Peripheral CD4 + T‐Cell Reserve as a Potential Biomarker of CD20 × CD3 Bispecific Antibody Outcomes and BTK Inhibitor–Associated Immune Modulation 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. We retrospectively evaluated associations between peripheral immune profiles and outcomes in 40 patients treated with CD20 × CD3 BsAbs and explored BTK inhibitor–associated immune changes using a paired BTK inhibitor cohort, functional assays, mouse models, and single‐cell RNA sequencing. 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. Across paired clinical samples and experimental models, BTK inhibition was associated with CD4 + T‐cell expansion and enhanced T/NK‐cell proliferative and cytotoxic signatures. In an exploratory real‐world observation, three patients received BTK inhibition before glofitamab; all achieved complete responses, with two remaining in remission at data cutoff and one relapsing after 8.4 months. These findings identify peripheral CD4 + T‐cell reserve as a potential biomarker associated with BsAb outcomes and provide a rationale for further investigation of BTK inhibitor–mediated immune modulation in BsAb treatment strategies.