Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Departments of Stem Cell Transplantation and Hemotherapy/Cellular Therapy, Hospital Israelita Albert Einstein, Sao Paulo, Brazil.
Clin Cancer Res. 2021 Jul 1;27(13):3744-3756. doi: 10.1158/1078-0432.CCR-21-0164. Epub 2021 May 13.
Natural killer (NK)-cell recognition and function against NK-resistant cancers remain substantial barriers to the broad application of NK-cell immunotherapy. Potential solutions include bispecific engagers that target NK-cell activity via an NK-activating receptor when simultaneously targeting a tumor-specific antigen, as well as enhancing functionality using IL12/15/18 cytokine pre-activation.
We assessed single-cell NK-cell responses stimulated by the tetravalent bispecific antibody AFM13 that binds CD30 on leukemia/lymphoma targets and CD16A on various types of NK cells using mass cytometry and cytotoxicity assays. The combination of AFM13 and IL12/15/18 pre-activation of blood and cord blood-derived NK cells was investigated and .
We found heterogeneity within AFM13-directed conventional blood NK cell (cNK) responses, as well as consistent AFM13-directed polyfunctional activation of mature NK cells across donors. NK-cell source also impacted the AFM13 response, with cNK cells from healthy donors exhibiting superior responses to those from patients with Hodgkin lymphoma. IL12/15/18-induced memory-like NK cells from peripheral blood exhibited enhanced killing of CD30 lymphoma targets directed by AFM13, compared with cNK cells. Cord-blood NK cells preactivated with IL12/15/18 and expanded with K562-based feeders also exhibited enhanced killing with AFM13 stimulation via upregulation of signaling pathways related to NK-cell effector function. AFM13-NK complex cells exhibited enhanced responses to CD30 lymphomas and .
We identify AFM13 as a promising combination with cytokine-activated adult blood or cord-blood NK cells to treat CD30 hematologic malignancies, warranting clinical trials with these novel combinations.
自然杀伤 (NK) 细胞对 NK 耐药性癌症的识别和功能仍然是 NK 细胞免疫疗法广泛应用的重大障碍。潜在的解决方案包括双特异性结合物，当同时靶向肿瘤特异性抗原时，通过 NK 激活受体靶向 NK 细胞活性，以及使用 IL12/15/18 细胞因子预激活来增强功能。
我们使用质谱细胞术和细胞毒性测定法评估了与白血病/淋巴瘤靶标上的 CD30 结合的四价双特异性抗体 AFM13 刺激的单细胞 NK 细胞反应，以及各种类型的 NK 细胞上的 CD16A。研究了 AFM13 与 IL12/15/18 预激活血液和脐带血衍生的 NK 细胞的组合。
我们发现 AFM13 定向常规血液 NK 细胞 (cNK) 反应存在异质性，并且在供体之间一致存在 AFM13 定向多能激活的成熟 NK 细胞。NK 细胞来源也影响 AFM13 的反应，来自健康供体的 cNK 细胞表现出比霍奇金淋巴瘤患者的 cNK 细胞更好的反应。与 cNK 细胞相比，来自外周血的 IL12/15/18 诱导的记忆样 NK 细胞在表达 AFM13 时对 CD30 淋巴瘤靶标具有增强的杀伤作用。用 IL12/15/18 预激活并通过 K562 基饲料扩增的脐带血 NK 细胞在用 AFM13 刺激时也通过上调与 NK 细胞效应功能相关的信号通路显示出增强的杀伤作用。AFM13-NK 复合物细胞对 CD30 淋巴瘤表现出增强的反应。
我们将 AFM13 鉴定为与细胞因子激活的成人血液或脐带血 NK 细胞联合治疗 CD30 血液恶性肿瘤的有前途的组合，值得进行这些新型组合的临床试验。
