CD19 chimeric antigen receptor (CAR)-T cells have been used to treat patients with refractory chronic lymphocytic leukemia (CLL). However, approximately 50% of patients do not respond to this therapy. To improve the clinical outcome of these patients, it is necessary to develop strategies with other optimal targets to enable secondary or combinational CAR-T cell therapy. By screening a panel of surface antigens, we found that CD32b (FcγRIIb) was homogeneously expressed at high site density on tumor cells from CLL patients. We then developed a second-generation CAR construct targeting CD32b, and T cells transduced with the CD32 CAR efficiently eliminated the CD32b+ Raji leukemic cell line in vitro and in a mouse xenograft model. Furthermore, CD32b CAR-T cells showed cytotoxicity against primary human CLL cells that were cultured in vitro or transplanted into immunodeficient mice. The efficacy of CD32b CAR T cells correlated with the CD32b density on CLL cells. CD32b is not significantly expressed by non-B hematopoietic cells. Our study thus identifies CD32b as a potential target of CAR-T cell therapy for CLL, although further modification of the CAR construct with a safety mechanism may be required to minimize off-target toxicity.

中文翻译：

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CD32b 的均匀高表达使其成为慢性淋巴细胞白血病 CAR-T 治疗的潜在靶点

CD19 嵌合抗原受体 (CAR)-T 细胞已被用于治疗难治性慢性淋巴细胞白血病 (CLL) 患者。然而，大约 50% 的患者对这种疗法没有反应。为了改善这些患者的临床结果，有必要制定具有其他最佳靶点的策略，以实现二次或联合 CAR-T 细胞疗法。通过筛选一组表面抗原，我们发现 CD32b (FcγRIIb) 在来自 CLL 患者的肿瘤细胞上以高位点密度均匀表达。然后，我们开发了针对 CD32b 的第二代 CAR 构建体，用 CD32 CAR 转导的 T 细胞在体外和小鼠异种移植模型中有效地消除了 CD32b+ Raji 白血病细胞系。此外，CD32b CAR-T 细胞对体外培养或移植到免疫缺陷小鼠的原代人类 CLL 细胞显示出细胞毒性。CD32b CAR T 细胞的功效与 CLL 细胞上的 CD32b 密度相关。CD32b 不被非 B 造血细胞显着表达。因此，我们的研究将 CD32b 确定为 CLL CAR-T 细胞疗法的潜在靶点，尽管可能需要进一步修改具有安全机制的 CAR 构建体以最大限度地减少脱靶毒性。