T-cell prolymphocytic leukemia (T-PLL) is a poor prognostic disease with very limited options of efficient therapies. Most patients are refractory to chemotherapies and despite high response rates after alemtuzumab, virtually all patients relapse. Therefore, there is an unmet medical need for novel therapies in T-PLL. As the chemokine receptor CCR7 is a molecule expressed in a wide range of malignancies and relevant in many tumor processes, the present study addressed the biologic role of this receptor in T-PLL. Furthermore, we elucidated the mechanisms of action mediated by an anti-CCR7 monoclonal antibody (mAb) and evaluated whether its anti-tumor activity would warrant development towards clinical applications in T-PLL. Our results demonstrate that CCR7 is a prognostic biomarker for overall survival in T-PLL patients and a functional receptor involved in the migration, invasion, and survival of leukemic cells. Targeting CCR7 with a mAb inhibited ligand-mediated signaling pathways and induced tumor cell killing in primary samples. In addition, directing antibodies against CCR7 was highly effective in T-cell leukemia xenograft models. Together, these findings make CCR7 an attractive molecule for novel mAb-based therapeutic applications in T-PLL, a disease where recent drug screen efforts and studies addressing new compounds have focused on chemotherapy or small molecules.

中文翻译：

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CCR7作为t细胞幼淋巴细胞白血病的新治疗靶点

T 细胞幼淋巴细胞白血病 (T-PLL) 是一种预后不良的疾病，有效治疗的选择非常有限。大多数患者对化疗无效，尽管阿仑单抗后反应率很高，但几乎所有患者都会复发。因此，对 T-PLL 的新疗法存在未满足的医疗需求。由于趋化因子受体 CCR7 是一种在多种恶性肿瘤中表达并与许多肿瘤过程相关的分子，本研究探讨了该受体在 T-PLL 中的生物学作用。此外，我们阐明了由抗 CCR7 单克隆抗体 (mAb) 介导的作用机制，并评估了其抗肿瘤活性是否值得向 T-PLL 临床应用发展。我们的研究结果表明，CCR7 是 T-PLL 患者总体存活的预后生物标志物，也是参与白血病细胞迁移、侵袭和存活的功能性受体。用 mAb 靶向 CCR7 可抑制配体介导的信号通路并诱导初级样品中的肿瘤细胞杀伤。此外，针对 CCR7 的定向抗体在 T 细胞白血病异种移植模型中非常有效。总之，这些发现使 CCR7 成为 T-PLL 中基于 mAb 的新型治疗应用的有吸引力的分子，T-PLL 是一种疾病，最近的药物筛选工作和针对新化合物的研究都集中在化学疗法或小分子上。此外，针对 CCR7 的定向抗体在 T 细胞白血病异种移植模型中非常有效。总之，这些发现使 CCR7 成为 T-PLL 中基于 mAb 的新型治疗应用的有吸引力的分子，T-PLL 是一种疾病，最近的药物筛选工作和针对新化合物的研究都集中在化学疗法或小分子上。此外，针对 CCR7 的定向抗体在 T 细胞白血病异种移植模型中非常有效。总之，这些发现使 CCR7 成为 T-PLL 中基于 mAb 的新型治疗应用的有吸引力的分子，T-PLL 是一种疾病，最近的药物筛选工作和针对新化合物的研究都集中在化学疗法或小分子上。