Chimeric antigen receptor T cells targeting Fc μ receptor selectively eliminate CLL cells while sparing healthy B cells
Chimeric antigen receptor T cells targeting Fc μ receptor selectively eliminate CLL cells while sparing healthy B cells
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DOI：
10.1182/blood-2016-01-692046
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发表时间：
2016-09-29
期刊：
影响因子：
20.3
通讯作者：
Abken, Hinrich
中科院分区：
文献类型：
--
作者：
Faitschuk, Elena;Hombach, Andreas A.;Abken, Hinrich
针对CD19的嵌合抗原受体(CAR)修饰的T细胞过继细胞治疗慢性淋巴细胞白血病(CLL)在许多患者中导致了这种难治性疾病的持久缓解。然而，由于靶向消除健康的B细胞要求在靶向CLL细胞方面有更多的选择性，这种治疗与长期的“靶向靶向非肿瘤”毒性有关。我们发现免疫球蛋白M Fc受体(Fc MuR)，也被称为Fas凋亡抑制分子-3或TOSO，是CAR T细胞更具选择性地治疗CLL的靶点。Fc-Mu-R在CLL细胞中高表达且持续表达；在健康B细胞或其他造血细胞上仅检测到少量表达。具有Fc-mU-R特异性CAR的T细胞有效地对CLL细胞产生反应，释放一组促炎细胞因子和溶解因子，如可溶性FasL和颗粒酶B，并清除白血病细胞。与CD19 Car T细胞不同，抗Fc mU R Car T细胞不攻击健康B细胞。抗Fc-Mu-R的T细胞在异种小鼠模型中延缓了Mec-1诱导的白血病的生长。来自不同疾病阶段的CLL患者的T细胞经抗Fc muR Car修饰后，在体外清除其自体CLL细胞，而不减少健康B细胞的数量，这与抗CD19 Car T细胞的情况相同。与目前使用的治疗方法相比，这些数据有力地暗示了抗Fc-Mu-R-Car T细胞治疗CLL具有优越的治疗指标。
Adoptive cell therapy of chronic lymphocytic leukemia (CLL) with chimeric antigen receptor (CAR)-modified T cells targeting CD19 induced lasting remission of this refractory disease in a number of patients. However, the treatment is associated with prolonged "on-target off-tumor" toxicities due to the targeted elimination of healthy B cells demanding more selectivity in targeting CLL cells. We identified the immunoglobulin M Fc receptor (Fc mu R), also known as the Fas apoptotic inhibitory molecule-3 or TOSO, as a target for a more selective treatment of CLL by CAR T cells. Fc mu R is highly and consistently expressed by CLL cells; only minor levels are detected on healthy B cells or other hematopoietic cells. T cells with a CAR specific for Fc mu R efficiently responded toward CLL cells, released a panel of proinflammatory cytokines and lytic factors, like soluble FasL and granzyme B, and eliminated the leukemic cells. In contrast to CD19 CAR T cells, anti-Fc mu R CAR T cells did not attack healthy B cells. T cells with anti-Fc mu R CAR delayed outgrowth of Mec-1-induced leukemia in a xenograft mouse model. T cells from CLL patients in various stages of the disease, modified by the anti-Fc mu R CAR, purged their autologous CLL cells in vitro without reducing the number of healthy B cells, which is the case with anti-CD19 CAR T cells. Compared with the currently used therapies, the data strongly imply a superior therapeutic index of anti-Fc mu R CAR T cells for the treatment of CLL.