| Autor: |
Fritz C; Department of Pathology, Case Western Reserve University, Cleveland, OH, USA., Wong DP; Department of Pathology, Case Western Reserve University, Cleveland, OH, USA., Rock P; Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA., Burack R; Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA., Radhakrishnan A; Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University, Cleveland, OH, USA., Parameswaran R; Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.; Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University, Cleveland, OH, USA.; Pediatric Hematology and Oncology, The Angie Fowler Adolescent & Young Adult Cancer Institute, University Hospitals Rainbow Babies & Children's Hospital, Cleveland, OH, USA.; The Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA. |
| Abstrakt: |
Hairy cell leukemia variant (HCL-v) is a rare malignancy of clonal mature B-cells that follows a chronic disease course. HCL-v patients are often resistant to purine nucleoside analogs, which are the first-line therapy. To address the shortcomings of current therapy for HCL-v, we investigated the activity of a BAFF ligand-based CAR-T cell which binds to all three BAFF receptors, BAFF-receptor, TACI, and BCMA. Here, we demonstrate that HCLv patient-derived cells highly express all three BAFF receptors and that BAFF CAR-T cells induce significant cytotoxicity in vitro against both cell lines and HCL-v patient cells. This cytotoxicity corresponds with significant CAR-T cell activation, degranulation, and release of pro-inflammatory cytokines after co-incubation with HCLv cells. Furthermore, we successfully generated BAFF CAR-T cells directly from an HCLv patient and observed direct autologous killing against patient tumor cells in vitro. These HCLv patient-derived CAR-T cells were also effective in killing the Hair-M cell line and tumor cells derived from a different HCLv patient. Lastly, we also developed two mouse xenograft models for HCL, a subcutaneous Bonna-12 model and intravenous Hair-M xenograft model. We observed decreases in tumor burden and prolonged overall survival without significant toxicity. In conclusion, here we show that BAFF CAR-T cells exert anti-tumor effects in vitro and in vivo against multiple cell lines and patient-derived HCL-v samples and may be a successful therapeutic strategy for HCLv patients. |
