Synergistic effect of ibrutinib and CD19 CAR-T cells on Raji cells in vivo and in vitro

Liu, Meijing; Wang, Xuelin; Zheng, Li; Zhang, Rui; Mu, Juan; Jiang, Yanyu; Sun, Lei; Deng, Qi

doi:10.21203/rs.3.rs-21887/v1

Cited by 5 publications

(8 citation statements)

References 29 publications

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“…Furthermore, it was confirmed that the expansion of anti‐CD19‐CAR T cells from 3 CLL patients who had been treated with ibrutinib more than 12 mo improved significantly compared with the anti‐CD19‐CAR T cells before ibrutinib treatment 32 . Our previous study observed that PD‐1 expression of anti‐CD19‐CAR T cells increased when co‐cultured with lymphoma cells in vitro, and ibrutinib could weaken this effect 20 . In this study, the mean expression of PD‐1 on CD3 + T cells in peripheral blood declined after 7‐16 mo of ibrutinib salvage treatment, which is consistent with the previous studies that showed that function of T cells and defective microenvironment in CLL patients were improved through several cycles of ibrutinib therapy 32,35‐37 .…”

Section: Discussionmentioning

confidence: 57%

“…In addition, inhibition of IL‐2‐inducible T‐cell kinase (ITK) activity would lead to the inhibition of Th2 cell differentiation and promotion of a Th1 cell immune response 38 . Our previous study suggested that ibrutinib might have a synergistic effect with anti‐CD19‐CAR T cells by improving the TME 20 . In our study, these 7 patients were all R/R B‐NHL patients with unsatisfactory efficacy of the first‐time anti‐CD19‐CAR T‐cell therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Then, release of IFN‐γ and cytotoxicity of the second‐time anti‐CD19‐CAR T cells in the presence of ibrutinib in vitro were detected under the same conditions. The dose of ibrutinib was set at 5 µmol/L based on our previous research 20 . The expression of PD‐1 in CD3 + T cells in peripheral blood was observed by FCM before 2 times anti‐CD19‐CAR T‐cell production and on days 0, 7, 14, 21, and 28 after CAR T‐cell infusion.…”

Section: Methodsmentioning

confidence: 99%

“…Our previous study provided evidence that ibrutinib could improve the curative effect of anti‐CD19‐CAR T cells in Raji cell subcutaneous tumorigenic mice other than in the tail vein tumorigenic model. It suggested that ibrutinib might have a synergistic effect with anti‐CD19‐CAR T cells by improving the TME 20 …”

Section: Introductionmentioning

confidence: 99%

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Ibrutinib improves the efficacy of anti‐CD19‐CAR T‐cell therapy in patients with refractory non‐Hodgkin lymphoma

Liu

Deng

et al. 2021

Cancer Science

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The efficacy and side effects of the second‐time humanized CD19 chimeric antigen receptor (CD19‐CAR) T‐cell therapy after unsuccessful first‐time anti‐CD19‐CAR T‐cell therapy and subsequent ibrutinib salvage treatment were observed in patients with refractory B‐cell lymphoma. In our study, 3 patients with refractory mantle cell lymphoma (MCL) and 4 patients with refractory follicular lymphoma (FL) reached stable disease (SD), partial remission (PR), or progression of disease (PD) after first‐time humanized anti‐CD19‐CAR T‐cell therapy. They received ibrutinib as a salvage treatment and kept an SD in the following 7‐16 mo, but their disease progressed again during ibrutinib salvage treatment. All 7 patients received a second‐time humanized anti‐CD19‐CAR T‐cell therapy, which was the same as their first‐time anti‐CD19‐CAR T‐cell therapy. In total, 3 MCL patients and 3 FL patients reached complete response (CR) with the second‐time anti‐CD19‐CAR T‐cell therapy combined with ibrutinib, whereas 1 FL patient reached PR. There were no differences in the transduction efficiency and proliferation between the 2 instances of anti‐CD19‐CAR T‐cell therapy. However, the second‐time anti‐CD19‐CAR T‐cell therapy led to higher peaks of anti‐CD19‐CAR T cells and anti‐CD19‐CAR gene copies, but also to higher grades of cytokine release syndrome (CRS) and more serious hematological toxicity. The successful outcome of the second‐time anti‐CD19‐CAR T‐cell therapy might suggest that the previous ibrutinib treatment improved the activities of anti‐CD19‐CAR T cells.

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ibrutinib improves the efficacy of anti‐CD19‐CAR T‐cell therapy in patients with refractory non‐Hodgkin lymphoma

Liu

Deng

et al. 2021

Cancer Science

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“…We have previously reported the e cacy of BTK inhibitors combined with anti-CD19-CAR T cell in vitro, in vivo [30] and in clinical studies [31,32]. In our study, three refractory mantle cell lymphoma (MCL) patients and four refractory FL patients obtained PR or PD in their rst time anti-CD19-CAR T cell therapy.…”

Section: Discussionmentioning

confidence: 78%

Efficacy and safety related factors of BTK inhibitors as a bridge to CAR-T therapy in R/R FL

Fan

Cui

et al. 2022

Preprint

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Background: Although anti-CD19 chimeric antigen receptor (CAR) T cell therapy has achieved satisfactory results in relapsed/refractory (R/R) Follicular lymphoma (FL), R/R FL patients with high-risk disease characteristics, previous HSCT, bulky disease, and POD24 had a low complete response (CR).Patients and methods: Twenty-seven R/R FL patients with higher advanced disease stage, higher tumor burden or higher previous treatment lines had already received Bruton tyrosine kinase (BTK) inhibitors prior to anti-CD19-CAR T-cell therapy, or received BTK inhibitors as combination/maintenance therapy in this study. The clinical response and adverse events (AEs) were observed in this study.Results: All R/R FL patients who received BTK inhibitors prior to the study had higher advanced disease stage, tumor burden, and previous treatment lines than those who did not receive BTK inhibitors. Patients who received combination/maintenance therapy with BTK inhibitors had higher advanced disease stage and tumor burden than those who did not receive BTK inhibitors. There was no difference of POD 24, TP53, tFL, IPI score in the three groups with or without BTK inhibitors. The clinical response was lower in POD 24 group than that of in no POD 24 group. But the other poor prognostic factors did not affect the clinical response with the methods of BTK inhibitors as a bridge to CAR-T cell therapy or a combination/maintenance treatment with CAR-T cell therapy. There was no difference of the mean peaks of anti-CD19-CAR T cells in three groups with or without BTK inhibitors. It was higher in no POD 24 group and in FL group. But it was no difference between the FLIPI 1 1-2 and FLIPI 1 3-5 group, the FLIPI 2 1-2 and FLIPI 2 3-5 group. The CRS grades were higher in BTK inhibitors before CAR-T cell therapy group, no POD 24 group, FL group, FLIPI 3-5 grade group. The ICANS grade was higher in BTK inhibitors before CAR-T cell therapy group.Conclusion: Other poor prognostic factors except POD 24 did not affect clinical response with the methods of BTK inhibitors as a bridge to anti-CD19-CAR T cell therapy or a combination/maintenance treatment with CAR-T cell therapy in R/R FL patients.Trial registration: The study was registered at http://www.chictr.org.cn/index.aspx as ChiCTR-ONN-16009862 and http://www.chictr.org.cn/index.aspx as ChiCTR1800019622.

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Ibrutinib combined with low‐dose histone deacetylases inhibitor chidamide synergistically enhances the anti‐tumor effect in B‐cell lymphoma

Heng

Zhang

et al. 2022

Hematological Oncology

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Aberrant activity of histone deacetylases (HDACs) is frequently detected in B-cell lymphomas, which indicated the therapeutic implications of HDAC inhibitors for B-cell malignancies. We have discovered that lymphoma cells treated with HDAC inhibitor presented with activation of Bruton tyrosine kinase (BTK) which played an important role in the development of B-cell malignancies. Therefore, our study intended to explore whether the addition of ibrutinib (BTK inhibitor) to chidamide (HDAC inhibitor) could generate combined anti-tumor effects in B-cell lymphomas.Using cell viability assay, cell cycle and apoptosis kit, we demonstrated an evident synergistic action of ibrutinib and chidamide in inhibiting tumor cell proliferation and motility. Consistent with in vitro data, the synergistic anti-tumor effects were also observed in multiple tumor-bearing mice models. By performing RNA-seq and flow cytometry of tumor tissue, the enhancement of anti-tumor immunity was observed with the co-treatment of chidamide and ibrutinib. Together, these mechanistic insights indicated that simultaneously targeting BTK and HDAC could be a promising clinical therapy for B-cell lymphomas.

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Synergistic effect of ibrutinib and CD19 CAR-T cells on Raji cells in vivo and in vitro

Abstract: KEYWORDSBruton tyrosine kinase inhibitor, Chimeric antigen receptor, Programmed cell death 1 ligand 1, Raji cell line, Tumor microenvironment

Cited by 5 publications

References 29 publications

Ibrutinib improves the efficacy of anti‐CD19‐CAR T‐cell therapy in patients with refractory non‐Hodgkin lymphoma

Ibrutinib improves the efficacy of anti‐CD19‐CAR T‐cell therapy in patients with refractory non‐Hodgkin lymphoma

Efficacy and safety related factors of BTK inhibitors as a bridge to CAR-T therapy in R/R FL

Ibrutinib combined with low‐dose histone deacetylases inhibitor chidamide synergistically enhances the anti‐tumor effect in B‐cell lymphoma

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