CD19/BAFF-R dual-targeted CAR T cells for the treatment of mixed antigen-negative variants of acute lymphoblastic leukemia

Chimeric antigen receptor (CAR) T cells targeting CD19 mediate potent antitumor effects in B-cell malignancies including acute lymphoblastic leukemia (ALL), but antigen loss remains the major cause of treatment failure. To mitigate antigen escape and potentially improve the durability of remission,...

Full description

Saved in:
Bibliographic Details
Published inLeukemia Vol. 36; no. 4; pp. 1015 - 1024
Main Authors Wang, Xiuli, Dong, Zhenyuan, Awuah, Dennis, Chang, Wen-Chung, Cheng, Wesley A, Vyas, Vibhuti, Cha, Soung-Chul, Anderson, Aaron J, Zhang, Tiantian, Wang, Zhe, Szymura, Szymon J, Kuang, Benjamin Z, Clark, Mary C, Aldoss, Ibrahim, Forman, Stephen J, Kwak, Larry W, Qin, Hong
Format Journal Article
LanguageEnglish
Published England Nature Publishing Group 01.04.2022
Subjects
Acute lymphoblastic leukemia
Animals
Anticancer properties
Antigens
Antigens, CD19
Antitumor activity
Biocompatibility
BLyS protein
CD19 antigen
Chimeric antigen receptors
Cytokines
Cytotoxicity
Degranulation
Durability
Humans
Immunodeficiency
Immunotherapy, Adoptive
Leukemia
Lymphatic leukemia
Lymphocytes
Lymphocytes B
Lymphocytes T
Mice
Precursor Cell Lymphoblastic Leukemia-Lymphoma - therapy
Receptors, Chimeric Antigen - genetics
Remission
T-Lymphocytes
Toxicity
Tumors
Online AccessGet full text

Cover

More Information
Summary:Chimeric antigen receptor (CAR) T cells targeting CD19 mediate potent antitumor effects in B-cell malignancies including acute lymphoblastic leukemia (ALL), but antigen loss remains the major cause of treatment failure. To mitigate antigen escape and potentially improve the durability of remission, we developed a dual-targeting approach using an optimized, bispecific CAR construct that targets both CD19 and BAFF-R. CD19/BAFF-R dual CAR T cells exhibited antigen-specific cytokine release, degranulation, and cytotoxicity against both CD19-/- and BAFF-R-/- variant human ALL cells in vitro. Immunodeficient mice engrafted with mixed CD19-/- and BAFF-R-/- variant ALL cells and treated with a single dose of CD19/BAFF-R dual CAR T cells experienced complete eradication of both CD19-/- and BAFF-R-/- ALL variants, whereas mice treated with monospecific CD19 or BAFF-R CAR T cells succumbed to outgrowths of CD19-/BAFF-R+ or CD19+/BAFF-R- tumors, respectively. Further, CD19/BAFF-R dual CAR T cells showed prolonged in vivo persistence, raising the possibility that these cells may have the potential to promote durable remissions. Together, our data support clinical translation of BAFF-R/CD19 dual CAR T cells to treat ALL.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
These authors contributed equally to this work as co-first authors.
L.W.K., S.J.F., X.W., I.A., and H.Q. designed and directed the study, analyzed and organized the data, and wrote the manuscript. W.C.C, V.V., D.A designed the vectors and produced lentivirus. D.A, Z.D., S.C., T.Z., Z.W., S.S., B.K., and A.A. performed experimental work in mice and immune assays. M.C.C. and W.A.C. reviewed and edited the manuscript. All authors read and approved the final version.
Author Contributions
ISSN:0887-6924
1476-5551
DOI:10.1038/s41375-021-01477-x