Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Neutrophil:lymphocyte ratios and serum cytokine changes after hepatic artery chimeric antigen receptor-modified T-cell infusions for liver metastases

Cancer Gene Therapy volume 21, pages 457–462 (2014)Cite this article

Subjects

Abstract

Our phase I Hepatic Immunotherapy for Metastases (HITM) trial tested the safety of chimeric antigen receptor-modified T-cell (CAR-T) hepatic artery infusions (HAI) for unresectable carcinoembryonic antigen (CEA)+ liver metastases (LM). High neutrophil:lymphocyte ratios (NLR) predict poor outcome in cancer patients and we hypothesized that NLR changes would correlate with early responses to CAR-T HAI. Six patients completed the protocol. Three patients received CAR-T HAI in dose escalation (1 × 108, 1 × 109 and 1 × 1010 cells) and the remainder received three doses (1 × 1010 cells) with interleukin (IL)2 support. Serum cytokines and NLR were measured at multiple time points. The mean NLR for all patients was 13.9 (range 4.8–38.1). NLR increased in four patients following treatment with a mean fold change of 1.9. Serum IL6 levels and NLR fold changes demonstrated a trend towards a positive correlation (r=0.77, P=0.10). Patients with poor CEA responses were significantly more likely to have higher NLR level increases (P=0.048). Increased NLR levels were associated with poor responses following CAR-T HAI. NLR variations and associated cytokine changes may be useful surrogates of response to CAR-T HAI.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D . Global cancer statistics. CA Cancer J Clin 2011; 61: 69–90.

    Article  Google Scholar 

  2. Ismaili N . Treatment of colorectal liver metastases. World J Surg Oncol 2011; 9: 154.

    Article  Google Scholar 

  3. Abdalla EK, Vauthey JN, Ellis LM et al. Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg. 2004; 239: 818–825 discussion 825.

    Article  Google Scholar 

  4. Adam R, Wicherts DA, de Haas RJ et al. Patients with initially unresectable colorectal liver metastases: is there a possibility of cure? J Clin Oncol 2009; 27: 1829–1835.

    Article  Google Scholar 

  5. Tomlinson JS, Jarnagin WR, DeMatteo RP et al. Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol 2007; 25: 4575–4580.

    Article  Google Scholar 

  6. Falcone A, Ricci S, Brunetti I et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol 2007; 25: 1670–1676.

    Article  CAS  Google Scholar 

  7. Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME . Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer 2008; 8: 299–308.

    Article  CAS  Google Scholar 

  8. Rosenberg SA . Cell transfer immunotherapy for metastatic solid cancer—what clinicians need to know. Nat Rev Clin Oncol 2011; 8: 577–585.

    Article  CAS  Google Scholar 

  9. Saied A, Pillarisetty VG, Katz SC . Immunotherapy for solid tumors-a review for surgeons. J Surg Res 2013; 187: 525–535.

    Article  Google Scholar 

  10. Nishino M, Jagannathan JP, Krajewski KM et al. Personalized tumor response assessment in the era of molecular medicine: cancer-specific and therapy-specific response criteria to complement pitfalls of RECIST. AJR Am J Roentgenol 2012; 198: 737–745.

    Article  Google Scholar 

  11. Wolchok JD, Hoos A, O’Day S et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009; 15: 7412–7420.

    Article  CAS  Google Scholar 

  12. Knupfer H, Preiss R . Serum interleukin-6 levels in colorectal cancer patients—a summary of published results. Int J Colorectal Dis 2010; 25: 135–140.

    Article  Google Scholar 

  13. Okugawa Y, Miki C, Toiyama Y et al. Loss of tumoral expression of soluble IL-6 receptor is associated with disease progression in colorectal cancer. Br J Cancer 2010; 103: 787–795.

    Article  CAS  Google Scholar 

  14. Waldner MJ, Foersch S, Neurath MF . Interleukin-6—a key regulator of colorectal cancer development. Int J Biol Sci 2012; 8: 1248–1253.

    Article  CAS  Google Scholar 

  15. Ueda T, Shimada E, Urakawa T . Serum levels of cytokines in patients with colorectal cancer: possible involvement of interleukin-6 and interleukin-8 in hematogenous metastasis. J Gastroenterol 1994; 29: 423–429.

    Article  CAS  Google Scholar 

  16. Kinoshita T, Ito H, Miki C . Serum interleukin-6 level reflects the tumor proliferative activity in patients with colorectal carcinoma. Cancer 1999; 85: 2526–2531.

    Article  CAS  Google Scholar 

  17. de Jong KP, von Geusau BA, Rottier CA et al. Serum response of hepatocyte growth factor, insulin-like growth factor-I, interleukin-6, and acute phase proteins in patients with colorectal liver metastases treated with partial hepatectomy or cryosurgery. J Hepatol 2001; 34: 422–427.

    Article  CAS  Google Scholar 

  18. Evrard S, Menetrier-Caux C, Biota C et al. Cytokines pattern after surgical radiofrequency ablation of liver colorectal metastases. Gastroenterol Clin Biol 2007; 31: 141–145.

    Article  CAS  Google Scholar 

  19. Hammerich L, Heymann F, Tacke F . Role of IL-17 and Th17 cells in liver diseases. Clin Dev Immunol 2011; 2011: 345803.

    Article  Google Scholar 

  20. Vizio B, Novarino A, Giacobino A et al. Potential plasticity of T regulatory cells in pancreatic carcinoma in relation to disease progression and outcome. Exp Ther Med 2012; 4: 70–78.

    Article  CAS  Google Scholar 

  21. Kishi Y, Kopetz S, Chun YS, Palavecino M, Abdalla EK, Vauthey JN . Blood neutrophil-to-lymphocyte ratio predicts survival in patients with colorectal liver metastases treated with systemic chemotherapy. Ann Surg Oncol 2009; 16: 614–622.

    Article  Google Scholar 

  22. Suwa T, Hogg JC, English D, Van Eeden SF . Interleukin-6 induces demargination of intravascular neutrophils and shortens their transit in marrow. Am J Physiol Heart Circ Physiol 2000; 279: H2954–H2960.

    Article  CAS  Google Scholar 

  23. Paramanathan A, Saxena A, Morris DL . A systematic review and meta-analysis on the impact of pre-operative neutrophil lymphocyte ratio on long term outcomes after curative intent resection of solid tumours. Surg Oncol 2013; 23: 31–39.

    Article  Google Scholar 

  24. Roxburgh CSD, McMillan DC . Role of systemic inflammatory response in predicting survival in patients with primary operable cancer. Future Oncol 2010; 6: 149–163.

    Article  CAS  Google Scholar 

  25. Wang DS, Ren C, Qiu MZ et al. Comparison of the prognostic value of various preoperative inflammation-based factors in patients with stage III gastric cancer. Tumour Biol 2012; 33: 749–756.

    Article  Google Scholar 

  26. Halazun KJ, Aldoori A, Malik HZ et al. Elevated preoperative neutrophil to lymphocyte ratio predicts survival following hepatic resection for colorectal liver metastases. Eur J Surg Oncol 2008; 34: 55–60.

    Article  CAS  Google Scholar 

  27. Walsh SR, Cook EJ, Goulder F, Justin TA, Keeling NJ . Neutrophil-lymphocyte ratio as a prognostic factor in colorectal cancer. J Surg Oncol 2005; 91: 181–184.

    Article  CAS  Google Scholar 

  28. Katz SC . Hepatic Immunotherapy for Liver Metastases phase I trial. Society of Surgical Oncology 67th Cancer Symposium 2014; 40: 52.

    Google Scholar 

  29. Azab B, Bhatt VR, Phookan J et al. Usefulness of the neutrophil-to-lymphocyte ratio in predicting short-and long-term mortality in breast cancer patients. Ann Surg Oncol 2012; 19: 217–224.

    Article  Google Scholar 

  30. Ding PR, An X, Zhang RX et al. Elevated preoperative neutrophil to lymphocyte ratio predicts risk of recurrence following curative resection for stage IIA colon cancer. Int J Colorectal Dis 2010; 25: 1427–1433.

    Article  Google Scholar 

  31. Lotze MT, Matory YL, Ettinghausen SE et al. In vivo administration of purified human interleukin 2. II. Half life, immunologic effects, and expansion of peripheral lymphoid cells in vivo with recombinant IL 2. J Immunol 1985; 135: 2865–2875.

    CAS  PubMed  Google Scholar 

  32. Neal CP, Mann CD, Sutton CD et al. Evaluation of the prognostic value of systemic inflammation and socioeconomic deprivation in patients with resectable colorectal liver metastases. Eur J Cancer 2009; 45: 56–64.

    Article  CAS  Google Scholar 

  33. Hammarstrom S . The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues. Semin Cancer Biol 1999; 9: 67–81.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Financial Support: Support for this work was provided by the National Institute of Health (1K08CA160662-01A1), the Society of Surgical Oncology Clinical Investigator Award supported by an education grant for Genentech, the Rhode Island Foundation and Roger Williams Medical Center Graduate Medical Education Fund.

Author information

Authors and Affiliations

  1. Department of Surgery, Roger Williams Medical Center, Providence, RI/Boston University School of Medicine, Boston, MA, USA

    A Saied, L Licata, R A Burga, M Thorn, N J Espat & S C Katz

  2. Department of Medicine, Roger Williams Medical Center, Providence, RI/Boston University School of Medicine, Boston, MA, USA

    E McCormack & R P Junghans

  3. Department of Radiology, Roger Williams Medical Center, Providence, RI/Boston University School of Medicine, Boston, MA, USA

    B F Stainken & E O Assanah

  4. Roger Williams Medical Center, GMP Core Facility and Clinical Protocol Office, Providence, RI, USA

    P D Khare & R Davies

Authors
  1. A Saied
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L Licata
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R A Burga
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Thorn
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E McCormack
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. B F Stainken
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E O Assanah
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. P D Khare
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. R Davies
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. N J Espat
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. R P Junghans
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. S C Katz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S C Katz.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Saied, A., Licata, L., Burga, R. et al. Neutrophil:lymphocyte ratios and serum cytokine changes after hepatic artery chimeric antigen receptor-modified T-cell infusions for liver metastases. Cancer Gene Ther 21, 457–462 (2014). https://doi.org/10.1038/cgt.2014.50

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cgt.2014.50

This article is cited by

Search

Advanced search

Quick links