CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Self-sufficient primary natural killer cells engineered to express T cell receptors and interleukin-15 exhibit improved effector function and persistence.
Self-sufficient primary natural killer cells engineered to express T cell receptors and interleukin-15 exhibit improved effector function and persistence.
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本研究表明，NK:TCR/IL-15 细胞分泌低水平 IL-15，并能在缺乏细胞因子的环境中增殖。重复的体外和体内实验证实了我们产品的有效性和靶点特异性，其中添加 IL-15 支持 TCR 和 NK 介导的细胞毒性。
NK 细胞可以通过基因工程改造来表达转基因 T 细胞受体（TCR）。这种方法为靶向异质性肿瘤提供了替代策略，因为 NK:TCR 细胞既能清除高表达 HLA I 类和目标抗原的肿瘤细胞，也能清除 HLA I 类阴性的肿瘤。NK 细胞的扩增和存活依赖于 IL-15 的存在。因此，NK:TCR 细胞自主产生 IL-15 可能改善 NK 细胞的功能持久性。在此，我们提出一种优化的 NK:TCR 产品，其搭载编码可溶性 IL-15 的构建体（NK:TCR/IL-15），以支持其增殖、持久性和细胞毒性能力。
肿瘤特异性TCR在外周血来源NK细胞中的表达通过逆转录病毒转导实现。将NK:TCR/IL-15细胞与NK:TCR细胞在自主细胞因子产生、增殖和存活方面进行比较。NK:BOB1-TCR/IL-15细胞表达针对BOB1的HLA-B*07:02限制性TCR，BOB1是一种B细胞谱系特异性转录因子，在所有B细胞恶性肿瘤中高表达，将其与对照NK:BOB1-TCR和NK:CMV-TCR/IL-15细胞在体外和体内针对TCR抗原阳性恶性B细胞系的效应功能进行比较。
将白细胞介素-15基因病毒整合到工程化NK:TCR细胞中是可行的，且TCR的高表达得以维持，从而从多个供体外周血中制备出纯的NK:TCR/IL-15细胞产品。NK:TCR细胞自给自足地分泌IL-15使工程化NK细胞能够在体外无需添加额外细胞因子的情况下增殖。NK:TCR/IL-15表现出TCR介导的细胞毒性显著增强以及NK介导的细胞毒性增强，从而在原位多发性骨髓瘤小鼠模型中改善了NK:BOB1-TCR/IL-15细胞的持久性和性能。然而，与NK:BOB1-TCR/IL-15持久的抗肿瘤反应性相反，我们在其中一项实验中观察到NK:BOB1-TCR/IL-15细胞在治疗小鼠的多个器官中积聚，导致NK输注后30天出现意外死亡。
NK cells can be genetically engineered to express a transgenic T-cell receptor (TCR). This approach offers an alternative strategy to target heterogenous tumors, as NK:TCR cells can eradicate both tumor cells with high expression of HLA class I and antigen of interest or HLA class I negative tumors. Expansion and survival of NK cells relies on the presence of IL-15. Therefore, autonomous production of IL-15 by NK:TCR cells might improve functional persistence of NK cells. Here we present an optimized NK:TCR product harnessed with a construct encoding for soluble IL-15 (NK:TCR/IL-15), to support their proliferation, persistence and cytotoxic capabilities.
Expression of tumor-specific TCRs in peripheral blood derived NK-cells was achieved following retroviral transduction. NK:TCR/IL-15 cells were compared with NK:TCR cells for autonomous cytokine production, proliferation and survival. NK:BOB1-TCR/IL-15 cells, expressing a HLA-B*07:02-restricted TCR against BOB1, a B-cell lineage specific transcription factor highly expressed in all B-cell malignancies, were compared with control NK:BOB1-TCR and NK:CMV-TCR/IL-15 cells for effector function against TCR antigen positive malignant B-cell lines in vitro and in vivo.
Viral incorporation of the interleukin-15 gene into engineered NK:TCR cells was feasible and high expression of the TCR was maintained, resulting in pure NK:TCR/IL-15 cell products generated from peripheral blood of multiple donors. Self-sufficient secretion of IL-15 by NK:TCR cells enables engineered NK cells to proliferate in vitro without addition of extra cytokines. NK:TCR/IL-15 demonstrated a marked enhancement of TCR-mediated cytotoxicity as well as enhanced NK-mediated cytotoxicity resulting in improved persistence and performance of NK:BOB1-TCR/IL-15 cells in an orthotopic multiple myeloma mouse model. However, in contrast to prolonged anti-tumor reactivity by NK:BOB1-TCR/IL-15, we observed in one of the experiments an accumulation of NK:BOB1-TCR/IL-15 cells in several organs of treated mice, leading to unexpected death 30 days post-NK infusion.
This study showed that NK:TCR/IL-15 cells secrete low levels of IL-15 and can proliferate in an environment lacking cytokines. Repeated in vitro and in vivo experiments confirmed the effectiveness and target specificity of our product, in which addition of IL-15 supports TCR- and NK-mediated cytotoxicity.
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