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 - Funding Information:
We are grateful for the support from the Toni Stephenson Lymphoma Center at Beckman Research Institute of City of Hope. The study was also supported by the Leukemia and Lymphoma Society (LLS): Translational Research Program (TRP 6540-18; PI: L.W.K.), Mantle Cell Lymphoma Research Initiative (MCL 7000-18; PI: L.W.K.), and SCOR grants (SCOR 7011-16 and 7012-16; PI: G.G.I.); the NIH/NCI (SPORE 2P50CA107399; PIs: S.J.F. and L.W.K.; 1R21CA223141; PI: H.Q.); the Department of Defense (CA170783; PI: L.W.K.); and the Hope Portfolio Fund at City of Hope (PI: H.Q.). Research in the Müschen laboratory is funded by the NIH/NCI through the Outstanding Investigator Award R35CA197628 (to M.M.), U10CA180827 (to M.M.), R01CA137060, R01CA157644, R01CA172558, and R01CA213138 (to M.M.); the Howard Hughes Medical Institute HHMI-55108547 (to M.M.); and the Falk Trust through a Falk Medical Research Transformational Award (to M.M.). M.M. is a Howard Hughes Medical Institute (HHMI) Faculty Scholar.
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 -