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Anti-mesothelin CAR-T immunotherapy in patients with ovarian cancer

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A Correction to this article was published on 14 August 2023

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Abstract

Recently, chimeric antigen receptor T cell (CAR-T) therapy has received increasing attention as an adoptive cellular immunotherapy that targets tumors. However, numerous challenges remain for the effective use of CAR-T to treat solid tumors, including ovarian cancer, which is an aggressive and metastatic cancer with a poor therapeutic response. We screened for an effective anti-MSLN single-chain Fv antibody with comparable binding activity and non-off-target properties using human phage display library. A second-generation of anti-MSLN CAR was designed and generated. We demonstrated the efficacy of our anti-MSLN CAR-T cells for ovarian cancer treatment in an in vitro experiment to kill ovarian tumor cell lines. The anti-MSLN CAR-T cells impeded MSLN-positive tumor growth concomitant with a significant increase in cytokine levels compared with the control. Then, we demonstrated the efficacy of anti-MSLN CAR-T cells in an in vivo experiment against ovarian cancer cell-derived xenografts. Furthermore, we herein report three cases with ovarian cancer who were treated with autologous anti-MSLN CAR-T cells and evaluate the safety and effectiveness of adoptive cell therapy. In this investigator-initiated clinical trials, no patients experienced cytokine release syndrome or neurological symptoms over 2 grads. Disease stabilized in two patients, with progression-free survival times of 5.8 and 4.6 months. Transient CAR expression was detected in patient blood after infusion each time. The tumor partially subsided, and the patient’s condition was relieved. In conclusion, this work proves the efficacy of the anti-MSLN CAR-T treatment strategy in ovarian cancer and provides preliminary data for the development of further clinical trials.

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Data availability

The authors declare that all data supporting the results in this study are available within the paper and its supplementary information. Source data for the figures in this study are available from the corresponding author upon reasonable request.

Change history

Abbreviations

CDX:

Cell-derived xenografts

CRS:

Cytokine release syndrome

CT:

Computed tomography

DLT:

Dose-limiting toxicity

ELISA:

Enzyme-linked immunosorbent assay

FDA:

Food and Drug Administration

H&E:

Hematoxylin and eosin

IARC:

International Agency for Research on Cancer

NSCLC:

Non-small cell lung cancer

PBMC:

Peripheral blood mononuclear cells

PET:

Positron emission tomography

PR:

Partial response

SD:

Stable disease

WBC:

White blood cell

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (81872284) and the Priority Academic Program Development of Jiangsu Higher Education Institutions. We thank every member of the laboratory, as well as the patients and their families, and Nanjing Blue Shield Co. Thanks also to Junfeng Zhang, Liang Jing and Yaoyao Zhao from Nanjing Blue Shield Co. for technical support.

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Author notes

  1. Jiannan Chen, Jianhua Hu and Lili Gu have equally contributed to this work.

Authors and Affiliations

  1. Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, 210023, China

    Jiannan Chen, Lili Gu, Feng Ji, Fan Zhang, Miaomiao Zhang, Zhigang Hu & Zhigang Guo

  2. Department of Biotherapy, Jinling Hospital of Nanjing University School of Medicine, Nanjing, 210002, China

    Jianhua Hu, Longwei Jiang, Yan Zhang, Ruifang Shi, Lihua Ma & Shaochang Jia

  3. Nanjing Blue Shield Biotechnology Co., Ltd., Nanjing, 210023, China

    Jun Li & Zhengliang Chen

  4. Department of Pathology, Jinling Hospital of Nanjing University School of Medicine, Nanjing, 210002, China

    Ying Zhang

  5. Center of Interventional Radiology and Vascular Surgery, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, 210009, China

    Qi Zhang

  6. Inner Mongolia Autonomous Region Cancer Hospital, Hohhot, 010010, China

    Junqing Liang

  7. Baylor University, 1311 S 5th St, Waco, USA

    Shunyu Yao

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  1. Jiannan Chen
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Contributions

JC, ZG and ZH contributed to the conception and design; JC, JH, LG, FJ, JL, ZC, LJ, YZ2, RS, LM, SJ, YZ4, QZ, JL and SY contributed to the acquisition of data; JC, JH, FJ, LJ, JL, MZ and FZ contributed to the analysis and interpretation of data; JC, LG and FJ contributed to the writing, review, and/or revision of the manuscript; JH, LJ, RS, LM, YZ2, SJ, YZ4, QZ, JL and SY collected the data of clinical characteristics; JC, JH, YZ, LJ, LG, FJ, JL, SJ, YZ, QZ, SY, ZG and ZH contributed to the administrative, technical, or material support; ZG and ZH supervised the study.

Corresponding authors

Correspondence to Zhigang Hu or Zhigang Guo.

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The authors declare no conflict of interests.

Ethical approval and consent to participate

All in vivo animal experiments were approved by the Committee on the Ethics of Animal Experiments of Nanjing Normal University (IRB#2020–0047). The clinical experiment was approved by the Experimental Ethics Committee of the Eastern Theater General Hospital (formerly the 81st Hospital of the People's Liberation Army) (81YY-KYLL-04–25-02).

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Chen, J., Hu, J., Gu, L. et al. Anti-mesothelin CAR-T immunotherapy in patients with ovarian cancer. Cancer Immunol Immunother 72, 409–425 (2023). https://doi.org/10.1007/s00262-022-03238-w

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