Targeting chronic lymphocytic leukemia with B-cell activating factor receptor CAR T cells

The challenge of disease relapsed/refractory (R/R) remains a therapeutic hurdle in chimeric antigen receptor (CAR) T-cell therapy, especially for hematological diseases, with chronic lymphocytic leukemia (CLL) being particularly resistant to CD19 CAR T cells. Currently, there is no approved CAR T-cell therapy for CLL patients. In this study, we aimed to address this unmet medical need by choosing the B-cell activating factor receptor (BAFF-R) as a promising target for CAR design against CLL. BAFF-R is essential for B-cell survival and is consistently expressed on CLL tumors. Our research discovered that BAFF-R CAR T-cell therapy exerted the cytotoxic effects on both CLL cell lines and primary B cells derived from CLL patients. In addition, the CAR T cells exhibited cytotoxicity against CD19-knockout CLL cells that are resistant to CD19 CAR T therapy. Furthermore, we were able to generate BAFF-R CAR T cells from small blood samples collected from CLL patients and then demonstrated the cytotoxic effects of these patient-derived CAR T cells against autologous tumor cells. Given these promising results, BAFF-R CAR T-cell therapy has the potential to meet the long-standing need for an effective treatment on CLL patients. BAFF-R CAR T cells were created (A) using a lentiviral system and tested against various malignant B-cell lines, including CLL cells. CLL patient-derived BAFF-R CAR T cells were also generated to test their cytotoxicity on autologous primary malignant B cells (B). The cytotoxicity of CAR T cells was measured using degranulation, interferon-gamma release, and green fluorescent protein-labeled killing assays (C). image