Effect and changes in PD‑1 expression of CD19 CAR‑T cells from T cells highly expressing PD‑1 combined with reduced‑dose PD‑1 inhibitor

Zhang,Rui; Deng,Qi; Jiang,Yan‑Yu; Zhu,Hai‑Bo; Wang,Jia; Zhao,Ming‑Feng

doi:10.3892/or.2019.7096

Effect and changes in PD‑1 expression of CD19 CAR‑T cells from T cells highly expressing PD‑1 combined with reduced‑dose PD‑1 inhibitor

Authors:
- Rui Zhang
- Qi Deng
- Yan‑Yu Jiang
- Hai‑Bo Zhu
- Jia Wang
- Ming‑Feng Zhao
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Affiliations: Department of Hematology, Tianjin First Central Hospital, Nankai, Tianjin 300192, P.R. China
Published online on: April 3, 2019 https://doi.org/10.3892/or.2019.7096
Pages: 3455-3463

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Abstract

CD19 chimeric antigen receptor (CAR) T cell therapy has changed the outcomes of relapsed/refractory B‑cell leukemia and lymphoma. However, its efficacy in patients with relapsed/refractory non‑Hodgkin lymphoma (NHL) has been less impressive compared with that in patients with acute lymphoid leukemia. Furthermore, immune checkpoints have a critical role in the immune system. Several clinical trials have confirmed the dramatic effects of programmed death‑1/programmed death‑ligand 1 (PD‑1/PD‑L1) inhibitors in numerous malignancies, but the immune‑associated adverse events of PD‑1/PD‑L1 inhibitors may occur in a number of systems. The aim of the present study was to investigate the combination of CD19 CAR‑T cells with a reduced dose of PD‑1 inhibitor. This method is expected to overcome the side-effects of PD‑1 inhibitors, while maintaining therapeutic efficacy. The findings demonstrated that a reduced dose of PD‑1 inhibitor did not affect the transfection rate, proliferation rate or cytokine secretion of CD19 CAR‑T cells. An interesting finding of the present study was that the number of PD‑1‑positive cells CAR‑T cells, measured by flow cytometry, declined when they were cultured in vitro, but returned to high levels with gradual prolongation of the co‑culture time of CD19 CAR‑T cells with lymphoma cells; however, there was no change in the mRNA expression of T cells and CAR‑T cells during this process. This phenomenon may be one of the reasons why the curative effect of CAR‑T cells on B‑cell lymphoma is unsatisfactory compared with B‑cell leukemia. The synergistic effect of a reduced‑dose PD‑1 inhibitor combined with CD19 CAR‑T cells from T cells highly expressing PD‑1 was confirmed in a mouse trial. Mice in the combined treatment group achieved the longest survival time. In this group, the proportion of CAR‑T cells and the level of interleukin‑6 were higher compared with those in the CAR‑T cell group. In conclusion, a reduced dose of a PD‑1 inhibitor combined with CD19 CAR‑T cells appears to be a promising treatment option for relapsed/refractory B‑NHL exhibiting high PD‑1 expression by T cells. This method may achieve good clinical efficacy while reducing the side-effects of PD‑1 inhibitors.

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