Circosta Paola, Elia Angela Rita, Landra Indira, Machiorlatti Rodolfo, Todaro Maria, Aliberti Sabrina, Brusa Davide, Deaglio Silvia, Chiaretti Sabina, Bruna Riccardo, Gottardi Daniela, Massaia Massimo, Giacomo Filomena Di, Guarini Anna Rita, Foà Robin, Kyriakides Peter W, Bareja Rohan, Elemento Olivier, Chichili Gurunadh R, Monteleone Emanuele, Moore Paul A, Johnson Syd, Bonvini Ezio, Cignetti Alessandro, Inghirami Giorgio
Molecular Biotechnology Center, University of Torino, Italy, and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino, Italy.
Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino, Italy.
Oncoimmunology. 2018 Feb 8;7(4):e1341032. doi: 10.1080/2162402X.2017.1341032. eCollection 2018.
Many patients with B-cell malignancies can be successfully treated, although tumor eradication is rarely achieved. T-cell-directed killing of tumor cells using engineered T-cells or bispecific antibodies is a promising approach for the treatment of hematologic malignancies. We investigated the efficacy of CD19xCD3 DART bispecific antibody in a broad panel of human primary B-cell malignancies. The CD19xCD3 DART identified 2 distinct subsets of patients, in which the neoplastic lymphocytes were eliminated with rapid or slow kinetics. Delayed responses were always overcome by a prolonged or repeated DART exposure. Both CD4 and CD8 effector cytotoxic cells were generated, and DART-mediated killing of CD4 cells into cytotoxic effectors required the presence of CD8 cells. Serial exposures to DART led to the exponential expansion of CD4 and CD8 cells and to the sequential ablation of neoplastic cells in absence of a PD-L1-mediated exhaustion. Lastly, patient-derived neoplastic B-cells (B-Acute Lymphoblast Leukemia and Diffuse Large B Cell Lymphoma) could be proficiently eradicated in a xenograft mouse model by DART-armed cytokine induced killer (CIK) cells. Collectively, patient tailored DART exposures can result in the effective elimination of CD19 positive leukemia and B-cell lymphoma and the association of bispecific antibodies with unmatched CIK cells represents an effective modality for the treatment of CD19 positive leukemia/lymphoma.
许多B细胞恶性肿瘤患者可以得到成功治疗，尽管很少能实现肿瘤根除。使用工程化T细胞或双特异性抗体对肿瘤细胞进行T细胞定向杀伤是治疗血液系统恶性肿瘤的一种有前景的方法。我们研究了CD19xCD3 DART双特异性抗体在多种人类原发性B细胞恶性肿瘤中的疗效。CD19xCD3 DART识别出2个不同的患者亚组，其中肿瘤淋巴细胞以快速或缓慢的动力学被清除。延迟反应总是通过延长或重复暴露于DART来克服。CD4和CD8效应细胞毒性细胞均产生，且DART介导的将CD4细胞杀伤为细胞毒性效应细胞需要CD8细胞的存在。连续暴露于DART导致CD4和CD8细胞呈指数级扩增，并在不存在PD-L1介导的耗竭情况下对肿瘤细胞进行序贯清除。最后，在异种移植小鼠模型中，携带DART的细胞因子诱导杀伤（CIK）细胞可以有效根除患者来源的肿瘤性B细胞（B急性淋巴细胞白血病和弥漫性大B细胞淋巴瘤）。总体而言，针对患者定制的DART暴露可有效清除CD19阳性白血病和B细胞淋巴瘤，双特异性抗体与不匹配的CIK细胞联合是治疗CD19阳性白血病/淋巴瘤的有效方式。
