Abstract
B-cell malignancies can potentially be cured by CD19 chimeric antigen receptor (CAR) T-cell therapy. Although clinical response rates can be up to 93% in acute lymphoblastic leukemia, treatment-related antigen loss and lack of therapeutic persistence contribute to disease relapse. These shortcomings of current CAR T-cell therapy indicate the need for biologically relevant target selection and for improving the efficacy and persistence of the CAR T cells, which we have addressed by developing a novel B-cell activating factor receptor (BAFF-R) CAR T-cell therapy with improved therapeutic persistence. BAFF-R is a B-cell survival receptor and highly expressed in B-cell malignancies. We developed a prototype CAR T cell that efficiently and specifically eliminated BAFF-R expressing human B-cell tumors in several xenogeneic mouse models, including models of CD19 antigen loss. We proceeded with translational development and validation of BAFF-R CAR T cells produced under current good manufacturing practices (cGMP). cGMP-grade BAFF-R CAR T cells underwent in vitro and in vivo validation in established models to confirm that the potency and efficacy of our original research modeling was replicated. Food and Drug Administration required release testing was performed to ensure our BAFF-R CAR T cells meet specifications for new drug products. Completing and exceeding these requirements, the data fully support the initiation of a first-in-human Phase 1 trial for BAFF-R-positive relapsed/refractory (r/r) B-ALL.
Highlights
Chimeric antigen receptor (CAR) T-cell therapy has matured with the recent Food and Drug Administration (FDA)approval of CD19 CAR T cells marking a new era in cancer immunotherapy
Cells produced under current good manufacturing practices. cGMP-grade BAFF-R CAR T cells underwent in vitro and in vivo validation in established models to confirm that the potency and efficacy of our original research modeling was replicated
Encouraging results have been seen in recent clinical trials in non-Hodgkin lymphoma (NHL)
Summary
Chimeric antigen receptor (CAR) T-cell therapy has matured with the recent Food and Drug Administration (FDA). CAR T cells to treat B-cell malignancies is tempered by treatment-related antigen loss and lack of therapeutic persistence that results in disease relapse [3,4,5]. These shortcomings of current CAR T-cell therapy indicate the need for biologically relevant target selection and for improving the efficacy and persistence of the CAR T cells. BAFF-R is a well-studied B-cell survival receptor that is highly expressed in B-cell malignancies [7,8,9]. We have described the development of a specific, high affinity humanized monoclonal antibody against natively expressed BAFF-R, which has limited off-target effects [10]. Survival data are reported in Kaplan–Meier plots and analyzed by log-rank tests
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