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Research
Lei Sun
Institute of Developmental Biology and Molecular Medicine, Fudan University, Shanghai, China
Corresponding Author
Qi Deng
Department of Hematology, Tianjin First Central Hospital, Tianjin, China
Corresponding Author
ORCiD: https://orcid.org/0000-0002-3646-4953
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
Ibrutinib might improve the efficacy of CD19 CAR-T cell therapy in chronic lymphocytic leukemia (CLL). We expect to study the possibility and mechanism of synergistic effect of ibrutinib and CAR-T cells in other types of lymphoma.
Methods
We selected the CD19 CAR-T cells of a patient who failed in this therapy and a dose of 8 mg/kg/day ibrutinib to study the synergistic effect. Subcutaneous and tail vein tumorigenic mice were established with Raji cells. The differences of the synergistic effect between these two models were compared by bioluminescence imaging (BLI) monitoring and flow cytometry (FCM). Then the expression of STAT-3 signaling pathway was assessed by western blot analysis.
Results
The expression of PD-L1 was 0.23±0.06% in Raji cells. In subcutaneous tumorigenic model, the luciferase signal was reduced significantly in the ibrutinib combined with CD19 CAR-T cell group. The proportion of CD19 CAR-T cells was higher in the polytherapy group than that of the CAR-T cell monotherapy group. But we didn't get analogous synergistic effect in tail vein tumorigenic model. There was no difference between the STAT-3 signaling pathway expression in residual tumor cells with or without ibrutinib.
Conclusions
Our result might indicate that no IL-10/STAT-3/PD-L1 pathway were involved in the synergistic effect. Then some other mechanism about tumor microenvironment might be a possible target for ibrutinib. We expect our results provide evidence for the use of ibrutinib in polytherapy to other types of B cell lymphoma.
Keywords
Bruton tyrosine kinase inhibitor, Chimeric antigen receptor, Programmed cell death 1 ligand 1, Raji cell line, Tumor microenvironment
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A new preprint design is coming!
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This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Research
Lei Sun
Institute of Developmental Biology and Molecular Medicine, Fudan University, Shanghai, China
Corresponding Author
Qi Deng
Department of Hematology, Tianjin First Central Hospital, Tianjin, China
Corresponding Author
ORCiD: https://orcid.org/0000-0002-3646-4953
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
View the published article at Cancer Science.
Version 1
Posted 15 Apr, 2020
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Translational Medicine
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Cancer Science.
Background
Ibrutinib might improve the efficacy of CD19 CAR-T cell therapy in chronic lymphocytic leukemia (CLL). We expect to study the possibility and mechanism of synergistic effect of ibrutinib and CAR-T cells in other types of lymphoma.
Methods
We selected the CD19 CAR-T cells of a patient who failed in this therapy and a dose of 8 mg/kg/day ibrutinib to study the synergistic effect. Subcutaneous and tail vein tumorigenic mice were established with Raji cells. The differences of the synergistic effect between these two models were compared by bioluminescence imaging (BLI) monitoring and flow cytometry (FCM). Then the expression of STAT-3 signaling pathway was assessed by western blot analysis.
Results
The expression of PD-L1 was 0.23±0.06% in Raji cells. In subcutaneous tumorigenic model, the luciferase signal was reduced significantly in the ibrutinib combined with CD19 CAR-T cell group. The proportion of CD19 CAR-T cells was higher in the polytherapy group than that of the CAR-T cell monotherapy group. But we didn't get analogous synergistic effect in tail vein tumorigenic model. There was no difference between the STAT-3 signaling pathway expression in residual tumor cells with or without ibrutinib.
Conclusions
Our result might indicate that no IL-10/STAT-3/PD-L1 pathway were involved in the synergistic effect. Then some other mechanism about tumor microenvironment might be a possible target for ibrutinib. We expect our results provide evidence for the use of ibrutinib in polytherapy to other types of B cell lymphoma.
Figure 2
Figure 3
Figure 5
Figure 8
Figure 10
Figure 11
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