Skip to main content

Advertisement

SpringerLink
Log in

Chemotherapy with or without autologous cytokine-induced killer cell transfusion as the first-line treatment for stage IV gastrointestinal cancer: a phase II clinical trial

  • Original Article – Clinical Oncology
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Objective

To investigate the efficacy of autologous cytokine-induced killer (CIK) cell therapy combined with chemotherapy versus chemotherapy alone for the treatment of stage IV gastrointestinal (GI) cancer in the first-line setting.

Methods

Thirty-three patients diagnosed with stage IV GI cancer were divided into chemotherapy plus CIK group (chemo–CIK, n = 16) and chemotherapy-alone group (chemo-alone, n = 17). Autologous peripheral blood mononuclear cells were separated by flow cytometry, cultured in vitro to induce CIK cells, and transfused into patients on days 14 and 16 of the first and second chemotherapy cycles.

Results

The median progression-free survival (PFS) was 5.6 months for patients in the chemo–CIK group and 3.83 months for those in the chemo-alone group. The difference was borderline significant (P = 0.06), indicating a potential advantage for combined CIK cell transfusion with chemotherapy in improving PFS. A favored objective response rate was also observed in the chemo–CIK group than in the chemo-alone group. This study also revealed that CIK cell transfusion restored the cellular immunity in these GI cancer patients. The percentage of natural killer T cells, NK cells, CD3+ T cells, and T-cell subgroups CD4+ proportion in the peripheral blood of cancer patients significantly increased after the CIK cell transfusion, while the change in T-cell subgroups CD8+ and CD4+/CD8+ did not differ significantly.

Conclusions

The study showed that the addition of CIK cell transfusion to traditional chemotherapy in the first-line setting was associated with a prolonged PFS and enhanced T-lymphocyte subset activity, supporting a potential treatment choice for advanced GI cancer patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Bonanno G, Iudicone P, Mariotti A, Procoli A, Pandolfi A, Fioravanti D et al (2010) Thymoglobulin, interferon- γ and interleukin-2 efficiently expand cytokine-induced killer (CIK) cells in clinical-grade cultures. J Transl Med 7:129–143

    Article  Google Scholar 

  • Chung MJ, Park JY, Bang S, Park SW, Song SY (2014) Phase II clinical trial of ex vivo-expanded cytokine-induced killer cells therapy in advanced pancreatic cancer. Cancer Immunol Immunother 63(9):939–946

    Article  CAS  PubMed  Google Scholar 

  • Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127(12):2893–2917

    Article  CAS  PubMed  Google Scholar 

  • Finn OJ (2012) Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Ann Oncol 23(Suppl 8):viii6–viii9

    Article  PubMed  PubMed Central  Google Scholar 

  • Hercend T, Griffin JD, Bensussan A, Schmidt RE, Edson MA, Brennan A et al (1985) Generation of monoclonal antibodies to a human natural killer clone. Characterization of two natural killer associated antigens, NKH1A and NKH2, expressed on subsets of large granular lymphocytes. J Clin Invest 75:932–943

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hontscha C, Borck Y, Zhou H, Messmer D, Schmidt-Wolf IG (2010) Clinical trials on CIK cells: first report of the international registry on CIK cells (IRCC). J Cancer Res Clin Oncol 137:305–310

    Article  PubMed  Google Scholar 

  • Hontscha C, Borck Y, Zhou H, Messmer D, Schmidt-Wolf IGH (2011) Clinical trials on CIK cells: first report of the international registry on CIK cells (IRCC). J Cancer Res Clin Oncol 137(2):305–310

    Article  CAS  PubMed  Google Scholar 

  • Hui D, Qiang L, Jian W, Ti Z, Da-Lu K (2009) A randomized, controlled trial of postoperative adjuvant cytokine-induced killer cells immunotherapy after radical resection of hepatocellular carcinoma. Dig Liver Dis 41:36–41

    Article  PubMed  Google Scholar 

  • Jiang J, Wu C, Deng H (2005) Compare cytotoxicity of cytokine induced killer cells with tumor infiltrating lymphocytes in vitro. Lab Med 20:322–324

    CAS  Google Scholar 

  • Jiang J, Xu N, Wu C, Deng H, Lu M, Li M, Xu B, Wu J, Wang R, Xu J, Nilsson-Ehle P (2006) Treatment of advanced gastric cancer by chemotherapy combined with autologous cytokine-induced killer cells. Anticancer Res 26:2237–2242

    CAS  PubMed  Google Scholar 

  • Kantoff PW, Higano CS, Shore ND et al (2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363:411–422

    Article  CAS  PubMed  Google Scholar 

  • Kim HM, Kang JS, Lim J, Park SK, Lee K, Yoon YD, Lee CW, Lee KH, Han G, Yang KH, Kim YJ, Kim Y, Han SB (2007) Inhibition of human ovarian tumor growth by cytokine-induced killer cells. Arch Pharm Res 30:1464–1470

    Article  CAS  PubMed  Google Scholar 

  • Leemhuis T, Wells S, Scheffold C, Edinger M, Negrin RS (2005) A phase I trial of autologous cytokine-induced killer cells for the treatment of relapsed Hodgkin disease and non-Hodgkin lymphoma. Biol Blood Marrow Transplant 11:181–187

    Article  PubMed  Google Scholar 

  • Li XD, Ji M, Zheng X, Ning ZH, Wu J, Lu BF, Wu CP, Jiang JT (2014) Evaluation of tumor response to cytokine-induced killer cells therapy in malignant solid tumors. J Transl Med 12:215–219

    Article  PubMed  PubMed Central  Google Scholar 

  • Li Y, Pan K, Liu L-z, Li Y-q, Mo-fa G, Zhang H, Shen W-x, Xia J-c, Li J-j (2015) Sequential cytokine-induced killer cell immunotherapy enhances the efficacy of the gemcitabine plus cisplatin chemotherapy regimen for metastatic nasopharyngeal carcinoma. PLoS ONE 10(6):e0130620

    Article  PubMed  PubMed Central  Google Scholar 

  • Ling W, Fan J, Yue M, Yuan M, Wang H (2010) Capecitabine-based chemotherapy for metastatic colorectal cancer. J Cancer Res Clin Oncol 137(6):927–938

    Article  PubMed  Google Scholar 

  • Linn YC, Hui KM (2010) Cytokine-induced NK-like T cells: from bench to bedside. J Biomed Biotechnol 1–8. doi:10.1155/2010/435745

  • Liu L, Zhang W, Qi X, Li H, Yu J, Wei S, Hao X, Ren X (2012) Randomized study of autologous cytokine-induced killer cell immunotherapy in metastatic renal carcinoma. Clin Cancer Res 18:1751–1759

    Article  CAS  PubMed  Google Scholar 

  • Ma Y, Tang L, Wang HX et al (2012a) Capecitabine for the treatment of advanced gastric cancer: efficacy, safety and ethnicity. J Clin Pharm Ther 37(3):266–275

    Article  CAS  PubMed  Google Scholar 

  • Ma Y, Zhang Z, Tang L, Xu YC, Xie ZM, Gu XF, Wang HX (2012b) Cytokine-induced killer (CIK) cells in the treatment of patients with solid carcinomas: a systematic review and pooled analysis. Cytotherapy 14(4):483–493

    Article  CAS  PubMed  Google Scholar 

  • Ma Y, Xu YC, Tang L et al (2012c) Cytokine-induced killer (CIK) cell therapy for patients with hepatocellular carcinoma: efficacy and safety. Exp Hematol Oncol 1:11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Märten A, Renoth S, von Lilienfeld-Toal M et al (2001) Enhanced lytic activity of cytokine-induced killer cells against multiple myeloma cells after co-culture with idiotype-pulsed dendritic cells. Haematologica 86(10):1029–1037

    PubMed  Google Scholar 

  • Parkin DM (2001) Global cancer statistics in the year 2000. Lancet Oncol 2(9):533–543

    Article  CAS  PubMed  Google Scholar 

  • Rosenberg S (1985) Lymphokine-activated killer cells: a new approach to immunotherapy of cancer. J Natl Cancer Inst 75:595–603

    CAS  PubMed  Google Scholar 

  • Rosenberg SA, Spiess P, Lafreniere R (1986) A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science 233:1318–1321

    Article  CAS  PubMed  Google Scholar 

  • Rosenberg SA, Yang JC, Sherry RM et al (2011) durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res 1(17):4550

    Article  Google Scholar 

  • Sangiolo D, Mesiano G, Gammaitoni L et al (2014) Cytokine-induced killer cells eradicate bone and soft-tissue sarcomas. Cancer Res 74:119

    Article  CAS  PubMed  Google Scholar 

  • Schmidt-Wolf IG, Negrin RS, Kiem HP, Blume KG, Weissman IL (1991) Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity. J Exp Med 174:139–149

    Article  CAS  PubMed  Google Scholar 

  • Schmidt-Wolf IGH, Finke S, Trojaneck B et al (1999) Phase I clinical study applying autologous immunological effector cells transfected with the interleukin-1 gene in patients with metastatic renal cancer, colorectal cancer and lymphoma. Br J Cancer 81(6):1009–1016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siegel R, Naishadham D, Jemal A (2013) Cancer statistics, 2013. CA Cancer J Clin 63(1):11–30

    Article  PubMed  Google Scholar 

  • Takahashi H, Nakada T, Puisieux I (1993) Inhibition of human colon cancer growth by antibody-directed human LAK cells in SCID mice. Science 259:1460–1463

    Article  CAS  PubMed  Google Scholar 

  • Verneris MR, Kornacker M, Mailander V, Negrin RS (2000) Resistance of ex vivo expanded CD3+ CD56+ T-cells to Fas mediated apoptosis. Cancer Immunol Immunother 49:335–345

    Article  CAS  PubMed  Google Scholar 

  • Wu CP, Jiang JT, Shi LR, Xu N (2008) Prospective study of chemotherapy in combination with cytokine-induced killer cells in patients suffering from advanced non-small cell lung cancer. Anticancer Res 28:3997–4002

    CAS  PubMed  Google Scholar 

  • Yun YS, Hargrove ME, Ting CC (1989) In vivo antitumor activity of anti-CD3-induced activated killer cells. Cancer Res 49:4770–4774

    CAS  PubMed  Google Scholar 

  • Zhanga J, Zhua L, Dua H, Heb X, Yina Y, Gua Y, Liua L, Lua K, Guoa R, Liua P, Shu Y (2015) Autologous cytokine-induced killer cell therapy in lung cancer patients: a retrospective study. Biomed Pharmacother 70:248–252

    Article  Google Scholar 

Download references

Acknowledgments

This study was supported by the National Natural Science Fund (81102015 and 81301858) and the Special Fund for Technological Innovation of Shanghai Jiao Tong University (YG2012MS46).

Authors’ contributions

Yingchun Xu and Hong-min Lu participated in the selection of cases, interpretation of results, and writing of the manuscript. Hongxia Wang and Yi-ran Huang designed the experiment. Qi Xu, Jun-jian Li, Xiao-feng Gu, Lei Tang, and Yue Ma collected the clinical details of the patients and carried out statistical analyses. Li Sun carried out the immunohistochemistry. All authors read and approved the final manuscript.

Author information

Author notes

    Authors and Affiliations

    1. Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, 200081, China

      Ying-Chun Xu, Jun-Jian Li & Hong-Xia Wang

    2. Department of Oncology, Shanghai Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China

      Ying-Chun Xu, Qi Xu, Xiao-Feng Gu, Xiao-Lin Lin, Li Sun, Hong-Min Lu, Lei Tang & Yue Ma

    3. Department of Neuro-Oncology - Research Unit Number: 1002, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA

      Zhimin Lu

    Authors
    1. Ying-Chun Xu
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Qi Xu
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Jun-Jian Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Xiao-Feng Gu
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Xiao-Lin Lin
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Li Sun
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Hong-Min Lu
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Lei Tang
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Yue Ma
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Zhimin Lu
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Hong-Xia Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Hong-Xia Wang.

    Ethics declarations

    Conflict of interest

    None of the authors declare any conflicts of interest in relation to this submission.

    Ethical approval

    All procedures performed in studies involving human participants were in accordance with the ethical standards of Shanghai Renji Hospital, School of Medicine, Shanghai Jiao Tong University, and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

    Informed consent

    Informed consent was obtained from all individual participants included in the study.

    Additional information

    Ying-Chun Xu and Qi Xu have contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Xu, YC., Xu, Q., Li, JJ. et al. Chemotherapy with or without autologous cytokine-induced killer cell transfusion as the first-line treatment for stage IV gastrointestinal cancer: a phase II clinical trial. J Cancer Res Clin Oncol 142, 1315–1323 (2016). https://doi.org/10.1007/s00432-016-2127-2

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00432-016-2127-2

    Keywords

    Search

    Navigation