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      Clinical implications of monitoring nivolumab immunokinetics in non–small cell lung cancer patients

      research-article
      1 , 2 , 3 , 1 , 2 , 4 , 5 , 6 , 1 , 1 , 3 , 3 , 1 , 2 , 1 , 2 , 1 , 3 , 1 , 1 , 1 , 2 , 1 , 2 , 3 , 1 , 2 , 3 , 1 , 1 , 1 , 2 , 1 , 1 , 1 , 7 , 8 , 9 , 8 , 3 , 1 , 2 , 1 , 2 , 10 ,
      JCI Insight
      American Society for Clinical Investigation
      Immunology, Pulmonology, Cancer immunotherapy, Lung cancer

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          Abstract

          BACKGROUND. The PD-1–blocking antibody nivolumab persists in patients several weeks after the last infusion. However, no study has systematically evaluated the maximum duration that the antibody persists on T cells or the association between this duration and residual therapeutic efficacy or potential adverse events.

          METHODS. To define the duration of binding and residual efficacy of nivolumab after discontinuation, we developed a simplified strategy for T cell monitoring and used it to analyze T cells from peripheral blood from 11 non–small cell lung cancer patients previously treated with nivolumab. To determine the suitability of our method for other applications, we compared transcriptome profiles between nivolumab-bound and nivolumab-unbound CD8 T cells. We also applied T cell monitoring in 2 nivolumab-treated patients who developed progressive lung tumors during long-term follow-up.

          RESULTS. Prolonged nivolumab binding was detected more than 20 weeks after the last infusion, regardless of the total number of nivolumab infusions (2–15 doses) or type of subsequent treatment, in 9 of the 11 cases in which long-term monitoring was possible. Ki-67 positivity, a proliferation marker, in T cells decreased in patients with progressive disease. Transcriptome profiling identified the signals regulating activation of nivolumab-bound T cells, which may contribute to nivolumab resistance. In 2 patients who restarted nivolumab, T cell proliferation markers exhibited the opposite trend and correlated with clinical response.

          CONCLUSIONS. Although only a few samples were analyzed, our strategy of monitoring both nivolumab binding and Ki-67 in T cells might help determine residual efficacy under various types of concurrent or subsequent treatment.

          TRIAL REGISTRATION. University Hospital Medical Information Network Clinical Trials Registry, UMIN000024623.

          FUNDING. This work was supported by Japan Society for the Promotion of Science KAKENHI (JP17K16045, JP18H05282, and JP15K09220), Japan Agency for Medical Research and Development (JP17cm0106310, JP18cm0106335 and JP18cm059042), and Core Research for Evolutional Science and Technology (JPMJCR16G2).

          Abstract

          A method for detecting nivolumab binding and T cell activation status, which could be used to predict residual efficacy and toxicity, is developed.

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          Most cited references12

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          Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy.

          Checkpoint blockade immunotherapies can be extraordinarily effective, but might benefit only the minority of patients whose tumors are pre-infiltrated by T cells. Here, using lung adenocarcinoma mouse models, including genetic models, we show that autochthonous tumors that lacked T cell infiltration and resisted current treatment options could be successfully sensitized to host antitumor T cell immunity when appropriately selected immunogenic drugs (e.g., oxaliplatin combined with cyclophosphamide for treatment against tumors expressing oncogenic Kras and lacking Trp53) were used. The antitumor response was triggered by direct drug actions on tumor cells, relied on innate immune sensing through toll-like receptor 4 signaling, and ultimately depended on CD8(+) T cell antitumor immunity. Furthermore, instigating tumor infiltration by T cells sensitized tumors to checkpoint inhibition and controlled cancer durably. These findings indicate that the proportion of cancers responding to checkpoint therapy can be feasibly and substantially expanded by combining checkpoint blockade with immunogenic drugs.
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            Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer

            Vijayanand and colleagues use genome-wide RNA sequencing for transcriptional profiling of CD8+ T cells from tumors and adjacent uninvolved lung tissue from patients with early-stage lung cancer. A tissue-resident memory signature is associated with enhanced cytotoxicity and improved survival.
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              STK11/LKB1 Deficiency Promotes Neutrophil Recruitment and Proinflammatory Cytokine Production to Suppress T-cell Activity in the Lung Tumor Microenvironment.

              STK11/LKB1 is among the most commonly inactivated tumor suppressors in non-small cell lung cancer (NSCLC), especially in tumors harboring KRAS mutations. Many oncogenes promote immune escape, undermining the effectiveness of immunotherapies, but it is unclear whether the inactivation of tumor suppressor genes, such as STK11/LKB1, exerts similar effects. In this study, we investigated the consequences of STK11/LKB1 loss on the immune microenvironment in a mouse model of KRAS-driven NSCLC. Genetic ablation of STK11/LKB1 resulted in accumulation of neutrophils with T-cell-suppressive effects, along with a corresponding increase in the expression of T-cell exhaustion markers and tumor-promoting cytokines. The number of tumor-infiltrating lymphocytes was also reduced in LKB1-deficient mouse and human tumors. Furthermore, STK11/LKB1-inactivating mutations were associated with reduced expression of PD-1 ligand PD-L1 in mouse and patient tumors as well as in tumor-derived cell lines. Consistent with these results, PD-1-targeting antibodies were ineffective against Lkb1-deficient tumors. In contrast, treating Lkb1-deficient mice with an IL6-neutralizing antibody or a neutrophil-depleting antibody yielded therapeutic benefits associated with reduced neutrophil accumulation and proinflammatory cytokine expression. Our findings illustrate how tumor suppressor mutations can modulate the immune milieu of the tumor microenvironment, and they offer specific implications for addressing STK11/LKB1-mutated tumors with PD-1-targeting antibody therapies.
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                Author and article information

                Contributors
                Journal
                JCI Insight
                JCI Insight
                JCI Insight
                JCI Insight
                American Society for Clinical Investigation
                2379-3708
                4 October 2018
                4 October 2018
                4 October 2018
                : 3
                : 19
                : e59125
                Affiliations
                [1 ]Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
                [2 ]Laboratory of Immunopathology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
                [3 ]Department of Thoracic Oncology, National Hospital Organization, Toneyama National Hospital, Toyonaka, Osaka, Japan.
                [4 ]Department of Immunology and Genomics, Osaka City University Graduate School of Medicine, Osaka, Osaka, Japan.
                [5 ]Division of Innate Immune Regulation, International Research and Development Center for Mucosal Vaccines, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
                [6 ]DNA-Chip Developmental Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
                [7 ]Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.
                [8 ]Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
                [9 ]Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York, USA.
                [10 ]Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Osaka, Japan.
                Author notes
                Address correspondence to: Shohei Koyama, Takashi Kijima, or Atsushi Kumanogoh, Osaka University, 2-2 Yamadaoka, Osaka, Suita 565-0871, Japan. Phone: 81.6.6879.3833; Email: koyama@ 123456imed3.med.osaka-u.ac.jp (S. Koyama). Email: tkijima@ 123456imed3.med.osaka-u.ac.jp (T. Kijima). Email: kumanogo@ 123456imed3.med.osaka-u.ac.jp (A. Kumanogoh).

                Authorship note: AO, TU, SK, and KF contributed equally to this work.

                Author information
                http://orcid.org/0000-0002-4552-783X
                http://orcid.org/0000-0002-6829-1778
                http://orcid.org/0000-0003-4405-1929
                Article
                59125
                10.1172/jci.insight.59125
                6237460
                30282824
                48edce01-6874-4164-90b4-a0b1e2f5e119
                Copyright © 2018 Osa et al.

                This work is licensed under the Creative Commons Attribution 4.0 International License.

                History
                : 29 May 2018
                : 21 August 2018
                Funding
                Funded by: JSPS
                Award ID: KAKENHI Grant Number 17K16045
                Funded by: AMED-Core Research for Evolutional Science and Technology
                Award ID: JPMJCR16G2
                Funded by: JSPS
                Award ID: KAKENHI Grant Number 15K09220
                Funded by: JSPS
                Award ID: JP18H05282
                Funded by: AMED
                Award ID: JP18cm0106335
                Funded by: AMED
                Award ID: JP18cm059042
                Categories
                Research Article

                immunology,pulmonology,cancer immunotherapy,lung cancer
                immunology, pulmonology, cancer immunotherapy, lung cancer

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