Cytokine-induced killer (CIK) cells in cancer immunotherapy: report of the international registry on CIK cells (IRCC)

Abstract

Purpose

Cytokine-induced killer (CIK) cells represent an exceptional T cell population uniting a T cell and natural killer cell like phenotype in their terminally differentiated CD3+CD56+ subset, which features non-MHC-restricted tumor-killing activity. CIK cells are expandable from peripheral blood mononuclear cells and mature following the addition of certain cytokines. CIK cells have provided encouraging results in initial clinical studies and revealed synergistic antitumor effects when combined with standard therapeutic procedures.

Methods

Therefore, we established the international registry on CIK cells in order to collect and evaluate data about clinical trials using CIK cells for the treatment of cancer patients. Moreover, our registry is expected to set new standards on the reporting of results from clinical trials using CIK cells. Clinical responses, overall survival (OS), adverse reactions and immunologic effects were analyzed in 45 studies present in our database. These studies investigated 22 different tumor entities altogether enrolling 2,729 patients.

Results

A mean response rate of 39 % and significantly increased OS, accompanied by an improved quality of life, were reported. Interestingly, side effects of CIK cell treatment were minor. Mild fevers, chills, headache and fatigue were, however, seen regularly after CIK cell infusion. Moreover, CIK cells revealed numerous immunologic effects such as changes in T cell subsets, tumor markers, cytokine secretion and HBV viral load.

Conclusion

Due to their easy availability and potent antitumor activity, CIK cells emerged as a promising immunotherapy approach in oncology and may gain major importance on the prognosis of cancer.

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

References

  1. Cai LL, Yang Y, Yang B et al (2012) Short-term curative efficacy of autologous cytokine induced killer cells combined with low-dose IL-2 regimen containing immune enhancement by thymic peptide in elderly patients with B-cell chronic lymphocytic leukemia. Zhongguo Shi Yan Xue Ye Xue Za Zhi 20:564–570

    CAS  PubMed  Google Scholar 

  2. Franceschetti M, Pievani A, Borleri G et al (2009) Cytokine-induced killer cells are terminally differentiated activated CD8 cytotoxic T-EMRA lymphocytes. Exp Hematol 37:616–628

    Article  CAS  PubMed  Google Scholar 

  3. Gao D, Li C, Xie X et al (2014) Autologous tumor lysate-pulsed dendritic cell immunotherapy with cytokine-induced killer cells improves survival in gastric and colorectal cancer patients. PLoS One 9:e93886

    Article  PubMed Central  PubMed  Google Scholar 

  4. Groh V, Rhinehart R, Secrist H, Bauer S, Grabstein KH, Spies T (1999) Broad tumor-associated expression and recognition by tumor-derived γδ T cells of MICA and MICB. PNAS 96:6879–6884

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Hao MZ, Lin HL, Chen Q, Ye YB, Chen QZ, Chen MS (2010) Efficacy of transcatheter arterial chemoembolization combined with cytokine-induced killer cell therapy on hepatocellular carcinoma: a comparative study. Chin J Cancer 29:172–177

    Article  PubMed  Google Scholar 

  6. 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 137:305–310

    Article  CAS  PubMed  Google Scholar 

  7. Huang HQ, Cai QC, Shi YX et al (2006) Preliminary assessment of immune reconstitution after autologous peripheral hematopoietic stem cell transplantation (AHSCT). Ai Zheng 25:1023–1028

    CAS  PubMed  Google Scholar 

  8. 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 

  9. Introna M, Borleri G, Conti E et al (2007) Repeated infusions of donor-derived cytokine-induced killer cells in patients relapsing after allogeneic stem cell transplantation: a phase I study. Haematologica 92:952–959

    Article  PubMed  Google Scholar 

  10. Introna M, Pievani A, Borleri G et al (2010) Feasibility and safety of adoptive immunotherapy with CIK cells after cord blood transplantation. Biol Blood Marrow Transplant 16:1603–1607

    Article  PubMed  Google Scholar 

  11. Jiang H, Liu KY, Tong CR, Jiang B, Lu DP (2005) The efficacy of chemotherapy in combination with auto-cytokine-induced killer cells in acute leukemia. Zhonghua Nei Ke Za Zhi 44:198–201

    PubMed  Google Scholar 

  12. Jiang J, Xu N, Wu C et al (2006) Treatment of advanced gastric cancer by chemotherapy combined with autologous cytokine-induced killer cells. Anticancer Res 26:2237–2242

    CAS  PubMed  Google Scholar 

  13. Kilinc MO, Gu T, Harden JL, Virtuoso LP, Egilmez NK (2009) Central role of tumor-associated CD8+ T effector/memory cells in restoring systemic antitumor immunity. J Immunol 182:4217–4225

    Article  CAS  PubMed  Google Scholar 

  14. Kim HM, Kang JS, Lim J et al (2007) Inhibition of human ovarian tumor growth by cytokine-induced killer cells. Arch Pharm Res 30:1464–1470

    Article  CAS  PubMed  Google Scholar 

  15. Laport GG, Sheehan K, Baker J et al (2011) Adoptive immunotherapy with cytokine-induced killer cells for patients with relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 17:1679–1687

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. 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 

  17. Li R, Wang C, Liu L et al (2012) Autologous cytokine-induced killer cell immunotherapy in lung cancer: a phase II clinical study. Cancer Immunol Immunother 61:2125–2133

    Article  CAS  PubMed  Google Scholar 

  18. Linn YC, Niam M, Chu S et al (2012a) The anti-tumour activity of allogeneic cytokine-induced killer cells in patients who relapse after allogeneic transplant for haematological malignancies. Bone Marrow Transplant 47:957–966

    Article  CAS  PubMed  Google Scholar 

  19. Linn YC, Yong HX, Niam M et al (2012b) A phase I/II clinical trial of autologous cytokine-induced killer cells as adjuvant immunotherapy for acute and chronic myeloid leukemia in clinical remission. Cytotherapy 14:851–859

    Article  CAS  PubMed  Google Scholar 

  20. Liu Y, Bao EN, Yang B et al (2011) Clinical study of autologous cytokine induced killer cell infusion treating for elderly patients with myelodysplastic syndrome. Zhongguo Shi Yan Xue Ye Xue Za Zhi 19:787–792

    PubMed  Google Scholar 

  21. Liu L, Zhang W, Qi X et al (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 

  22. Liu H, Song J, Yang Z, Zhang X (2013) Effects of cytokine-induced killer cell treatment combined with FOLFOX4 on the recurrence and survival rates for gastric cancer following surgery. Exp Ther Med 6:953–956

    PubMed Central  CAS  PubMed  Google Scholar 

  23. Liu J, Li H, Cao S et al (2014) Maintenance therapy with autologous cytokine-induced killer cells in patients with advanced epithelial ovarian cancer after first-line treatment. J Immunother 37:115–122

    Article  CAS  PubMed  Google Scholar 

  24. Lopez RD, Waller EK, Lu PH, Negrin RS (2000) CD58/LFA-3 and IL-12 provided by activated monocytes are critical in the in vitro expansion of CD56+ T cells. Cancer Immunol Immunother 49:629–640

    Article  Google Scholar 

  25. Lu PH, Negrin RS (1994) A novel population of expanded human CD3+CD56+ cells derived from T cells with potent in vivo antitumor activity in mice with severe combined immunodeficiency. J Immunol 153:1687–1696

    CAS  PubMed  Google Scholar 

  26. Lu XC, Yang B, Yu RL et al (2012) Clinical study of autologous cytokine-induced killer cells for the treatment of elderly patients with diffuse large B-cell lymphoma. Cell Biochem Biophys 62:257–265

    Article  CAS  PubMed  Google Scholar 

  27. Niu Q, Wang W, Li Y et al (2011) Cord blood-derived cytokine-induced killer cells biotherapy combined with second-line chemotherapy in the treatment of advanced solid malignancies. Int Immunopharmacol 11:449–456

    Article  CAS  PubMed  Google Scholar 

  28. Ochoa AC, Gromo G, Alter BJ, Sondel PM, Bach FH (1987) Long-term growth of lymphokine-activated killer (LAK) cells: role of anti-CD3, beta-IL 1, interferon-gamma and -beta. J Immunol 138:2728–2733

    CAS  PubMed  Google Scholar 

  29. Oleinika K, Nibbs RJ, Graham GJ, Fraser AR (2013) Suppression, subversion and escape: the role of regulatory T cells in cancer progression. Clin Exp Immunol 171:36–45

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Olioso P, Giancola R, Di Riti M, Contento A, Accorsi P, Iacone A (2009) Immunotherapy with cytokine induced killer cells in solid and hematopoietic tumours: a pilot clinical trial. Hematol Oncol 27:130–139

    Article  CAS  PubMed  Google Scholar 

  31. Pan K, Li YQ, Wang W et al (2013) The efficacy of cytokine-induced killer cell infusion as an adjuvant therapy for postoperative hepatocellular carcinoma patients. Ann Surg Oncol 20:4305–4311

    Article  PubMed  Google Scholar 

  32. Pan K, Guan XX, Li YQ et al (2014) Clinical activity of adjuvant cytokine-induced killer cell immunotherapy in patients with post-mastectomy triple-negative breast cancer. Clin Cancer Res. doi:10.1158/1078-0432.CCR-14-0082

    PubMed Central  Google Scholar 

  33. Pende D, Rivera P, Marcenaro S et al (2002) Major histocompatibility complex class I-related chain A and UL16-binding protein expression on tumor cell lines of different histotypes: analysis of tumor susceptibility to NKG2D-dependent natural killer cell cytotoxicity. Cancer Res 62:6178–6186

    CAS  PubMed  Google Scholar 

  34. Qiu Y, Xu MB, Yun MM et al (2011) Hepatocellular carcinoma-specific immunotherapy with synthesized α1,3- galactosyl epitope-pulsed dendritic cells and cytokine-induced killer cells. World J Gastroenterol 17:5260–5266

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Rettinger E, Kuçi S, Naumann I, Becker P et al (2012) The cytotoxic potential of interleukin-15-stimulated cytokine-induced killer cells against leukemia cells. Cytotherapy 14:91–103

    Article  CAS  PubMed  Google Scholar 

  36. Robinson E, Segal R, Struminger L, Faraggi D, El’ad-Yarum R, Mekori T (1999) Lymphocyte subpopulations in patients with multiple primary tumors. Cancer 85:2073–2076

    Article  CAS  PubMed  Google Scholar 

  37. Salih HR, Antropius H, Gieseke F et al (2003) Functional expression and release of ligands for the activating immunoreceptor NKG2D in leukemia. Blood 102:1389–1396  

    Article  CAS  PubMed  Google Scholar 

  38. Schmeel FC, Schmeel LC, Gast SM, Schmidt-Wolf IG (2014) Adoptive immunotherapy strategies with cytokine-induced killer (CIK) cells in the treatment of hematological malignancies. Int J Mol Sci 15:14632–14648

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Schmidt-Wolf IGH, 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 

  40. Schmidt-Wolf IGH, Lefterova P, Mehta BA et al (1993) Phenotypic characterization and identification of effector cells involved in tumor cell recognition of cytokine-induced killer cells. Exp Hematol 21:1673–1679

    CAS  PubMed  Google Scholar 

  41. Schmidt-Wolf IGH, Lefterova P, Johnston V, Huhn D, Blume KG, Negrin RS (1994) Propagation of large numbers of T cells with natural killer cell markers. Br J Haematol 87:453–458

    Article  CAS  PubMed  Google Scholar 

  42. 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 81:1009–1016

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Schroder K, Hertzog PJ, Ravasi T, Hume DA (2004) Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol 75:163–189

    Article  CAS  PubMed  Google Scholar 

  44. Shi M, Zhang B, Tang ZR et al (2004) Autologous cytokine-induced killer cell therapy in clinical trial phase I is safe in patients with primary hepatocellular carcinoma. World J Gastroenterol 10:1146–1151

    CAS  PubMed  Google Scholar 

  45. Shi L, Zhou Q, Wu J et al (2012a) Efficacy of adjuvant immunotherapy with cytokine-induced killer cells in patients with locally advanced gastric cancer. Cancer Immunol Immunother 61:2251–2259

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Shi SB, Ma TH, Li CH, Tang XY (2012b) Effect of maintenance therapy with dendritic cells: cytokine-induced killer cells in patients with advanced non-small cell lung cancer. Tumori 98:314–319

    CAS  PubMed  Google Scholar 

  47. Su X, Zhang L, Jin L et al (2010) Immunotherapy with cytokine-induced killer cells in metastatic renal cell carcinoma. Cancer Biother Radiopharm 25:465–470

    Article  CAS  PubMed  Google Scholar 

  48. Tao Q, Chen T, Tao L et al (2013) IL-15 improves the cytotoxicity of cytokine-induced killer cells against leukemia cells by upregulating CD3+CD56+ cells and downregulating regulatory T cells as well as IL-35. J Immunother 36:462–467

    Article  CAS  PubMed  Google Scholar 

  49. Thanendrarajan S, Nowak M, Abken H, Schmidt-Wolf IG (2011) Combining cytokine-induced killer cells with vaccination in cancer immunotherapy: more than one plus one? Leuk Res 35:1136–1142

    Article  CAS  PubMed  Google Scholar 

  50. Thanendrarajan S, Kim Y, Schmidt-Wolf IGH (2012) New adoptive immunotherapy strategies for solid tumours with CIK cells. Expert Opin Biol Ther 12:565–572

    Article  CAS  PubMed  Google Scholar 

  51. Verneris MR, Ito M, Baker J, Arshi A, Negrin RS, Shizuru JA (2001) Engineering hematopoietic grafts: purified allogeneic hematopoietic stem cells plus expanded CD8+ NK-T cells in the treatment of lymphoma. Biol Blood Marrow Transplant 7:532–542

    Article  CAS  PubMed  Google Scholar 

  52. Verneris MR, Karami M, Baker J, Jayaswal A, Negrin RS (2004) Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8 + T cells. Blood 103:3065–3072

    Article  CAS  PubMed  Google Scholar 

  53. Von Roenn J, Harris JE, Braun DP (1987) Suppressor cell function in solid tumor cancer patients. J Clin Oncol 5:150–159

    Google Scholar 

  54. Wang Y, Bo J, Dai HR et al (2013) CIK cells from recurrent or refractory AML patients can be efficiently expanded in vitro and used for reduction of leukemic blasts in vivo. Exp Hematol 41:241–252

    Article  CAS  PubMed  Google Scholar 

  55. Wang Z, Zhang Y, Liu Y et al (2014) Association of myeloid-derived suppressor cells and efficacy of cytokine-induced killer cell immunotherapy in metastatic renal cell carcinoma patients. J Immunother 37:43–50

    Article  CAS  PubMed  Google Scholar 

  56. Wei C, Wang W, Pang W et al (2014) The CIK cells stimulated with combination of IL-2 and IL-15 provide an improved cytotoxic capacity against human lung adenocarcinoma. Tumour Biol 35:1997–2007

    Article  CAS  PubMed  Google Scholar 

  57. Yang B, Lu XC, Zhu HL et al (2010) Clinical study of autologous cytokine induced killer cells combined with IL-2 for therapy of elderly patients with B-cell malignant lymphoma. Zhongguo Shi Yan Xue Ye Xue Za Zhi 18:1244–1249

    CAS  PubMed  Google Scholar 

  58. Yang B, Lu XC, Yu RL et al (2012) Repeated transfusions of autologous cytokine-induced killer cells for treatment of haematological malignancies in elderly patients: a pilot clinical trial. Hematol Oncol 30:115–122

    Article  CAS  PubMed  Google Scholar 

  59. Yang L, Ren B, Li H et al (2013) Enhanced antitumor effects of DC-activated CIKs to chemotherapy treatment in a single cohort of advanced non-small-cell lung cancer patients. Cancer Immunol Immunother 62:65–73

    Article  PubMed  Google Scholar 

  60. Yang B, Wang J, Cai LL et al (2014a) Treatment of multiple solitary plasmacytomas with cytokine-induced killer cells. Cytotherapy 16:278–284

    Article  CAS  PubMed  Google Scholar 

  61. Yang Y, Yang B, Cai LL et al (2014b) Clinical study of autologous cytokine induced killer cells combined with chemotherapy for elderly patients with acute myeloid leukemia. Zhongguo Shi Yan Xue Ye Xue Za Zhi 22:58–63

    PubMed  Google Scholar 

  62. Yu X, Zhao H, Liu L et al (2014) A randomized phase II study of autologous cytokine-induced killer cells in treatment of hepatocellular carcinoma. J Clin Immunol 34:194–203

    Article  CAS  PubMed  Google Scholar 

  63. Zhan HL, Gao X, Pu XY et al (2012) A randomized controlled trial of postoperative tumor lysate-pulsed dendritic cells and cytokine-induced killer cells immunotherapy in patients with localized and locally advanced renal cell carcinoma. Chin Med J 125:3771–3777

    PubMed  Google Scholar 

  64. Zhang J, Zhu L, Wei J et al (2012) The effects of cytokine-induced killer cells for the treatment of patients with solid tumors: a clinical retrospective study. J Cancer Res Clin Oncol 138:1057–1062

    Article  CAS  PubMed  Google Scholar 

  65. Zhao H, Fan Y, Li H et al (2013) Immunotherapy with cytokine-induced killer cells as an adjuvant treatment for advanced gastric carcinoma: a retrospective study of 165 patients. Cancer Biother Radiopharm 28:303–309

    Article  CAS  PubMed  Google Scholar 

  66. Zhong R, Teng J, Han B, Zhong H (2011) Dendritic cells combining with cytokine-induced killer cells synergize chemotherapy in patients with late-stage non-small cell lung cancer. Cancer Immunol Immunother 60:1497–1502

    Article  CAS  PubMed  Google Scholar 

  67. Zhong GC, Yan B, Sun Y et al (2012) Clinical efficacy of immunotherapy of dendritic cell and cytokine-induced killer cell combined with chemotherapy for treatment of multiple myeloma. Zhonghua Xue Ye Xue Za Zhi 33:1000–1003

    CAS  PubMed  Google Scholar 

  68. Zhou QM, Wu PH, Zhao M et al (2006) Short-term curative efficacy of cytokine-induced killer cells combined micro-invasive treatments on hepatocellular carcinoma. Ai Zheng 25:1414–1418

    PubMed  Google Scholar 

  69. Zhou X, Zhu J, Sun H, Shao L, Xu M, Guo H (2013) Family haploidentical donor-derived cytokine-induced killer cell biotherapy combined with bortezomib in two patients with relapsed multiple myeloma in a non-allogeneic transplant setting. Leuk Lymphoma 54:209–211

    Article  CAS  PubMed  Google Scholar 

  70. Zhu Y, Zhang H, Li Y et al (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 

Download references

Conflict of interest

There exists no financial or other relationship that might lead to a conflict of interest.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Ingo G. H. Schmidt-Wolf.

Additional information

Leonard Christopher Schmeel and Frederic Carsten Schmeel have contributed equally to this work.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Schmeel, L.C., Schmeel, F.C., Coch, C. et al. Cytokine-induced killer (CIK) cells in cancer immunotherapy: report of the international registry on CIK cells (IRCC). J Cancer Res Clin Oncol 141, 839–849 (2015). https://doi.org/10.1007/s00432-014-1864-3

Download citation

Keywords

  • Cytokine-induced killer cells
  • CIK
  • Clinical trials
  • Immunotherapy
  • International registry
  • Cancer treatment