CD4⁺ T-cell reserve predicts bispecific antibody efficacy and can be enhanced by BTK inhibition in B-cell lymphoma

Bispecific antibodies (BsAbs) targeting CD20×CD3 have achieved remarkable efficacy in relapsed or refractory (R/R) B-cell lymphoma, yet clinical responses remain heterogeneous and predictive biomarkers are lacking. In this study, we identified peripheral CD4⁺ T-cell abundance as a robust predictor of BsAb efficacy. Among 40 patients treated with CD20×CD3 BsAbs, higher baseline CD4⁺ T-cell counts correlated with superior response rates and prolonged progression-free survival, whereas CD8⁺ counts showed no association. Elevated CD4⁺ T-cell levels were linked to increased activation of effector CD8⁺CD28⁺ T cells and greater induction of IL-2 and IFN-γ following treatment, indicating that CD4⁺ help potentiates cytotoxic T-cell function. Mechanistic analyses revealed that Bruton’s tyrosine kinase (BTK) inhibitors expanded CD4⁺ T cells and reprogrammed T/NK compartments toward proliferative (MKI67⁺) and cytotoxic (GZMB⁺, IFNG⁺) phenotypes, with upregulation of T-cell activation and interferon signaling pathways. In clinical observation, sequential BTK inhibition before BsAb therapy was associated with durable remissions in most patients. Collectively, these findings establish CD4⁺ T-cell reserve as a key determinant of BsAb responsiveness and support BTK inhibition as a feasible immune-priming strategy to enhance BsAb efficacy in B-cell lymphoma.