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Preclinical evaluation and structural optimization of anti-BCMA CAR to target multiple myeloma.
- Source :
-
Haematologica [Haematologica] 2022 Oct 01; Vol. 107 (10), pp. 2395-2407. Date of Electronic Publication: 2022 Oct 01. - Publication Year :
- 2022
-
Abstract
- 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, B-cell maturation antigen (BCMA) is an attractive tumor-associated antigen to be targeted in multiple myeloma (MM). Herein, we aimed at assessing the function and optimal configuration of different BCMA-specific CAR, 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 co-culture with multiple myeloma targets. Nonetheless, critical differences were observed in off-target activation, exhaustion, and activation marker 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-tumoral activity both in vitro and long-term in vivo efficacy.
Details
- Language :
- English
- ISSN :
- 1592-8721
- Volume :
- 107
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Haematologica
- Publication Type :
- Academic Journal
- Accession number :
- 35354252
- Full Text :
- https://doi.org/10.3324/haematol.2021.280169