TY - JOUR
T1 - CAR T cells targeting BAFF-R can overcome CD19 antigen loss in B cell malignancies
AU - Qin, Hong
AU - Dong, Zhenyuan
AU - Wang, Xiuli
AU - Cheng, Wesley A.
AU - Wen, Feng
AU - Xue, Weili
AU - Sun, Han
AU - Walter, Miriam
AU - Wei, Guowei
AU - Smith, D. Lynne
AU - Sun, Xiuhua
AU - Fei, Fan
AU - Xie, Jianming
AU - Panagopoulou, Theano I.
AU - Chen, Chun Wei
AU - Song, Joo Y.
AU - Aldoss, Ibrahim
AU - Kayembe, Clarisse
AU - Sarno, Luisa
AU - Müschen, Markus
AU - Inghirami, Giorgio G.
AU - Forman, Stephen J.
AU - Kwak, Larry W.
N1 - Publisher Copyright:
Copyright © 2019 The Authors.
PY - 2019/9/25
Y1 - 2019/9/25
N2 - 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.
AB - 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.
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U2 - 10.1126/scitranslmed.aaw9414
DO - 10.1126/scitranslmed.aaw9414
M3 - Article
C2 - 31554741
AN - SCOPUS:85072673091
SN - 1946-6234
VL - 11
JO - Science translational medicine
JF - Science translational medicine
IS - 511
M1 - eaaw9414
ER -