de Weerdt Iris, Lameris Roeland, Ruben Jurjen M, de Boer Renate, Kloosterman Jan, King Lisa A, Levin Mark-David, Parren Paul W H I, de Gruijl Tanja D, Kater Arnon P, van der Vliet Hans J
Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Department of Hematology, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
Clin Cancer Res. 2021 Mar 15;27(6):1744-1755. doi: 10.1158/1078-0432.CCR-20-4576. Epub 2021 Jan 15.
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 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.
尽管基于自体T细胞的疗法在B细胞恶性肿瘤治疗方面取得了显著进展，但在慢性淋巴细胞白血病（CLL）中的应用却滞后了，这是因为缓解率令人失望，且毒性较大，而这在老年CLL患者群体中尤为令人担忧。Vγ9Vδ2-T细胞是一个保守的T细胞亚群，具有强大的内在免疫治疗潜力，这主要是由于它们能够被磷酸抗原来触发，而CLL和其他恶性细胞能够过量产生这些磷酸抗原。双特异性抗体对Vγ9Vδ2-T细胞的特异性激活可能会提高基于自体T细胞的疗法在CLL治疗中的疗效和降低毒性。
我们评估了78例未经治疗的CLL患者队列中CD1d的表达情况，并基于单域抗体（VHH）生成了一种CD1d特异性Vγ9Vδ2-T细胞衔接器，并对其进行了功能表征。
大多数CLL患者的肿瘤细胞表达CD1d，尤其是晚期疾病患者。CD1d特异性Vγ9Vδ2-T细胞衔接器可诱导Vγ9Vδ2-T细胞强烈激活和脱颗粒，使CLL患者的Vγ9Vδ2-T细胞能够在低效应细胞与靶细胞比例下裂解自体白血病细胞。维甲酸可上调CLL细胞上CD1d的表达，并使恶性细胞对双特异性VHH诱导的裂解敏感。此外，我们提供的证据表明，当双特异性VHH结合时，Vγ9Vδ2-T细胞受体对磷酸抗原仍保持反应性，因此氨基双膦酸盐可增强双特异性Vγ9Vδ2-T细胞衔接器介导的肿瘤特异性杀伤作用。
总体而言，我们的数据证明了这种新型CD1d特异性Vγ9Vδ2-T细胞衔接器在CLL治疗中的免疫治疗潜力。
