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Advanced cholangiocarcinoma (CCA) presents a clinical challenge due to limited treatment options, necessitating exploration of innovative therapeutic approaches. Bispecific T cell engager (BTE)-armed T cell therapy shows promise in hematological and solid malignancies, offering potential advantages in safety over continuous BTE infusion. In this context, we developed a novel BTE, targeting CD3 on T cells and integrin αvβ6, an antigen elevated in various epithelial malignancies, on cancer cells. The novel BTE was generated by fusing an integrin αvβ6-binding peptide (A20) to an anti-CD3 (OKT3) single-chain variable fragment (scFv) through a G 4 S peptide linker (A20/αCD3 BTE). T cells were then armed with A20/αCD3 BTE (A20/αCD3-armed T cells) and assessed for antitumor activity. Our results highlight the specific binding of A20/αCD3 BTE to CD3 on T cells and integrin αvβ6 on target cells, effectively redirecting T cells towards these targets. After co-culture, A20/αCD3-armed T cells exhibited significantly heightened cytotoxicity against integrin αvβ6-expressing target cells compared to unarmed T cells in both KKU-213A cells and A375.β6 cells. Moreover, in a five-day co-culture, A20/αCD3-armed T cells demonstrated superior cytotoxicity against KKU-213A spheroids compared to unarmed T cells. Importantly, A20/αCD3-armed T cells exhibited an increased proportion of the effector memory T cell (Tem) subset, upregulation of T cell activation markers, enhanced T cell proliferation, and increased cytolytic molecule/cytokine production, when compared to unarmed T cells in an integrin αvβ6-dependent manner. These findings support the potential of A20/αCD3-armed T cells as a novel therapeutic approach for integrin αvβ6-expressing cancers., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Crown Copyright © 2024. Published by Elsevier Masson SAS. All rights reserved.)

Chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA) has been approved for treating multiple myeloma (MM). Some clinical studies reported suboptimal outcomes, including reduced cytotoxicity of CAR-T cells and tumor evasion through increased expression of programmed death-ligand 1 (PD-L1). To enhance CAR-T cell efficiency and overcome PD-L1-mediated T cell suppression, we developed anti-BCMA-CAR5-T cells equipped with three costimulatory domains and the ability to secrete anti-PD-L1 single-chain variable fragment (scFv) blockade molecules. Anti-BCMA-CAR4-T cells contained a fully human anti-BCMA scFv and three intracellular domains (CD28, 4-1BB, and CD27) joined with CD3ζ. Anti-BCMA-CAR5-T cells were generated by fusing anti-BCMA-CAR4 with anti-PD-L1 scFv. Both anti-BCMA-CAR4-T and anti-BCMA-CAR5-T cells demonstrated comparable antitumor activity against parental MM cells. However, at an effector-to-target ratio of 1:2, only anti-BCMA-CAR5-T cells maintained cytolytic activity against PD-L1 high MM cells, unlike anti-BCMA-CAR4 T cells. Anti-BCMA-CAR5-T cells were specifically activated by BCMA-expressing target cells, resulting in increased CAR-T cell proliferation, release of cytolytic mediators, and pro-inflammatory cytokines. Anti-BCMA-CAR5-T cells demonstrated specific cytotoxicity against BCMA-expressing target cells, leading to decreased target cell numbers, increased CAR-T cell numbers, and preserved CAR expression during antigenic re-stimulation. Interestingly, only anti-BCMA-CAR5-T cells showed reduced PD-1 receptor levels, which correlated with decreased PD-L1 expression on target cells. We successfully generated anti-BCMA-CAR5-T cells capable of secreting anti-PD-L1 scFv. These cells exhibited superior antitumor efficiency, proliferative capacity, and alleviated T-cell exhaustion against MM cells. Further investigation into the antitumor efficacy of anti-BCMA-CAR5-T cells is warranted in ex vivo and clinical research settings., Competing Interests: Declaration of Competing Interest The authors declare no competing interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)