Haematologica. 2013 Dec;98(12):1930-8. doi: 10.3324/haematol.2012.082248. Epub 2013 Jun 28.
Chronic lymphocytic leukemia is an incurable B-cell malignancy that is associated with tumor cell-mediated T-cell dysfunction. It therefore represents a challenging disease for T-cell immunotherapeutics. The CD19/CD3 bi-specific antibody construct blinatumomab (AMG103 or MT103) has been tested clinically in non-Hodgkin's lymphoma and acute lymphoblastic leukemia but has not been assessed in chronic lymphocytic leukemia. We investigated whether blinatumomab could overcome T-cell dysfunction in chronic lymphocytic leukemia in vitro. Blinatumomab was tested on peripheral blood mononuclear cells from 28 patients (treatment naïve and previously treated). T-cell activation and function, as well as cytotoxicity against leukemic tumor cells were measured. Blinatumomab induced T-cell activation, proliferation, cytokine secretion and granzyme B release in a manner similar to that occurring with stimulation with anti-CD3/anti-CD28 beads. However, only blinatumomab was able to induce tumor cell death and this was found to require blinatumomab-mediated conjugate formation between T cells and tumor cells. Cytotoxicity of tumor cells was observed at very low T-cell:tumor cell ratios. A three-dimensional model based on confocal microscopy suggested that up to 11 tumor cells could cluster round each T cell. Importantly, blinatumomab induced cytotoxicity against tumor cells in samples from both treatment-naïve and treated patients, and in the presence of co-culture pro-survival signals. The potent cytotoxic action of blinatumomab on tumor cells appears to involve conjugation of T cells with tumor cells at both the activation and effector stages. The efficacy of blinatumomab in vitro suggests that the bi-specific antibody approach may be a powerful immunotherapeutic strategy in chronic lymphocytic leukemia.
慢性淋巴细胞白血病是一种不可治愈的 B 细胞恶性肿瘤，与肿瘤细胞介导的 T 细胞功能障碍有关。因此，它是 T 细胞免疫治疗的一个挑战。CD19/CD3 双特异性抗体构建体blinatumomab（AMG103 或 MT103）已在非霍奇金淋巴瘤和急性淋巴细胞白血病的临床中进行了测试，但尚未在慢性淋巴细胞白血病中进行评估。我们研究了 blinatumomab 是否可以在体外克服慢性淋巴细胞白血病中的 T 细胞功能障碍。在 28 名患者（初治和既往治疗）的外周血单核细胞上测试了 blinatumomab。测量 T 细胞激活和功能以及对白血病肿瘤细胞的细胞毒性。blinatumomab 以类似于与抗 CD3/抗 CD28 珠刺激时发生的方式诱导 T 细胞激活、增殖、细胞因子分泌和颗粒酶 B 释放。然而，只有 blinatumomab 能够诱导肿瘤细胞死亡，并且发现这需要 T 细胞和肿瘤细胞之间的 blinatumomab 介导的缀合形成。在非常低的 T 细胞：肿瘤细胞比值下观察到肿瘤细胞的细胞毒性。基于共聚焦显微镜的三维模型表明，多达 11 个肿瘤细胞可以围绕每个 T 细胞聚集。重要的是，blinatumomab 在初治和治疗患者的样本中诱导了对肿瘤细胞的细胞毒性，并且存在共培养的生存信号。blinatumomab 对肿瘤细胞的强大细胞毒性作用似乎涉及在激活和效应阶段 T 细胞与肿瘤细胞的缀合。blinatumomab 在体外的疗效表明，双特异性抗体方法可能是慢性淋巴细胞白血病的一种强大的免疫治疗策略。
