Optimization Of Anti-BCMA CAR By Manipulating Domain Structure

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 such as multiple myeloma are being designed, mainly based on targeting tumor
associated antigens such as BCMA. Being a crucial determinant for its function, CAR composition
and structure is generally optimized empirically. Thus, we aimed at assessing the function of
different BCMA 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 published 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 co-culture with multiple myeloma targets.
Nonetheless, critical differences were observed in off-target activation, PD1 expression and in vivo
activity mediated by these different constructs, facilitating the identification of an optimal BCMA-
specific CAR. Overall, this work strengthens the need to evaluate empirically CARs in order to
determine optimal configuration and presents an ideal composition for a BCMA CAR that
demonstrated long-term in vivo protection.