迈向体内抗BCMA/CD19 CAR-T细胞治疗B细胞介导的自身免疫性疾病

B cell-mediated autoimmune disorders, including systemic lupus erythematosus (SLE), can represent lifelong inflammatory conditions with limited therapeutic options. Autologous CD19-specific CAR-T cells have been demonstrated as an effective treatment option. However, access to CAR-T cell therapies and the use of preparative chemotherapy will ultimately limit the reach of this powerful modality. Moreover, recent data suggest that CD19-negative pathogenic plasma cells can emerge and contribute to SLE disease etiology, suggesting that development of CAR-T cells addressing both CD19-positive and CD19-negative pathogenic B cells is warranted. Here, we describe the preclinical development of an engineered lentiviral vector (LVV) previously shown to specifically modify T cells in vivo (in vivo gene placement system (iGPS®)), encoding a chimeric antigen receptor (CAR) that recognizes both CD19 and B-cell maturation antigen (BCMA) antigens (“tandem CAR”). The operative arms of the tandem CAR were identified by screening a panel of human anti-BCMA and anti-CD19 antibodies incorporating a variety of design features. Candidate tandem CAR constructs were expressed in T cells from healthy donors and SLE patients using iGPS particles. The constructs that caused antigen-specific in vitro T cell activity, assayed by cytotoxicity and cytokine release to cell lines expressing BCMA and/or CD19, were tested in several animal models. First, an SLE mouse model was established using immunocompromised mice humanized with peripheral blood mononuclear cells from SLE patients. After a single dose of the lead tandem CAR iGPS particle, CAR-T cells were generated and expanded in vivo resulting in complete elimination of SLE B cells in the blood, spleen, and bone marrow. In a second mouse model treating an aggressive B cell lymphoma, the iGPS particle delivering the lead tandem CAR caused effective tumor control after a single treatment. These data demonstrated the potential of a tandem anti-BCMA/CD19 CAR-T cell generated in vivo with iGPS particles as an effective treatment of autoimmune disorders. Moreover, persistent CAR-T cells generated using an LVV may provide a single, off-the-shelf treatment capable of eliminating both pathogenic CD19-positive B cells and emergent CD19-negative plasma cells and provide a needed therapy for patients.