Abstract
Although considerable progress has been made with autologous T cell-based therapy in B-cell malignancies, application in chronic lymphocytic leukemia (CLL) lags behind due to disappointing response rates as well as substantial toxicity that is of particular concern in the elderly CLL population. Vγ9Vδ2-T cells form a conserved T-cell subset with strong intrinsic immunotherapeutic potential, largely because of their capacity to be triggered by phosphoantigens that can be overproduced by CLL and other malignant cells. Specific activation of Vγ9Vδ2-T cells by a bispecific antibody may improve the efficacy and toxicity of autologous T-cell-based therapy in CLL. We evaluated CD1d expression in a cohort of 78 untreated patients with CLL and generated and functionally characterized a CD1d-specific Vγ9Vδ2-T cell engager based on single-domain antibodies (VHH). CD1d was expressed by CLL in the majority of patients, particularly in patients with advanced disease. The CD1d-specific Vγ9Vδ2-T cell engager induced robust activation and degranulation of Vγ9Vδ2-T cells, enabling Vγ9Vδ2-T cells from patients with CLL to lyse autologous leukemic cells at low effector-to-target ratios. Expression of CD1d on CLL cells is upregulated by all-trans retinoic acid, and sensitizes the malignant cells to bispecific VHH-induced lysis. Furthermore, we provide evidence that the Vγ9Vδ2-T cell receptor retains responsiveness to phosphoantigens when the bispecific VHH is bound, and aminobisphosphonates can therefore enhance bispecific Vγ9Vδ2-T cell engager-mediated tumor-specific killing. Collectively, our data demonstrate the immunotherapeutic potential of this novel CD1d-specific Vγ9Vδ2-T cell engager in CLL.
Highlights
In recent years, the therapeutic arsenal for chronic lymphocytic leukemia (CLL) has substantially increased with the introduction of tyrosine kinase inhibitors, Bcl-2 inhibitors, and mAbs
Expression of CD1d on CLL cells is upregulated by all-trans retinoic acid, and sensitizes the malignant cells to bispecific VHH-induced lysis
Collectively, our data demonstrate the immunotherapeutic potential of this novel CD1d-specific Vg9Vd2-T cell engager in CLL
Summary
The therapeutic arsenal for chronic lymphocytic leukemia (CLL) has substantially increased with the introduction of tyrosine kinase inhibitors, Bcl-2 inhibitors, and mAbs. Recent attempts to exploit T cell–based therapies in CLL have focused on the development of chimeric antigen receptor (CAR) T cells, in which a diverse, non-antigen-specific pool of T cells is endowed with a CAR that recognizes a tumor-associated surface antigen. In contrast to the promising clinical responses observed with CAR T-cell therapy in acute lymphoblastic leukemia and diffuse large B-cell lymphomas, the response rate and response duration in CLL has been comparatively disappointing [4,5,6]. Toxicity is another important concern with CAR T-cell therapy, in the elderly CLL population [6, 7]
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