Abstract 6102: BAFF ligand CAR-T cells for hairy cell leukemia variant treatment

Abstract Hairy cell leukemia variant (HCL-v) is a rare B-cell malignancy that is biologically distinct from the classical form (HCL-c) and presents unique treatment challenges. The characteristic genetic or molecular markers of classical HCL include CD11c, CD25, CD103, CD123, the BRAFV600E point mutation, and tartrate resistant acid phosphatase (TRAP) expression. However, HCLv cells have a low immunologic score and don’t carry the BRAFV600E mutation or express TRAP. Treatment with the purine nucleoside analogs (PNAs) is effective in a majority of HCLc patients, who can look forward to a normal lifespan. However, HCLv patients are resistant to this treatment, which likely contributes to the significantly shorter prognosis of 6-9 years, in addition to the relative lack of druggable targets. To address poor clinical outcomes for HCL-v patients, we aimed to test a novel cellular therapy for HCL-v. We recently developed a third generation BAFF-ligand chimeric antigen receptor (CAR-T) cell product. B-cell activating factor (BAFF) is a critical factor that promotes B-cell maturation and survival. BAFF binds to three receptors, including BAFF-Receptor (BAFF-R), transmembrane activator and CAML interactor (TACI), and B-cell maturation antigen (BCMA). Because of the pro-survival signaling that BAFF enhances upon binding to its receptors, B-cell cancers tend to exploit this signaling, and serum BAFF levels are often elevated. In a panel of HCLv cell lines and patient-derived splenocytes, we found that HCLv cells have high expression levels of all three receptors. In co-culture assays with fluorescently labeled HCLv patient samples and cell lines, CAR-T cells express significantly elevated markers of degranulation (CD107a) and activation (CD69) and secrete elevated levels of pro-inflammatory cytokines and lytic enzymes relative to control T-cells. BAFF CAR-T cells also display significantly increased cancer cell killing relative to control T-cells. This enhanced cancer cell killing was also observed in an autologous model, where CAR-T cells were generated from a de-identified HCLv patient and co-cultured with the patients’ own cancer cells. Similar findings were seen in multiple novel in vivo HCL xenograft models, in which BAFF CAR-T cell treatment (intratumor or intravenous) resulted in decreased tumor burden without significant toxicities.While we have seen success in our in vivo models, we also aim to generate a novel patient-derived xenograft model of HCLv to more accurately model the disease, both for more CAR-T cell translational studies and for more basic investigations into HCLv mechanisms. An additional future direction is to explore whether our BAFF CAR-T cells, which bind three receptors can mitigate antigen escape, the process by which tumor cells downregulate a target to avoid killing. To do so, we will perform single and double receptor knockouts of BAFF-R, TACI, and BCMA and assess if cell killing is intact with in vitro co-culture assays. Citation Format: Claire Elizabeth Fritz, Derek P. Wong, Akshaya Radhakrishnan, Philip Rock, Richard Burack, Reshmi Parameswaran. BAFF ligand CAR-T cells for hairy cell leukemia variant treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6102.