Title | CAR T cells targeting BAFF-R can overcome CD19 antigen loss in B cell malignancies. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Qin H, Dong Z, Wang X, Cheng WA, Wen F, Xue W, Sun H, Walter M, Wei G, D Smith L, Sun X, Fei F, Xie J, Panagopoulou TI, Chen C-W, Song JY, Aldoss I, Kayembe C, Sarno L, Muschen M, Inghirami GG, Forman SJ, Kwak LW |
Journal | Sci Transl Med |
Volume | 11 |
Issue | 511 |
Date Published | 2019 09 25 |
ISSN | 1946-6242 |
Keywords | Animals, Antigens, CD19, B-Cell Activation Factor Receptor, Cell Line, Tumor, Cytotoxicity, Immunologic, Humans, Immunotherapy, Adoptive, Leukemia, B-Cell, Lymphocyte Activation, Mice, T-Lymphocytes |
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. |
DOI | 10.1126/scitranslmed.aaw9414 |
Alternate Journal | Sci Transl Med |
PubMed ID | 31554741 |
PubMed Central ID | PMC7015136 |
Grant List | P30 CA016672 / CA / NCI NIH HHS / United States R01 CA213138 / CA / NCI NIH HHS / United States R01 CA157644 / CA / NCI NIH HHS / United States R21 CA223141 / CA / NCI NIH HHS / United States R01 CA137060 / CA / NCI NIH HHS / United States 55108547 / HHMI / Howard Hughes Medical Institute / United States R37 CA233691 / CA / NCI NIH HHS / United States P30 CA033572 / CA / NCI NIH HHS / United States R00 CA197498 / CA / NCI NIH HHS / United States U10 CA180827 / CA / NCI NIH HHS / United States R01 CA172558 / CA / NCI NIH HHS / United States R35 CA197628 / CA / NCI NIH HHS / United States P50 CA107399 / CA / NCI NIH HHS / United States R01 CA236626 / CA / NCI NIH HHS / United States |
Related Faculty:
Giorgio Inghirami, M.D.