Chimeric antigen receptor (CAR) T-cell based immunotherapy has become a promising treatment mainly for hematological malignancies. Following the major success of CD19-targeted CAR, new potential targets for other malignancies are required. As such, BCMA is an attractive tumorassociated antigen to be targeted in multiple myeloma (MM). Herein, we aimed at assessing the function and optimal configuration of different BCMA-specific CARs, based on the same targeting moiety but with a different hinge and co-stimulatory domain. We compared their function to that of a previously characterized BCMA-CAR used in clinical trials. All constructs were expressed at high levels by primary human T-cells and could trigger cytokine production and cytotoxicity upon coculture with multiple myeloma targets. Nonetheless, critical differences were observed in off-target activation, exhaustion, and activation markers expression and in vivo antitumoral activity mediated by these different constructs. Interestingly, we noted that CD8-based hinge, combined with a 4-1BB intracellular domain, proved superior compared to IgG4 connecting regions, and/or a CD28 signaling moiety respectively. Overall, this study emphasizes the influence of CAR primary structure on its function and led to the identification of a highly efficient BCMA-specific CAR, namely H8BB, which displayed superior anti-tumor activity both in vitro and long-term in vivo efficacy.
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