Qin and Dong et al. generated human CAR T cells specific for B cell activating factor receptor (BAFF-R), a lineage marker critical for B cell survival. BAFF-R-CAR T cells lysed human BAFF-R+ B cell tumors in vitro, releasing TNFα, IFNγ, and granzyme B. A single dose of BAFF-R-CAR T cells eliminated pre-established BAFF-R+CD19+and/or– B lymphoma xenografts, whereas CD19-CAR T cells allowed tumors to ultimately progress. BAFF-R- but not CD19- CAR T cells were activated in vitro by BAFF-R+CD19- primary escape variants obtained after CD19-targeted therapy, and reduced progression of a BAFF-R+ CD19- patient-derived xenograft.
Contributed by Paula Hochman
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.