CAR T cells targeting BAFF-R can overcome CD19 antigen loss in B cell malignancies

Hong Qin, Zhenyuan Dong, Xiuli Wang, Wesley A. Cheng, Feng Wen, Weili Xue, Han Sun, Miriam Walter, Guowei Wei, D. Lynne Smith, Xiuhua Sun, Fan Fei, Jianming Xie, Theano I. Panagopoulou, Chun Wei Chen, Joo Y. Song, Ibrahim Aldoss, Clarisse Kayembe, Luisa Sarno, Markus MüschenGiorgio G. Inghirami, Stephen J. Forman, Larry W. Kwak

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbereaaw9414
JournalScience translational medicine
Volume11
Issue number511
DOIs
StatePublished - Sep 25 2019

ASJC Scopus subject areas

  • Medicine(all)

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