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Overcoming acquired resistance to PD-1 inhibitor with the addition of metformin in small cell lung cancer (SCLC)

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Abstract

Metformin has been widely used as the treatment of type II diabetes mellitus for its anti-hyperglycemic effect. In recent years, it has also been extensively studied for its anti-cancer effect as it diminishes immune exhaustion of CD8 + tumor-infiltrating lymphocytes (TILs). It decreases apoptosis of CD8 + TILs, thereby enhancing T cell-mediated immune response to tumor cells. Here, we present a unique case of a patient with small cell lung cancer (SCLC) who exhibited an overall partial response as per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) since starting metformin in combination with nivolumab therapy. Our patient had been treated with nivolumab monotherapy for 2 years until she had progression of disease. After she was started on metformin along with nivolumab therapy, she has shown a significant durable response for over 6 months. Many patients develop resistance to immunotherapy such as antibodies against cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1). Tumor hypoxia is one of the resistance factors. Signals activated by hypoxic environments in tumors are associated with decreased sensitivity to the PD-1 blockade. Metformin inhibits oxygen consumption in tumor cells in vitro and in vivo, reducing intratumoral hypoxia. These data suggest that metformin can improve susceptibility to anti-PD-1 treatment. To the best of our knowledge, our case is the first reported example demonstrating a proof-of-concept that metformin can contribute to overcoming acquired resistance to PD-1 inhibitors.

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Abbreviations

NSCLC:

Non-small cell lung cancer

CT:

Computed tomography

ED:

Extensive-disease

ICIs:

Immune checkpoint inhibitors

PD-1:

Programmed cell death 1

PD-L1:

Programmed cell death ligand 1

RECIST 1.1:

Response Evaluation Criteria in Solid Tumors, version 1.1

SCLC:

Small cell lung cancer

TILs:

Tumor-infiltrating lymphocytes

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Acknowledgements

Andrew Alexander is acknowledged for providing pictures of Fig. 1 and writing captions.

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Authors and Affiliations

  1. Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Yeseul Kim, Elena Vagia, Pedro Viveiros, Cyra Y. Kang, Ju Young Lee, Gahyun Gim, Sukjoo Cho, Inae Park, Jaeyoun Choi & Young Kwang Chae

  2. St. Elizabeth’s Medical Center, Tufts University School of Medicine, Brington, MA, USA

    Gahyun Gim, Horyun Choi & Leeseul Kim

  3. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Northwestern University Feinberg School of Medicine, Academic Office: 645 N. Michigan Avenue Suite 1006, Chicago, IL, 60611, USA

    Young Kwang Chae

Authors
  1. Yeseul Kim
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  2. Elena Vagia
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  3. Pedro Viveiros
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  4. Cyra Y. Kang
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  5. Ju Young Lee
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  6. Gahyun Gim
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  7. Sukjoo Cho
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  8. Horyun Choi
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  9. Leeseul Kim
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  10. Inae Park
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  11. Jaeyoun Choi
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  12. Young Kwang Chae
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Contributions

YK: writing and revising the manuscript content. YKC: supervision and validation. Others: review and editing. All authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Young Kwang Chae.

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Conflict of interests

Young Kwang Chae—Research Grant: Abbvie, BMS, Biodesix, Lexent Bio, and Freenome; Honoraria/Advisory Boards: Roche/Genentech, AstraZeneca, Foundation Medicine, Counsyl, Neogenomics, Guardant Health, Boehringher Ingelheim, Biodesix, Immuneoncia, Lilly Oncology, Merck, Takeda, Pfizer, and Tempus.

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We have obtained written informed consent from the patient for the publication of the case report.

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We have obtained written informed consent from the patient for the publication of the case report.

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Kim, Y., Vagia, E., Viveiros, P. et al. Overcoming acquired resistance to PD-1 inhibitor with the addition of metformin in small cell lung cancer (SCLC). Cancer Immunol Immunother 70, 961–965 (2021). https://doi.org/10.1007/s00262-020-02703-8

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  • DOI: https://doi.org/10.1007/s00262-020-02703-8

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