A BAFF ligand-based CAR-T cell targeting three receptors and multiple B cell cancers

Derek P. Wong, Nand K. Roy, Keman Zhang, Anusha Anukanth, Abhishek Asthana, Nicole J. Shirkey-Son, Samantha Dunmire, Bryan J. Jones, Walker S. Lahr, Beau R. Webber, Branden S. Moriarity, Paolo Caimi, Reshmi Parameswaran

Research output: Contribution to journalArticlepeer-review

Abstract

B cell-activating factor (BAFF) binds the three receptors BAFF-R, BCMA, and TACI, predominantly expressed on mature B cells. Almost all B cell cancers are reported to express at least one of these receptors. Here we develop a BAFF ligand-based chimeric antigen receptor (CAR) and generate BAFF CAR-T cells using a non-viral gene delivery method. We show that BAFF CAR-T cells bind specifically to each of the three BAFF receptors and are effective at killing multiple B cell cancers, including mantle cell lymphoma (MCL), multiple myeloma (MM), and acute lymphoblastic leukemia (ALL), in vitro and in vivo using different xenograft models. Co-culture of BAFF CAR-T cells with these tumor cells results in induction of activation marker CD69, degranulation marker CD107a, and multiple proinflammatory cytokines. In summary, we report a ligand-based BAFF CAR-T capable of binding three different receptors, minimizing the potential for antigen escape in the treatment of B cell cancers.

Original languageEnglish (US)
Article number217
JournalNature communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022

Bibliographical note

Funding Information:
This work was supported by St. Baldrick’s scholar award (RP), Case Comprehensive Cancer Centre Innovation award (RP), R21 CA246194 (RP), The Case Technology and Validation Program (RP), and the T32 GM007250 training grant (DPW). This research was supported by the Athymic Animal and Hemopoietic Biorepository and Cellular therapy core facilities, Shared Resources of the Case Comprehensive Cancer Center (P30CA043703) for their support. We thank the flow cytometry core and the small animal imaging core facilities at Case Western Reserve University.

Publisher Copyright:
© 2022, The Author(s).

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