Skip to main content

Advertisement

SpringerLink
Log in

Selective effect of cytokine-induced killer cells on survival of patients with early-stage melanoma

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Adoptive immunotherapy using cytokine-induced killer (CIK) cells has shown potential antitumor ability against several kinds of cancers, including melanoma. However, little is known about the achievable outcome of CIK cells in melanoma patients at different pathological stages. Here we recruited 55 patients treated with conventional therapy plus CIK cells as the CIK group, and 49 patients treated with conventional therapy alone as the control group. The pathological characteristics were comparable between two groups, with a follow-up period up to 40 months. Survival data and immune responses were evaluated after CIK cell treatment. In this study, CIK cells were successfully generated from peripheral blood of melanoma patients after in vitro culture for 14 days. The cultured CIK cells not only produced high levels of pro-inflammatory cytokines upon in vitro stimulation but also efficiently killed human melanoma cell lines. No serious side events were observed in all patients treated with CIK cells. Furthermore, infusions of CIK cells improved the quality of life in some patients, including advanced cases. More importantly, the CIK group exhibited better survival rates compared to the control group among early-stage melanoma patients, in consistent with the increased frequency of peripheral CD4+ T cells. However, the patients with advanced-stage melanoma did not benefit from the CIK cell therapy in terms of survival rate. In conclusion, CIK cells combined with conventional treatments may prolong the survival of early-stage melanoma patients and improve the quality of life for some advanced cases in a safe way.

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

Abbreviations

AJCC:

American Joint Committee on Cancer

CFSE:

Carboxyfluorescein succinimidyl ester

CI:

Confidence interval

CIK:

Cytokine-induced killer

FACT-M:

Functional assessment of cancer therapy-melanoma

IFN-γ:

Interferon-γ

IL-2:

Interleukin-2

KPS:

Karnofsky performance status

PMA:

Phorbol 12-myristate 13-acetate

TIL:

Tumor-infiltrating lymphocytes

TNF-α:

Tumor necrosis factor-α

References

  1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136:E359–E386

    Article  CAS  PubMed  Google Scholar 

  2. Salama AK, de Rosa N, Scheri RP, Pruitt SK, Herndon JE 2nd, Marcello J, Tyler DS, Abernethy AP (2013) Hazard-rate analysis and patterns of recurrence in early stage melanoma: moving towards a rationally designed surveillance strategy. PLoS One 8:e57665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, Buzaid AC, Cochran AJ, Coit DG, Ding S, Eggermont AM, Flaherty KT, Gimotty PA, Kirkwood JM, McMasters KM, Mihm MC Jr, Morton DL, Ross MI, Sober AJ, Sondak VK (2009) Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 27:6199–6206

    Article  PubMed  PubMed Central  Google Scholar 

  4. Siegel R, Ma J, Zou Z, Jemal A (2014) Cancer statistics, 2014. CA Cancer J Clin 64:9–29

    Article  PubMed  Google Scholar 

  5. Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, Robbins PF, Huang J, Citrin DE, Leitman SF, Wunderlich J, Restifo NP, Thomasian A, Downey SG, Smith FO, Klapper J, Morton K, Laurencot C, White DE, Rosenberg SA (2008) Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol 26:5233–5239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, Citrin DE, Restifo NP, Robbins PF, Wunderlich JR, Morton KE, Laurencot CM, Steinberg SM, White DE, Dudley ME (2011) Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res 17:4550–4557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 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 

  8. Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, Shimada K, Sakamoto M, Hirohashi S, Ohashi Y, Kakizoe T (2000) Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet 356:802–807

    Article  CAS  PubMed  Google Scholar 

  9. Pan K, Guan XX, Li YQ, Zhao JJ, Li JJ, Qiu HJ, Weng DS, Wang QJ, Liu Q, Huang LX, He J, Chen SP, Ke ML, Zeng YX, Xia JC (2014) Clinical activity of adjuvant cytokine-induced killer cell immunotherapy in patients with post-mastectomy triple-negative breast cancer. Clin Cancer Res 20:3003–3011

    Article  CAS  PubMed  Google Scholar 

  10. 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 

  11. Gammaitoni L, Giraudo L, Leuci V, Todorovic M, Mesiano G, Picciotto F, Pisacane A, Zaccagna A, Volpe MG, Gallo S, Caravelli D, Giacone E, Venesio T, Balsamo A, Pignochino Y, Grignani G, Carnevale-Schianca F, Aglietta M, Sangiolo D (2013) Effective activity of cytokine-induced killer cells against autologous metastatic melanoma including cells with stemness features. Clin Cancer Res 19:4347–4358

    Article  CAS  PubMed  Google Scholar 

  12. Gleason MK, Lenvik TR, McCullar V, Felices M, O’Brien MS, Cooley SA, Verneris MR, Cichocki F, Holman CJ, Panoskaltsis-Mortari A, Niki T, Hirashima M, Blazar BR, Miller JS (2012) Tim-3 is an inducible human natural killer cell receptor that enhances interferon gamma production in response to galectin-9. Blood 119:3064–3072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yamashita M, Kitano S, Aikawa H, Kuchiba A, Hayashi M, Yamamoto N, Tamura K, Hamada A (2016) A novel method for evaluating antibody-dependent cell-mediated cytotoxicity by flowcytometry using cryopreserved human peripheral blood mononuclear cells. Sci Rep 6:19772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF, Milone MC, Levine BL, June CH (2013) Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368:1509–1518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Besser MJ, Shapira-Frommer R, Treves AJ, Zippel D, Itzhaki O, Hershkovitz L, Levy D, Kubi A, Hovav E, Chermoshniuk N, Shalmon B, Hardan I, Catane R, Markel G, Apter S, Ben-Nun A, Kuchuk I, Shimoni A, Nagler A, Schachter J (2010) Clinical responses in a phase II study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients. Clin Cancer Res 16:2646–2655

    Article  CAS  PubMed  Google Scholar 

  16. Schmidt TL, Negrin RS, Contag CH (2014) A killer choice for cancer immunotherapy. Immunol Res 58:300–306

    Article  CAS  PubMed  Google Scholar 

  17. Ahmed N, Brawley VS, Hegde M, Robertson C, Ghazi A, Gerken C, Liu E, Dakhova O, Ashoori A, Corder A, Gray T, Wu MF, Liu H, Hicks J, Rainusso N, Dotti G, Mei Z, Grilley B, Gee A, Rooney CM, Brenner MK, Heslop HE, Wels WS, Wang LL, Anderson P, Gottschalk S (2015) Human epidermal growth factor receptor 2 (HER2)-specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-positive sarcoma. J Clin Oncol 33:1688–1696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, Bagg A, Marcucci KT, Shen A, Gonzalez V, Ambrose D, Grupp SA, Chew A, Zheng Z, Milone MC, Levine BL, Melenhorst JJ, June CH (2015) Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med 7:303ra139

    Article  PubMed  Google Scholar 

  19. Foureau DM, Amin A, White RL, Anderson W, Jones CP, Sarantou T, McKillop IH, Salo JC (2014) Sequential immune monitoring in patients with melanoma and renal cell carcinoma treated with high-dose interleukin-2: immune patterns and correlation with outcome. Cancer Immunol Immunother 63:1329–1340

    Article  CAS  PubMed  Google Scholar 

  20. Passalacqua R, Buzio C, Buti S, Porta C, Labianca R, Pezzuolo D, Camisa R, Sabbatini R, Benecchi L, Messina C, Cengarle R, Vaglio A, Dalla Chiesa M, Tomasello G, Caminiti C (2010) Phase III, randomised, multicentre trial of maintenance immunotherapy with low-dose interleukin-2 and interferon-alpha for metastatic renal cell cancer. Cancer Immunol Immunother 59:553–561

    Article  CAS  PubMed  Google Scholar 

  21. Garcia-Martinez E, Gil GL, Benito AC, Gonzalez-Billalabeitia E, Conesa MA, Garcia Garcia T, Garcia-Garre E, Vicente V, Ayala de la Pena F (2014) Tumor-infiltrating immune cell profiles and their change after neoadjuvant chemotherapy predict response and prognosis of breast cancer. Breast Cancer Res 16:488

    Article  PubMed  PubMed Central  Google Scholar 

  22. Ruffell B, Au A, Rugo HS, Esserman LJ, Hwang ES, Coussens LM (2012) Leukocyte composition of human breast cancer. Proc Natl Acad Sci USA 109:2796–2801

    Article  CAS  PubMed  Google Scholar 

  23. Tai LH, de Souza CT, Belanger S, Ly L, Alkayyal AA, Zhang J, Rintoul JL, Ananth AA, Lam T, Breitbach CJ, Falls TJ, Kirn DH, Bell JC, Makrigiannis AP, Auer RA (2013) Preventing postoperative metastatic disease by inhibiting surgery-induced dysfunction in natural killer cells. Cancer Res 73:97–107

    Article  CAS  PubMed  Google Scholar 

  24. Scurr MJ, Brown CM, Costa Bento DF, Betts GJ, Rees BI, Hills RK, Gallimore A, Godkin A (2015) Assessing the prognostic value of preoperative carcinoembryonic antigen-specific T-cell responses in colorectal cancer. J Natl Cancer Inst 107:djv001. doi:10.1093/jnci/djv001

    Article  PubMed  PubMed Central  Google Scholar 

  25. Liu H, Zhang T, Ye J, Li H, Huang J, Li X, Wu B, Huang X, Hou J (2012) Tumor-infiltrating lymphocytes predict response to chemotherapy in patients with advance non-small cell lung cancer. Cancer Immunol Immunother 61:1849–1856

    Article  CAS  PubMed  Google Scholar 

  26. Zhao X, Zhang Z, Li H, Huang J, Yang S, Xie T, Huang L, Yue D, Xu L, Wang L, Zhang W, Zhang Y (2015) Cytokine induced killer cell-based immunotherapies in patients with different stages of renal cell carcinoma. Cancer Lett 362:192–198

    Article  CAS  PubMed  Google Scholar 

  27. Shi L, Zhou Q, Wu J, Ji M, Li G, Jiang J, Wu C (2012) Efficacy of adjuvant immunotherapy with cytokine-induced killer cells in patients with locally advanced gastric cancer. Cancer Immunol Immunother 61:2251–2259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhu Y, Zhang H, Li Y, Bai J, Liu L, Liu Y, Qu Y, Qu X (2013) Efficacy of postoperative adjuvant transfusion of cytokine-induced killer cells combined with chemotherapy in patients with colorectal cancer. Cancer Immunol Immunother 62:1629–1635

    Article  CAS  PubMed  Google Scholar 

  29. Saavedra D, Garcia B, Lorenzo-Luaces P, González A, Popa X, Fuentes KP, Mazorra Z, Crombet T, Neninger E, Lage A (2016) Biomarkers related to immunosenescence: relationships with therapy and survival in lung cancer patients. Cancer Immunol Immunother 65:37–45

    Article  CAS  PubMed  Google Scholar 

  30. Qiu H, Xiao-Jun W, Zhi-Wei Z, Gong C, Guo-Qiang W, Li-Yi Z, Yuan-Fang L, Rajiv-Prasad K (2009) The prognostic significance of peripheral T-lymphocyte subsets and natural killer cells in patients with colorectal cancer. Hepatogastroenterology 56:1310–1315

    PubMed  Google Scholar 

  31. Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, Royal RE, Topalian SL, Kammula US, Restifo NP, Zheng Z, Nahvi A, de Vries CR, Rogers-Freezer LJ, Mavroukakis SA, Rosenberg SA (2006) Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314:126–129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Saida Y, Watanabe S, Tanaka T, Baba J, Sato K, Shoji S, Igarashi N, Kondo R, Okajima M, Koshio J, Ichikawa K, Nozaki K, Ishikawa D, Koya T, Miura S, Tanaka J, Kagamu H, Yoshizawa H, Nakata K, Narita I (2015) Critical roles of chemoresistant effector and regulatory T cells in antitumor immunity after lymphodepleting chemotherapy. J Immunol 195:726–735

    Article  CAS  PubMed  Google Scholar 

  33. Kroemer G, Galluzzi L, Kepp O, Zitvogel L (2013) Immunogenic cell death in cancer therapy. Annu Rev Immunol 31:51–72

    Article  CAS  PubMed  Google Scholar 

  34. Rybojad P, Jablonka A, Wilczynska B, Tabarkiewicz J (2013) Surgery decreases number of cells secreting cytotoxic mediators and increases secretion of interleukin 10 in patients with lung cancer. Eur J Surg Oncol 39:1269–1277

    Article  CAS  PubMed  Google Scholar 

  35. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247

    Article  CAS  PubMed  Google Scholar 

  36. Fichtner S, Hose D, Engelhardt M, Meißner T, Neuber B, Krasniqi F, Raab M, Schönland S, Ho AD, Goldschmidt H, Hundemer M (2015) Association of antigen-specific T-cell responses with antigen expression and immunoparalysis in multiple myeloma. Clin Cancer Res 21:1712–1721

    Article  CAS  PubMed  Google Scholar 

  37. Joseph RW, Peddareddigari VR, Liu P, Miller PW, Overwijk WW, Bekele NB, Ross MI, Lee JE, Gershenwald JE, Lucci A, Prieto VG, McMannis JD, Papadopoulos N, Kim K, Homsi J, Bedikian A, Hwu WJ, Hwu P, Radvanyi LG (2011) Impact of clinical and pathologic features on tumor-infiltrating lymphocyte expansion from surgically excised melanoma metastases for adoptive T-cell therapy. Clin Cancer Res 17:4882–4891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Volonte A, Di Tomaso T, Spinelli M, Todaro M, Sanvito F, Albarello L, Bissolati M, Ghirardelli L, Orsenigo E, Ferrone S, Doglioni C, Stassi G, Dellabona P, Staudacher C, Parmiani G, Maccalli C (2014) Cancer-initiating cells from colorectal cancer patients escape from T cell-mediated immunosurveillance in vitro through membrane-bound IL-4. J Immunol 192:523–532

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Dr. Pierre van der Bruggen for LB2201 melanoma cells. This work was supported by National Natural Science Foundation of China (Nos. 81171986, 81261120402, 81271815) and Research Grant from the Institute of Science and Technology Department of Henan Province, China (No. 142300410387).

Author information

Author notes

    Authors and Affiliations

    1. Biotherapy Center, The First Affiliated Hospital, Zhengzhou University, Building #9, 1 Jianshe East Road, Zhengzhou, 450052, Henan, China

      Hong Li, Lan Huang, Zhen Zhang, Dongli Yue, Jianmin Huang, Xuan Zhao, Shuangning Yang & Yi Zhang

    2. Department of Plastic Surgery, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, Henan, China

      Linbo Liu & Ximei Wang

    3. Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan, 450052, China

      Wei He & Kun Fu

    4. Department of Vascular Surgery, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, Henan, China

      Xueli Guo

    5. Department of Ophthalmology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, Henan, China

      Yu Zhu

    6. Department of Oncology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan, 450052, China

      Liping Wang, Wenjie Dong, Yan Yan, Li Xu & Ming Gao

    Authors
    1. Hong Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Lan Huang
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Linbo Liu
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Ximei Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Zhen Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Dongli Yue
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Wei He
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Kun Fu
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Xueli Guo
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Jianmin Huang
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Xuan Zhao
      View author publications

      You can also search for this author in PubMed Google Scholar

    12. Yu Zhu
      View author publications

      You can also search for this author in PubMed Google Scholar

    13. Liping Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    14. Wenjie Dong
      View author publications

      You can also search for this author in PubMed Google Scholar

    15. Yan Yan
      View author publications

      You can also search for this author in PubMed Google Scholar

    16. Li Xu
      View author publications

      You can also search for this author in PubMed Google Scholar

    17. Ming Gao
      View author publications

      You can also search for this author in PubMed Google Scholar

    18. Shuangning Yang
      View author publications

      You can also search for this author in PubMed Google Scholar

    19. Yi Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Yi Zhang.

    Ethics declarations

    Conflict of interest

    The authors have no conflict of interest to disclose.

    Ethical approval

    The study has been approved by the ethics committee of the First Affiliated Hospital of Zhengzhou University, China (No. 2010-45; December 2010), and performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

    Additional information

    Hong Li and Lan Huang have contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary material 1 (PDF 465 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Li, H., Huang, L., Liu, L. et al. Selective effect of cytokine-induced killer cells on survival of patients with early-stage melanoma. Cancer Immunol Immunother 66, 299–308 (2017). https://doi.org/10.1007/s00262-016-1939-x

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00262-016-1939-x

    Keywords

    Search

    Navigation