte-associated protein 4-immunoglobulin (CTLA-4-Ig). Conclusion These findings provide preclinical proof-of-concept that BLINA and ABATA can be combined to uncouple GvL from GvHD. This strategy preserves CD28-independent T-cell cytotoxicity while limiting allo-reactivity, providing a strong rationale for investigating this combination in the post-transplant setting.

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