肿瘤细胞治疗研究
英文原题：Increased Activity of a NK-Specific CAR-NK Framework Targeting CD3 and CD5 for T-Cell Leukemias.
Increased Activity of a NK-Specific CAR-NK Framework Targeting CD3 and CD5 for T-Cell Leukemias.
我们的结果表明，CD3-CAR-T在体外清除恶性T细胞方面比CD5-CAR-T更活跃，然而，CD3-CAR-T在体内清除肿瘤细胞的效率较低，而CD5-CAR-T在弥漫性异种移植模型中具有抗肿瘤活性。
表达 CAR 构建体的 NK 效应细胞可用于靶向 T 系标志物。在本研究中，我们比较了 NK 特异性 CAR-NK 和 CAR-T 框架在 NK 效应细胞上表达后靶向 T 细胞恶性肿瘤中 CD3 和 CD5 的活性。我们的结果表明，CD3-CAR-T 在体外清除恶性 T 细胞方面比 CD5-CAR-T 更活跃，然而，CD3-CAR-T 在体内清除肿瘤细胞的效率较低，而 CD5-CAR-T 在弥漫性异种移植模型中具有抗肿瘤活性。体内疗效的缺乏与靶 T 细胞在与 CD3-CAR 效应细胞共培养后 CD3 水平下调相关。CAR-NK 框架极大地提高了 CAR 的疗效，导致 CD5-CAR-NK 效应细胞的脱颗粒、细胞因子分泌和肿瘤异种移植清除增加。最后，所有 CAR 构建体在体外清除恶性 T 细胞方面效果相似。我们的结果表明，NK-CAR 框架提高了 CAR 在 NK 细胞中的活性，并且 CD5 可能比 CD3 更适合作为 T 细胞恶性肿瘤的靶点，因为靶表达的动态下调可能影响体内疗效。
NK effector cells expressing a CAR construct may be used to target T-lineage markers. In this work, we compared the activity of a NK-specific CAR-NK and a CAR-T framework when expressed on NK effector cells to target CD3 and CD5 in T-cell malignancies. Our results show that CD3-CAR-T is more active than CD5-CAR-T to eliminate malignant T cells in vitro, however, CD3-CAR-T were less efficient to eliminate tumor cells in vivo, while CD5-CAR-T had antitumor activity in a diffuse xenograft model. Lack of in vivo efficacy correlated with downregulation of CD3 levels in target T cells after coculture with CD3-CAR effector cells. The CAR-NK framework greatly improved the efficacy of CARs leading to increased degranulation, cytokine secretion and elimination of the tumor xenograft by CD5-CAR-NK effector cells. Finally, all CAR constructs were similarly effective to eliminate malignant T cells in vitro. Our results show that the NK-CAR framework improves the activity of CARs in NK cells and that CD5 would be a better target than CD3 for T-cell malignancies, as dynamic downregulation of target expression may affect in vivo efficacy.
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