Research ArticleCancer

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

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Science Translational Medicine  25 Sep 2019:
Vol. 11, Issue 511, eaaw9414
DOI: 10.1126/scitranslmed.aaw9414

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Circumventing CD19 antigen loss

Chimeric antigen receptor (CAR) T cell treatment for B cell malignancies was pioneered with CD19-targeted CAR T cells. Despite robust clinical responses, relapse due to CD19 antigen loss is common. Qin et al. examined B cell activating factor receptor (BAFF-R) as an alternate CAR T cell target. BAFF-R–targeted CAR T cells could kill multiple human lymphoma and leukemia cell lines, either in vitro or in mice, as well as patient-derived samples. The BAFF-R-CAR T cells could also eradicate tumors lacking CD19. Their compelling preclinical results support the clinical development of BAFF-R–targeted CAR T cells for combating B cell malignancies.

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.

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