ArticleJournal for immunotherapy of cancer2026
Blinatumomab bypasses CD28 blockade to sustain T-cell cytotoxicity and improve survival in a xenograft B-ALL model.
Article in Journal for immunotherapy of cancer, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundRelapse 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
methodsIn 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.
resultsABATA 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).
conclusionThese 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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