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Impact of early inflammatory cytokine elevation after commencement of PD-1 inhibitors to predict efficacy in patients with non-small cell lung cancer

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Abstract

Early elevation of inflammatory cytokines, such as IL-6 or TNF-α, or CRP, which is a surrogate marker for IL-6, following commencement of PD-1/L1 inhibitors (PD1-I) may represent early activation of immune-cells. Serum IL-6 and TNF-α were measured in 10 non-small cell lung cancer patients who were evaluable within the 7 days before and after commencement of PD1-I. For CRP, medical records were reviewed and 34 patients with measured CRP within the 7 days before and after the treatment were evaluated. In the 10 patients analyzed for IL-6/TNF-α, the serum levels of IL-6/TNF-α were not significantly different between pre- and post-initial PD1-I [IL-6 20.3 (2.6–49.9) and 22.9 (3.6–96.1) pg/mL, p = 0.453; TNF-α 1.6 (0.7–6.3) and 3.3 (0.7–9.6) pg/mL, p = 0.329]; however, all four responses were observed among the 7 IL-6-elevated cases, resulting in a response rate of 57%. In the 34 patients analyzed for CRP, CRP was significantly increased after initial PD1-I [1.8 (0.1–17.8) mg/dL, 2.4 (0.0–27.8), p = 0.001]. Notably, in the 31 evaluable cases, all responses were again observed in either the IL-6 or CRP elevated groups and the response rate was 46% (11 of 24). The median overall survival time was not reached in the elevated group and was 112 days in the non-elevated group (p = 0.069). The early increase in inflammatory cytokines with PD1-I was indicated to be predictive for the efficacy in patients with non-small cell lung cancer.

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References

  1. Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378:2288–301.

    Article  CAS  Google Scholar 

  2. Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389:255–65.

    Article  Google Scholar 

  3. Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018;378:2093–104.

    Article  CAS  Google Scholar 

  4. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373:1627–39.

    Article  CAS  Google Scholar 

  5. Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373:123–35.

    Article  CAS  Google Scholar 

  6. Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gumus M, Mazieres J, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018.

  7. Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378:2078–92.

    Article  CAS  Google Scholar 

  8. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375:1823–33.

    Article  CAS  Google Scholar 

  9. Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387:1540–50.

    Article  CAS  Google Scholar 

  10. Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med. 2007;13:1050–9.

    Article  CAS  Google Scholar 

  11. Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol. 2015;16:448–57.

    Article  CAS  Google Scholar 

  12. Patidar A, Selvaraj S, Sarode A, Chauhan P, Chattopadhyay D, Saha B. DAMP-TLR-cytokine axis dictates the fate of tumor. Cytokine. 2018;104:114–23.

    Article  CAS  Google Scholar 

  13. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439:682–7.

    Article  CAS  Google Scholar 

  14. Rui Y, Honjo T, Chikuma S. Programmed cell death 1 inhibits inflammatory helper T-cell development through controlling the innate immune response. Proc Natl Acad Sci USA. 2013;110:16073–8.

    Article  CAS  Google Scholar 

  15. Sanmamed MF, Perez-Gracia JL, Schalper KA, Fusco JP, Gonzalez A, Rodriguez-Ruiz ME, et al. Changes in serum interleukin-8 (IL-8) levels reflect and predict response to anti-PD-1 treatment in melanoma and non-small-cell lung cancer patients. Ann Oncol. 2017;28:1988–95.

    Article  CAS  Google Scholar 

  16. Haratani K, Hayashi H, Chiba Y, Kudo K, Yonesaka K, Kato R, et al. Association of immune-related adverse events with nivolumab efficacy in non-small-cell lung cancer. JAMA Oncol. 2018;4:374–8.

    Article  Google Scholar 

  17. Sato K, Akamatsu H, Murakami E, Sasaki S, Kanai K, Hayata A, et al. Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab. Lung Cancer. 2018;115:71–4.

    Article  Google Scholar 

  18. Teraoka S, Fujimoto D, Morimoto T, Kawachi H, Ito M, Sato Y, et al. Early immune-related adverse events and association with outcome in advanced non-small cell lung cancer patients treated with nivolumab: a prospective cohort study. J Thorac Oncol. 2017;12:1798–805.

    Article  Google Scholar 

  19. Nakamura Y, Kitano S, Takahashi A, Tsutsumida A, Namikawa K, Tanese K, et al. Nivolumab for advanced melanoma: pretreatment prognostic factors and early outcome markers during therapy. Oncotarget. 2016;7:77404–15.

    PubMed  PubMed Central  Google Scholar 

  20. Tanizaki J, Haratani K, Hayashi H, Chiba Y, Nakamura Y, Yonesaka K, et al. Peripheral blood biomarkers associated with clinical outcome in non-small cell lung cancer patients treated with nivolumab. J Thorac Oncol. 2018;13:97–105.

    Article  Google Scholar 

  21. Oya Y, Yoshida T, Kuroda H, Mikubo M, Kondo C, Shimizu J, et al. Predictive clinical parameters for the response of nivolumab in pretreated advanced non-small-cell lung cancer. Oncotarget. 2017;8:103117–28.

    Article  Google Scholar 

  22. Heppt MV, Heinzerling L, Kahler KC, Forschner A, Kirchberger MC, Loquai C, et al. Prognostic factors and outcomes in metastatic uveal melanoma treated with programmed cell death-1 or combined PD-1/cytotoxic T-lymphocyte antigen-4 inhibition. Eur J Cancer. 2017;82:56–65.

    Article  CAS  Google Scholar 

  23. Diem S, Kasenda B, Spain L, Martin-Liberal J, Marconcini R, Gore M, et al. Serum lactate dehydrogenase as an early marker for outcome in patients treated with anti-PD-1 therapy in metastatic melanoma. Br J Cancer. 2016;114:256–61.

    Article  CAS  Google Scholar 

  24. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.

    Article  CAS  Google Scholar 

  25. Mace TA, Shakya R, Pitarresi JR, Swanson B, McQuinn CW, Loftus S, et al. IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer. Gut. 2016.

  26. Franceschini D, Paroli M, Francavilla V, Videtta M, Morrone S, Labbadia G, et al. PD-L1 negatively regulates CD4+ CD25+ Foxp3+ Tregs by limiting STAT-5 phosphorylation in patients chronically infected with HCV. J Clin Invest. 2009;119:551–64.

    Article  CAS  Google Scholar 

  27. Roselli M, Cereda V, di Bari MG, Formica V, Spila A, Jochems C, et al. Effects of conventional therapeutic interventions on the number and function of regulatory T cells. Oncoimmunology. 2013;2:e27025.

    Article  Google Scholar 

  28. Yamazaki N, Kiyohara Y, Uhara H, Iizuka H, Uehara J, Otsuka F, et al. Cytokine biomarkers to predict antitumor responses to nivolumab suggested in a phase II study for advanced melanoma. Cancer Sci. 2017;108:1022–31.

    Article  CAS  Google Scholar 

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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Department of Respiratory Medicine, Respiratory Disease Center, Seirei Mikatahara General Hospital, 3453, Mikatahara, Kitaku, Hamamatsu, Shizuoka, 433-8558, Japan

    Yuichi Ozawa, Yusuke Amano, Kei Kanata, Hirotsugu Hasegwa, Takashi Matsui, Takuya Kakutani, Takafumi Koyauchi & Koshi Yokomura

  2. Division of Thoracic Surgery, Respiratory Disease Center, Seirei Mikatahara General Hospital, Hamamatsu, Japan

    Masayuki Tanahashi & Hiroshi Niwa

  3. Department of Internal Medicine III, Wakayama Medical University, Wakayama, Japan

    Yuichi Ozawa

  4. Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Takafumi Suda

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  1. Yuichi Ozawa
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  2. Yusuke Amano
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Ozawa, Y., Amano, Y., Kanata, K. et al. Impact of early inflammatory cytokine elevation after commencement of PD-1 inhibitors to predict efficacy in patients with non-small cell lung cancer. Med Oncol 36, 33 (2019). https://doi.org/10.1007/s12032-019-1255-3

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  • DOI: https://doi.org/10.1007/s12032-019-1255-3

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