Jensen M, Ernestus K, Kemshead J, Klehr M, Von Bergwelt-Baildon M S, Schinköthe T, Schultze J L, Berthold F
Department of Pediatric Oncology and Hematology, University of Cologne, Germany.
Clin Exp Immunol. 2003 Nov;134(2):253-63. doi: 10.1046/j.1365-2249.2003.02300.x.
To target the neural cell adhesion molecule (NCAM, CD56) on neuroblastoma by T cell-based immunotherapy we have generated a bi-specific CD3 x NCAM antibody (OE-1). This antibody can be used to redirect T cells to NCAM+ cells. Expectedly, the antibody binds specifically to NCAM+ neuroblastoma cells and CD3+ T cells. OE-1 induces T cell activation, expansion and effector function in peripheral blood mononuclear cell (PBMC)-derived CD4+ and CD8+ T cells. T cell activation was shown to depend on the presence of normal natural killer (NK) cells in the culture. Interestingly, while PBMC- derived T cells were activated by OE-1, NK cells were almost completely depleted, suggesting that T cells activated by OE-1 deleted the NK cells. Activated CD4+ and CD8+ T cells differentiate into a larger CCR7+ central memory and a smaller CCR7- effector memory cell population. Most importantly, preactivated T cells were highly cytotoxic for neuroblastoma cells. In eight of 11 experiments tumour-directed cytotoxicity was enhanced when NK cells were present during preactivation with OE-1. These data strongly support a bi-phasic therapeutic concept of primarily stimulating T cells with the bi-specific antibody in the presence of normal NCAM+ cells to induce T cell activation, migratory capacity and finally tumour cell lysis.
为了通过基于T细胞的免疫疗法靶向神经母细胞瘤上的神经细胞黏附分子（NCAM，CD56），我们制备了一种双特异性CD3×NCAM抗体（OE-1）。该抗体可用于将T细胞重定向至NCAM阳性细胞。不出所料，该抗体特异性结合NCAM阳性神经母细胞瘤细胞和CD3阳性T细胞。OE-1在外周血单个核细胞（PBMC）来源的CD4+和CD8+T细胞中诱导T细胞活化、扩增和效应功能。结果表明，T细胞活化依赖于培养物中正常自然杀伤（NK）细胞的存在。有趣的是，虽然PBMC来源的T细胞被OE-1激活，但NK细胞几乎完全耗竭，这表明被OE-1激活的T细胞清除了NK细胞。活化的CD4+和CD8+T细胞分化为较大的CCR7+中央记忆细胞群和较小的CCR7-效应记忆细胞群。最重要地，预激活的T细胞对神经母细胞瘤细胞具有高度细胞毒性。在11个实验中的8个中，当在OE-1预激活期间存在NK细胞时，肿瘤定向细胞毒性增强。这些数据有力地支持了一种双相治疗概念，即在正常NCAM阳性细胞存在的情况下，用双特异性抗体主要刺激T细胞，以诱导T细胞活化、迁移能力并最终实现肿瘤细胞裂解。
