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Enhanced antitumor efficacy, proliferative capacity, and alleviation of T cell exhaustion by fifth-generation chimeric antigen receptor T cells targeting B cell maturation antigen in multiple myeloma - 11/11/23

Doi : 10.1016/j.biopha.2023.115691 
Pornpimon Yuti a, b, Nunghathai Sawasdee a, b, Krissada Natungnuy a, b, Punchita Rujirachaivej c, d, Piriya Luangwattananun a, b, Jatuporn Sujjitjoon a, b, , Pa-thai Yenchitsomanus a, b,
a Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand 
b Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand 
c Graduate Program in Clinical Pathology, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand 
d Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand 

Correspondence to: Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok 10700, Thailand.Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University2 Wanglang Road, BangkoknoiBangkok10700Thailand

Abstract

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.

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Graphical Abstract




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Highlights

Anti-BCMA-CAR5-T cells exhibit heightened antitumor efficacy, attributable to their secretion of anti-PD-L1 scFv.
The presence of anti-PD-L1 scFv enhances the proliferation of anti-BCMA-CAR5-T cells, achieved through the PD-L1 blockade.
Anti-BCMA-CAR5-T cells bolstered with anti-PD-L1 scFv reduce T cell exhaustion and restore their antitumor function.

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Abbreviations : BCMA, CD3, CD4, CD8, CD19, CD25, CD27, CD28, CD69, PBMC, TNFα, IFNγ, IL-2, IL-4, IL-6, IL-7, IL-10, IL-15, MHC, MM, RR, CAR, FDA, scFv, HA tag, SDS-PAGE, PHA, PD-l, PD-L1, TIM-3, LAG-3

Keywords : Multiple myeloma, BCMA, Chimeric antigen receptor, CAR, Anti-PD-L1 scFv, Immune checkpoint blockade


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