期刊
BLOOD
卷 128, 期 13, 页码 1711-1722出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2016-01-692046
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- Deutsche Jose Carreras-Leukamie Stiftung, Munchen, Germany
- CLL Global Research Foundation, Houston, Texas
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.
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