Toni Stephenson Lymphoma Center, Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
Center for CAR T Cell Therapy, Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
Sci Transl Med. 2019 Sep 25;11(511). doi: 10.1126/scitranslmed.aaw9414.
CAR T cells targeting CD19 provide promising options for treatment of B cell malignancies. However, tumor relapse from antigen loss can limit efficacy. We developed humanized, second-generation CAR T cells against another B cell-specific marker, B cell activating factor receptor (BAFF-R), which demonstrated cytotoxicity against human lymphoma and acute lymphoblastic leukemia (ALL) lines. Adoptively transferred BAFF-R-CAR T cells eradicated 10-day preestablished tumor xenografts after a single treatment and retained efficacy against xenografts deficient in CD19 expression, including CD19-negative variants within a background of CD19-positive lymphoma cells. Four relapsed, primary ALLs with CD19 antigen loss obtained after CD19-directed therapy retained BAFF-R expression and activated BAFF-R-CAR, but not CD19-CAR, T cells. BAFF-R-CAR, but not CD19-CAR, T cells also demonstrated antitumor effects against an additional CD19 antigen loss primary patient-derived xenograft (PDX) in vivo. BAFF-R is amenable to CAR T cell therapy, and its targeting may prevent emergence of CD19 antigen loss variants.
嵌合抗原受体 T 细胞（CAR T 细胞）针对 CD19 为治疗 B 细胞恶性肿瘤提供了有前景的选择。然而，抗原丢失导致的肿瘤复发会限制疗效。我们开发了针对另一种 B 细胞特异性标志物 B 细胞激活因子受体（BAFF-R）的人源化第二代 CAR T 细胞，该细胞对人淋巴瘤和急性淋巴细胞白血病（ALL）系具有细胞毒性。单次治疗后，过继转移的 BAFF-R-CAR T 细胞根除了 10 天前建立的肿瘤异种移植物，并且对缺乏 CD19 表达的异种移植物仍然有效，包括在 CD19 阳性淋巴瘤细胞背景下的 CD19 阴性变体。在接受 CD19 定向治疗后获得的 4 例 CD19 抗原丢失的复发原发性 ALL 保留了 BAFF-R 表达，并激活了 BAFF-R-CAR，而不是 CD19-CAR T 细胞。BAFF-R-CAR，而不是 CD19-CAR T 细胞，也在体内对另一个 CD19 抗原丢失的原发性患者衍生异种移植物（PDX）显示出抗肿瘤作用。BAFF-R 可用于 CAR T 细胞治疗，其靶向可能预防 CD19 抗原丢失变体的出现。
