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Lenalidomide overcomes the resistance to third-generation CD19-CAR-T cell therapy in preclinical models of diffuse large B-cell lymphoma

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Abstract

Purpose

Chimeric antigen receptor (CAR)-T cells against CD19 have been proven to be effective in treating B-cell hematological malignancies. However, the efficacy of this promising therapy is limited by many factors.

Methods

In this study, the germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) cell line OCI-Ly1, and patient-derived xenografted (PDX) mice (CY-DLBCL) were used as the CAR-T cell-resistant model. Meanwhile, the activated B-cell-like (ABC) DLBCL cell line OCI-Ly3 and PDX mice (ZML-DLBCL) were defined as the CAR-T sensitive model. The enhancement of CAR-T cell function by lenalidomide (LEN) was examined in vitro and in vivo.

Results

Lenalidomide effectively enhanced the function of third-generation CD19-CAR-T cells by polarizing CD8+ CAR-T cells to CD8 early-differentiated stage and Th1 type, reducing CAR-T cell exhaustion and improving cell expansion. It was further demonstrated that CAR-T cells combined with LEN substantially reduce the tumor burden and prolong the survival time in various DLBCL mouse models. LEN was also found to promote the infiltration of CD19-CAR-T cells into the tumor site by modulating the tumor microenvironment.

Conclusion

In summary, the results of the present study suggest that LEN can improve the function of CD19-CAR-T cells, providing a basis for clinical trials using this combination therapy against DLBCL.

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Data availability

All data related to this study are available within the article and its Supplementary information files.

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Funding

This work was supported by the National Natural Sciences Foundation of China (Grant number 82000196); the Shanghai Sailing Program; the Science and Technology Commission of the Shanghai Municipality (Grant number 20YF1426800); and the National Key R&D Program (Grant number 2019YFA0905904).

Author information

Author notes

  1. Zhen Jin, Rufang Xiang, Kai Qing and Dan Li contributed equally to this work.

Authors and Affiliations

  1. Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, National Research Center for Translational Medicine, Ruijin Hospital affiliated to School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Zhen Jin, Rufang Xiang, Kai Qing, Dan Li, Zhao Liu, Xiaoyang Li, Hongming Zhu, Yunxiang Zhang, Lining Wang, Kai Xue, Han Liu & Junmin Li

  2. Department of General Practice, Ruijin Hospital affiliated to School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Rufang Xiang

  3. Faculty of Medical Laboratory Science, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Zizhen Xu

  4. Department of Bioengineering & Institute of Engineering in Medicine, University of California San Diego, La Jolla, CA, USA

    Yingxiao Wang

Authors
  1. Zhen Jin
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  2. Rufang Xiang
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  3. Kai Qing
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  4. Dan Li
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  5. Zhao Liu
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  7. Hongming Zhu
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  8. Yunxiang Zhang
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  9. Lining Wang
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  10. Kai Xue
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  11. Han Liu
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  12. Zizhen Xu
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  13. Yingxiao Wang
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  14. Junmin Li
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Contributions

Junmin Li, Yingxiao Wang and Zizhen Xu designed the study. Zhao Liu established the PDX mouse model. Yunxiang Zhang, Hongming Zhu, Lining Wang collected the blood samples from patients. Zhen Jin, Rufang Xiang, Kai Qing, and Dan Li performed the experiments and analyzed the data. Xiaoyang Li, Kai Xue and Han Liu reviewed the data. Zhen Jin wrote the paper.

Corresponding author

Correspondence to Junmin Li.

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Ethical approval

Patients’ materials used in this study was approved by IRB (No. 2006/38) of Ruijin Hospital Ethics Committee. All animal procedures described in this article have been approved by the Animal Care and Use Committee of Ruijin Hospital affiliated to School of Medicine, Shanghai Jiao Tong University.

Competing interests

The authors declare that they have no competing interests.

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Jin, Z., Xiang, R., Qing, K. et al. Lenalidomide overcomes the resistance to third-generation CD19-CAR-T cell therapy in preclinical models of diffuse large B-cell lymphoma. Cell Oncol. 46, 1143–1157 (2023). https://doi.org/10.1007/s13402-023-00833-6

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