Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University, Cleveland, OH, USA.
Nat Commun. 2022 Jan 11;13(1):217. doi: 10.1038/s41467-021-27853-w.
B cell-activating factor (BAFF) binds the three receptors BAFF-R, BCMA, and TACI, predominantly expressed on mature B cells. Almost all B cell cancers are reported to express at least one of these receptors. Here we develop a BAFF ligand-based chimeric antigen receptor (CAR) and generate BAFF CAR-T cells using a non-viral gene delivery method. We show that BAFF CAR-T cells bind specifically to each of the three BAFF receptors and are effective at killing multiple B cell cancers, including mantle cell lymphoma (MCL), multiple myeloma (MM), and acute lymphoblastic leukemia (ALL), in vitro and in vivo using different xenograft models. Co-culture of BAFF CAR-T cells with these tumor cells results in induction of activation marker CD69, degranulation marker CD107a, and multiple proinflammatory cytokines. In summary, we report a ligand-based BAFF CAR-T capable of binding three different receptors, minimizing the potential for antigen escape in the treatment of B cell cancers.
B 细胞激活因子 (BAFF) 结合三种受体 BAFF-R、BCMA 和 TACI，主要表达于成熟 B 细胞上。几乎所有的 B 细胞癌都被报道至少表达其中一种受体。在这里，我们开发了一种基于 BAFF 配体的嵌合抗原受体 (CAR)，并使用非病毒基因传递方法生成了 BAFF CAR-T 细胞。我们证明 BAFF CAR-T 细胞可以特异性地结合三种 BAFF 受体中的每一种，并且可以有效地杀伤多种 B 细胞癌，包括套细胞淋巴瘤 (MCL)、多发性骨髓瘤 (MM) 和急性淋巴细胞白血病 (ALL)，无论是在体外还是体内，都使用不同的异种移植模型。BAFF CAR-T 细胞与这些肿瘤细胞共培养会导致激活标志物 CD69、脱颗粒标志物 CD107a 和多种促炎细胞因子的诱导。总之，我们报告了一种基于配体的 BAFF CAR-T，能够结合三种不同的受体，最大限度地减少了 B 细胞癌治疗中抗原逃逸的可能性。
