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

Akio Osa, Takeshi Uenami, Shohei Koyama, Kosuke Fujimoto, Daisuke Okuzaki, Takayuki Takimoto, Haruhiko Hirata, Yukihiro Yano, Soichiro Yokota, Yuhei Kinehara, Yujiro Naito, Tomoyuki Otsuka, Masaki Kanazu, Muneyoshi Kuroyama, Masanari Hamaguchi, Taro Koba, Yu Futami, Mikako Ishijima, Yasuhiko Suga, Yuki Akazawa & 13 others Hirotomo Machiyama, Kota Iwahori, Hyota Takamatsu, Izumi Nagatomo, Yoshito Takeda, Hiroshi Kida, Esra Akbay, Peter S. Hammerman, Kwok Kin Wong, Glenn Dranoff, Masahide Mori, Takashi Kijima, Atsushi Kumanogoh

Research output: Contribution to journalArticle

4 Citations (Scopus)

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).

Original languageEnglish (US)
JournalJCI insight
Volume3
Issue number19
DOIs
StatePublished - Oct 4 2018

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Non-Small Cell Lung Carcinoma
T-Lymphocytes
nivolumab
Japan
Blocking Antibodies
Information Services
Gene Expression Profiling
Transcriptome
Research
Registries
Biomedical Research
Therapeutics
Cell Proliferation
Clinical Trials
Technology
Lung
Antibodies

Keywords

  • Cancer immunotherapy
  • Immunology
  • Lung cancer
  • Pulmonology

Cite this

Osa, A., Uenami, T., Koyama, S., Fujimoto, K., Okuzaki, D., Takimoto, T., ... Kumanogoh, A. (2018). Clinical implications of monitoring nivolumab immunokinetics in non-small cell lung cancer patients. JCI insight, 3(19). https://doi.org/10.1172/jci.insight.59125

Clinical implications of monitoring nivolumab immunokinetics in non-small cell lung cancer patients. / Osa, Akio; Uenami, Takeshi; Koyama, Shohei; Fujimoto, Kosuke; Okuzaki, Daisuke; Takimoto, Takayuki; Hirata, Haruhiko; Yano, Yukihiro; Yokota, Soichiro; Kinehara, Yuhei; Naito, Yujiro; Otsuka, Tomoyuki; Kanazu, Masaki; Kuroyama, Muneyoshi; Hamaguchi, Masanari; Koba, Taro; Futami, Yu; Ishijima, Mikako; Suga, Yasuhiko; Akazawa, Yuki; Machiyama, Hirotomo; Iwahori, Kota; Takamatsu, Hyota; Nagatomo, Izumi; Takeda, Yoshito; Kida, Hiroshi; Akbay, Esra; Hammerman, Peter S.; Wong, Kwok Kin; Dranoff, Glenn; Mori, Masahide; Kijima, Takashi; Kumanogoh, Atsushi.

In: JCI insight, Vol. 3, No. 19, 04.10.2018.

Research output: Contribution to journalArticle

Osa, A, Uenami, T, Koyama, S, Fujimoto, K, Okuzaki, D, Takimoto, T, Hirata, H, Yano, Y, Yokota, S, Kinehara, Y, Naito, Y, Otsuka, T, Kanazu, M, Kuroyama, M, Hamaguchi, M, Koba, T, Futami, Y, Ishijima, M, Suga, Y, Akazawa, Y, Machiyama, H, Iwahori, K, Takamatsu, H, Nagatomo, I, Takeda, Y, Kida, H, Akbay, E, Hammerman, PS, Wong, KK, Dranoff, G, Mori, M, Kijima, T & Kumanogoh, A 2018, 'Clinical implications of monitoring nivolumab immunokinetics in non-small cell lung cancer patients', JCI insight, vol. 3, no. 19. https://doi.org/10.1172/jci.insight.59125
Osa, Akio ; Uenami, Takeshi ; Koyama, Shohei ; Fujimoto, Kosuke ; Okuzaki, Daisuke ; Takimoto, Takayuki ; Hirata, Haruhiko ; Yano, Yukihiro ; Yokota, Soichiro ; Kinehara, Yuhei ; Naito, Yujiro ; Otsuka, Tomoyuki ; Kanazu, Masaki ; Kuroyama, Muneyoshi ; Hamaguchi, Masanari ; Koba, Taro ; Futami, Yu ; Ishijima, Mikako ; Suga, Yasuhiko ; Akazawa, Yuki ; Machiyama, Hirotomo ; Iwahori, Kota ; Takamatsu, Hyota ; Nagatomo, Izumi ; Takeda, Yoshito ; Kida, Hiroshi ; Akbay, Esra ; Hammerman, Peter S. ; Wong, Kwok Kin ; Dranoff, Glenn ; Mori, Masahide ; Kijima, Takashi ; Kumanogoh, Atsushi. / Clinical implications of monitoring nivolumab immunokinetics in non-small cell lung cancer patients. In: JCI insight. 2018 ; Vol. 3, No. 19.
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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).",
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T1 - Clinical implications of monitoring nivolumab immunokinetics in non-small cell lung cancer patients

AU - Osa, Akio

AU - Uenami, Takeshi

AU - Koyama, Shohei

AU - Fujimoto, Kosuke

AU - Okuzaki, Daisuke

AU - Takimoto, Takayuki

AU - Hirata, Haruhiko

AU - Yano, Yukihiro

AU - Yokota, Soichiro

AU - Kinehara, Yuhei

AU - Naito, Yujiro

AU - Otsuka, Tomoyuki

AU - Kanazu, Masaki

AU - Kuroyama, Muneyoshi

AU - Hamaguchi, Masanari

AU - Koba, Taro

AU - Futami, Yu

AU - Ishijima, Mikako

AU - Suga, Yasuhiko

AU - Akazawa, Yuki

AU - Machiyama, Hirotomo

AU - Iwahori, Kota

AU - Takamatsu, Hyota

AU - Nagatomo, Izumi

AU - Takeda, Yoshito

AU - Kida, Hiroshi

AU - Akbay, Esra

AU - Hammerman, Peter S.

AU - Wong, Kwok Kin

AU - Dranoff, Glenn

AU - Mori, Masahide

AU - Kijima, Takashi

AU - Kumanogoh, Atsushi

PY - 2018/10/4

Y1 - 2018/10/4

N2 - 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).

AB - 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).

KW - Cancer immunotherapy

KW - Immunology

KW - Lung cancer

KW - Pulmonology

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