Overcoming acquired resistance to PD-1 inhibitor with the addition of metformin in small cell lung cancer (SCLC)
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ORIGINAL ARTICLE
Overcoming acquired resistance to PD‑1 inhibitor with the addition of metformin in small cell lung cancer (SCLC) Yeseul Kim1 · Elena Vagia1 · Pedro Viveiros1 · Cyra Y. Kang1 · Ju Young Lee1 · Gahyun Gim1,2 · Sukjoo Cho1 · Horyun Choi2 · Leeseul Kim2 · Inae Park1 · Jaeyoun Choi1 · Young Kwang Chae1,3 Received: 28 June 2020 / Accepted: 15 August 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
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 + tumorinfiltrating 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 (PDL1). 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. Keywords Metformin · Small cell lung cancer · Immunotherapy · Acquired resistance · Durable response 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 * Young Kwang Chae [email protected] 1
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
2
St. Elizabeth’s Medical Center, Tufts University School of Medicine, Brington, MA, USA
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
SCLC Small cell lung cancer TILs Tumor-infiltrating lymphocytes
Introduction In recent years, immune checkpoint inhibitors (ICIs) have shown promising efficacy in treating various cancer types. Howev
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