A Bispecific Single-Domain Antibody Boosts Autologous Vγ9Vδ2-T Cell Responses Toward CD1d in Chronic Lymphocytic Leukemia (Clinical Cancer Research)
Purpose:Although considerable progress has been made withautologous T cell–based therapy in B-cell malignancies, appli-cation in chronic lymphocytic leukemia (CLL) lags behind dueto disappointing response rates as well as substantial toxicitythat is of particular concern in the elderly CLL population.Vg9Vd2-T cells form a conserved T-cell subset with strongintrinsic immunotherapeutic potential, largely because of theircapacity to be triggered by phosphoantigens that can be over-produced by CLL and other malignant cells. Specificactivationof Vg9Vd2-T cells by a bispecific antibody may improve theefficacy and toxicity of autologous T-cell–based therapy in CLL.Experimental Design:We evaluated CD1d expression in acohort of 78 untreated patients with CLL and generated andfunctionally characterized a CD1d-specificVg9Vd2-T cell engagerbased on single-domain antibodies (VHH).
Results:CD1d was expressed by CLL in the majority of patients,particularly in patients with advanced disease. The CD1d-specificVg9Vd2-T cell engager induced robust activation and degranula-tion of Vg9Vd2-T cells, enabling Vg9Vd2-T cells from patients withCLL to lyse autologous leukemic cells at low effector-to-target ratios.Expression of CD1d on CLL cells is upregulated byall-transretinoicacid, and sensitizes the malignant cells to bispecific VHH-inducedlysis. Furthermore, we provide evidence that the Vg9Vd2-T cellreceptor retains responsiveness to phosphoantigens when the bis-pecific VHH is bound, and aminobisphosphonates can thereforeenhance bispecificVg9Vd2-T cell engager–mediated tumor-specific killing.
Conclusions:Collectively, our data demonstrate the immuno-therapeutic potential of this novel CD1d-specificVg9Vd2-T cellengager in CLL
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