Dual effects of cyclooxygenase inhibitors in combination with CD19.CAR-T cell immunotherapy

• Verfasst von: Yang, Mingya [VerfasserIn]
• Verfasst von: Wang, Lei [VerfasserIn]
• Verfasst von: Neuber, Brigitte [VerfasserIn]
• Verfasst von: Wang, Sanmei [VerfasserIn]
• Verfasst von: Sauer, Tim [VerfasserIn]
• Verfasst von: Schubert, Maria-Luisa [VerfasserIn]
• Verfasst von: Hückelhoven-Krauss, Angela [VerfasserIn]
• Verfasst von: Kleist, Christian [VerfasserIn]
• Verfasst von: Eckstein, Volker [VerfasserIn]
• Verfasst von: Sellner, Leopold [VerfasserIn]
• Verfasst von: Müller-Tidow, Carsten [VerfasserIn]
• Verfasst von: Dreger, Peter [VerfasserIn]
• Verfasst von: Schmitt, Michael [VerfasserIn]
• Verfasst von: Schmitt, Anita [VerfasserIn]
• Titel: Dual effects of cyclooxygenase inhibitors in combination with CD19.CAR-T cell immunotherapy
• Verf.angabe: Mingya Yang, Lei Wang, Ming Ni, Brigitte Neuber, Sanmei Wang, Wenjie Gong, Tim Sauer, Maria-Luisa Schubert, Angela Hückelhoven-Krauss, Ruixiang Xia, Jian Ge, Christian Kleist, Volker Eckstein, Leopold Sellner, Carsten Müller-Tidow, Peter Dreger, Michael Schmitt and Anita Schmitt
• E-Jahr: 2021
• Jahr: 26 May 2021
• Umfang: 13 S.
• Fussnoten: Gesehen am 06.07.2021
• Titel Quelle: Enthalten in: Frontiers in immunology
• Ort Quelle: Lausanne : Frontiers Media, 2010
• Jahr Quelle: 2021
• Band/Heft Quelle: 12(2021) vom: 26. Mai, Artikel-ID 670088
• ISSN Quelle: 1664-3224
• DOI: doi:10.3389/fimmu.2021.670088
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Acetylsalycilic acid
• Sach-SW: CD19.CAR-T cells
• Sach-SW: Celecoxib
• Sach-SW: inhibitors
• Sach-SW: NSAIDs
• Sach-SW: Persistence
• K10plus-PPN: 1761975218
• K10plus-PPN:
  Universitätsbibliothek
• Lokale URL UB: Zum Volltext

Abstract

CAR-T cells targeting CD19 came into clinical practice for the treatment of B cell lymphoma in 2018. However, patients being treated for B cell lymphoma often suffer from comorbidities such as chronic pain, cardiovascular diseases and arthritis. Thus, these patients frequently receive concomitant medications that include NSAIDs like COX inhibitors. Celecoxib, a selective COX-2 inhibitor, and aspirin, a non-selective COX-1 and COX-2 inhibitor, are being used as anti-inflammatory, analgesic and anti-pyretic drugs. In addition, several studies have also focused on the anti-neoplastic properties of COX-inhibitors. As the influence of COX-inhibitors on CD19.CAR-T cells is still unknown, we investigated the effect of celecoxib and aspirin on the quantity and quality of CD19.CAR-T cells at different concentrations with special regard to cytotoxicity, activation, cytokine release, proliferation and exhaustion. A significant effect on CAR-T cells could be observed for 0.1 mmol/L of celecoxib and for 4 mmol/L of aspirin. At these concentrations, we found that both COX-inhibitors could induce intrinsic apoptosis of CD19.CAR-T cells showing a significant reduction in the ratio of JC-10red to JC-10green CAR-T cells from 6.46 ± 7.03 to 1.76 ± 0.67 by celecoxib and to 4.41 ± 0.32 by aspirin, respectively. Additionally, the ratios of JC-10red to JC-10green Daudi cells were also decreased from 3.41 ± 0.30 to 0.77 ± 0.06 by celecoxib and to 1.26 ± 0.04 by aspirin, respectively. Although the cytokine release by CD19.CAR-T cells upon activation was not hampered by both COX-inhibitors, activation and proliferation of CAR-T cells were significantly inhibited via diminishing the NF-ĸB signaling pathway by a significant down-regulation (about 45%) of expression of CD27 on CD4+/CD8+ CAR-T cells, followed by a clear decrease of phosphorylated NF-ĸB p65 in both CD4+/CD8+ CAR-T cells by a factor of 1.8. Of note, COX-inhibitors hampered expansion and induced exhaustion of CAR-T cells in an antigen stress assay. Collectively, our findings indicate that the use of COX-inhibitors is a double-edged sword that not only induces apoptosis in tumor cells but also impairs the quantity and quality of CAR-T cells. Therefore, COX-inhibitors should be used with caution in patients with B cell lymphoma under CAR-T cell therapy.