Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; Department I Internal Medicine, University Hospital Cologne, Cologne, Germany;
Department I Internal Medicine, University Hospital Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany; and.
Blood. 2016 Sep 29;128(13):1711-22. doi: 10.1182/blood-2016-01-692046. Epub 2016 Aug 17.
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 (FcμR), 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. FcμR 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 FcμR 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-FcμR CAR T cells did not attack healthy B cells. T cells with anti-FcμR 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-FcμR 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-FcμR CAR T cells for the treatment of CLL.
嵌合抗原受体（CAR）修饰的靶向 CD19 的 T 细胞过继细胞疗法治疗慢性淋巴细胞白血病（CLL），使许多患者对这种难治性疾病产生了持久缓解。然而，由于靶向消除健康 B 细胞，该治疗与延长的“靶内脱靶”毒性相关，这需要在针对 CLL 细胞时具有更高的选择性。我们发现免疫球蛋白 M Fc 受体（FcμR），也称为 Fas 凋亡抑制分子-3 或 TOSO，是 CAR T 细胞更选择性治疗 CLL 的靶点。FcμR 在 CLL 细胞中高度且一致表达；仅在健康 B 细胞或其他造血细胞上检测到少量水平。针对 FcμR 的 CAR 修饰的 T 细胞可有效针对 CLL 细胞作出反应，释放一系列促炎细胞因子和溶细胞因子，如可溶性 FasL 和颗粒酶 B，并消除白血病细胞。与 CD19 CAR T 细胞相反，抗-FcμR CAR T 细胞不会攻击健康 B 细胞。抗-FcμR CAR T 细胞延迟了异种移植小鼠模型中 Mec-1 诱导的白血病的生长。用抗-FcμR CAR 修饰的处于疾病各个阶段的 CLL 患者的 T 细胞在体外清除了自身的 CLL 细胞，而不会减少健康 B 细胞的数量，这是抗-CD19 CAR T 细胞的情况。与目前使用的疗法相比，这些数据强烈暗示抗-FcμR CAR T 细胞治疗 CLL 的治疗指数更高。
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