Dual targeting of BCMA and B7-H3 with CAR T cells and bispecific protein engagers enhances anti-myeloma activity
1
Issued Date
2025-12-01
Resource Type
ISSN
07533322
eISSN
19506007
Scopus ID
2-s2.0-105023161277
Pubmed ID
41297423
Journal Title
Biomedicine and Pharmacotherapy
Volume
193
Rights Holder(s)
SCOPUS
Bibliographic Citation
Biomedicine and Pharmacotherapy Vol.193 (2025)
Suggested Citation
Sontayananon N., Yuti P., Sawasdee N., Okada S., Junking M., Sujjitjoon J., Yenchitsomanus P.T. Dual targeting of BCMA and B7-H3 with CAR T cells and bispecific protein engagers enhances anti-myeloma activity. Biomedicine and Pharmacotherapy Vol.193 (2025). doi:10.1016/j.biopha.2025.118820 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/113398
Title
Dual targeting of BCMA and B7-H3 with CAR T cells and bispecific protein engagers enhances anti-myeloma activity
Author's Affiliation
Corresponding Author(s)
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Abstract
Background B cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cells have shown remarkable activity in relapsed/refractory multiple myeloma (R/R MM). However, therapeutic resistance often arises due to antigen heterogeneity and immune checkpoint upregulation. B7-H3, an immune checkpoint protein overexpressed in MM and linked to T cell dysfunction and poor prognosis, represents a promising complementary target. This study evaluates a dual targeting approach that combines αBCMA CAR T cells with a recombinant αB7-H3/CD3 bispecific protein engager (BiPE) to enhance anti-myeloma activity. Methods A cell-based system was engineered to continuously produce αB7-H3/CD3 BiPE. Fourth-generation αBCMA CAR T cells (CAR4; incorporating CD28, 4–1BB, CD27, and CD3ζ signaling domains) were combined with recombinant BiPE, and their anti-myeloma activities were assessed in vitro using cytotoxicity, proliferation, immunophenotyping, cytokine profiling, and tumor re-challenge assays. Results In BCMA<sup>+</sup> /B7-H3<sup>high</sup> MM cells (MM1.S), CAR T + BiPE co-treatment yielded stronger cytotoxicity than CAR T cells alone. In BCMA<sup>+</sup>/B7-H3<sup>low</sup> cells (H929), the combination markedly outperformed either monotherapy, particularly at low effector-to-target ratios. Enhanced tumor killing was accompanied by increased T cell activation (CD69), proliferation, effector memory differentiation, and secretion of IFN-γ, TNF-α, IL-2, FasL, granzyme B, and perforin. BiPE exposure initially upregulated exhaustion and inhibitory checkpoint markers (PD-1, PD-L1, B7-H3, TIGIT, and LAG-3), but these effects were transient, which declined upon tumor re-challenge with preserved central memory phenotype. Conclusions Dual targeting of BCMA and B7-H3 with CAR T cells and BiPE synergistically enhances T cell activation, effector function, and cytotoxicity against MM. This combinatorial strategy has the potential to overcome resistance mechanisms and represents a promising therapeutic approach for improving outcomes in MM and other BCMA<sup>+</sup>/B7-H3<sup>+</sup> malignancies.