{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T12:30:17Z","timestamp":1790512217239,"version":"4.1.0"},"reference-count":48,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2014,8,21]],"date-time":"2014-08-21T00:00:00Z","timestamp":1408579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cytokine-induced killer (CIK) cells are a heterogeneous population of immune effector cells that feature a mixed T- and Natural killer (NK) cell-like phenotype in their  terminally-differentiated CD3+CD56+ subset. The easy availability, high proliferation rate and widely major histocompatibility complex (MHC)-unrestricted antitumor activity of  CIK cells contribute to their particularly advantageous profile, making them an attractive approach for adoptive immunotherapy. CIK cells have shown considerable cytotoxicity against both solid tumors and hematological malignancies in vitro and in animal studies. Recently, initial clinical experiences demonstrated the feasibility and efficacy of CIK cell immunotherapy in cancer patients, even at advanced disease stages. Likewise, the clinical application of CIK cells in combination with standard therapeutic procedures revealed synergistic antitumor effects. In this report, we will focus our consideration on CIK cells in the treatment of hematological malignancies. We will give insight into the latest advances and future perspectives and outline the most prominent results obtained in 17 clinical studies. Overall, CIK cells demonstrated a crucial impact on the treatment of patients with hematological malignancies, as evidenced by complete remissions, prolonged survival durations and improved quality of life. However, up to now, the optimal application schedule eventually favoring their integration into clinical practice has still to be developed.<\/jats:p>","DOI":"10.3390\/ijms150814632","type":"journal-article","created":{"date-parts":[[2014,8,21]],"date-time":"2014-08-21T11:00:23Z","timestamp":1408618823000},"page":"14632-14648","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Adoptive Immunotherapy Strategies with Cytokine-Induced Killer (CIK) Cells in the Treatment of  Hematological Malignancies"],"prefix":"10.3390","volume":"15","author":[{"given":"Frederic","family":"Schmeel","sequence":"first","affiliation":[{"name":"Medizinische Klinik und Poliklinik III, Center for Integrated Oncology (CIO),  University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universit\u00e4t Bonn,  Sigmund-Freud-Stra\u00dfe 25, 53105 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonard","family":"Schmeel","sequence":"additional","affiliation":[{"name":"Medizinische Klinik und Poliklinik III, Center for Integrated Oncology (CIO),  University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universit\u00e4t Bonn,  Sigmund-Freud-Stra\u00dfe 25, 53105 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanna-Marie","family":"Gast","sequence":"additional","affiliation":[{"name":"Medizinische Klinik und Poliklinik III, Center for Integrated Oncology (CIO),  University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universit\u00e4t Bonn,  Sigmund-Freud-Stra\u00dfe 25, 53105 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingo","family":"Schmidt-Wolf","sequence":"additional","affiliation":[{"name":"Medizinische Klinik und Poliklinik III, Center for Integrated Oncology (CIO),  University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universit\u00e4t Bonn,  Sigmund-Freud-Stra\u00dfe 25, 53105 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2014,8,21]]},"reference":[{"key":"ref_1","first-page":"221","article-title":"General guidelines for the management of older patients with cancer","volume":"14","author":"Balducci","year":"2000","journal-title":"Oncology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1084\/jem.174.1.139","article-title":"Use of a SCID mouse\/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity","volume":"174","author":"Negrin","year":"1991","journal-title":"J. Exp. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.4049\/jimmunol.153.4.1687","article-title":"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","volume":"153","author":"Lu","year":"1994","journal-title":"J. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Schmeel, L.C., Schmeel, F.C., Coch, C., and Schmidt-Wolf, I.G. (Unpublished work, 2014). 25 years of CIK cells in cancer immunotherapy: Report of the International Registry on CIK cells (IRCC), Unpublished work.","DOI":"10.1007\/s00432-014-1864-3"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1007\/s00432-010-0887-7","article-title":"Clinical trials on CIK cells: First report of the international registry on CIK cells (IRCC)","volume":"137","author":"Hontscha","year":"2011","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_6","first-page":"905","article-title":"An update on new adoptive immunotherapy strategies for solid tumors with cytokine-induced killer cells","volume":"147","year":"2014","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"J\u00e4kel, C.E., Vogt, A., Gonzalez-Carmona, M.A., and Schmidt-Wolf, I.G. (2014). Clinical studies applying cytokine-induced killer cells for the treatment of gastrointestinal tumors. J. Immunol. Res., 897214.","DOI":"10.1155\/2014\/897214"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1200\/JCO.1987.5.1.150","article-title":"Suppressor cell function in solid tumor cancer patients","volume":"5","author":"Harris","year":"1987","journal-title":"J. Clin. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1006\/cimm.1996.0094","article-title":"Sensitivity of multidrug-resistant tumor cell lines to immunologic effector cells","volume":"169","author":"Lefterova","year":"1996","journal-title":"Cell. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1038\/sj.bjc.6690800","article-title":"Phase I clinical study applying autologous immunological effector cells transfected with the interleukin-2 gene in patients with metastatic renal cancer, colorectal cancer and lymphoma","volume":"81","author":"Finke","year":"1999","journal-title":"Br. J. Cancer"},{"key":"ref_11","first-page":"1673","article-title":"Phenotypic characterization and identification of effector cells involved in tumor cell recognition of cytokine-induced killer cells","volume":"21","author":"Lefterova","year":"1993","journal-title":"Exp. Hematol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1093\/intimm\/dxn042","article-title":"Alloreactivity and anti-tumor activity segregate within two distinct subsets of cytokine-induced killer (CIK) cells: Implications for their infusion across major HLA barriers","volume":"20","author":"Sangiolo","year":"2008","journal-title":"Int. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3065","DOI":"10.1182\/blood-2003-06-2125","article-title":"Role of NKG2D signalling in the cytotoxicity of activated and expanded CD8+ T cells","volume":"103","author":"Verneris","year":"2004","journal-title":"Blood"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6879","DOI":"10.1073\/pnas.96.12.6879","article-title":"Broad tumor-associated expression and recognition by tumor-derived \u03b3\u03b4 T cells of MICA and MICB","volume":"96","author":"Groh","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1182\/blood-2003-01-0019","article-title":"Functional expression and release of ligands for the activating immunoreceptor NKG2D in leukemia","volume":"102","author":"Salih","year":"2003","journal-title":"Blood"},{"key":"ref_16","first-page":"6178","article-title":"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","volume":"62","author":"Pende","year":"2002","journal-title":"Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3301","DOI":"10.1182\/blood-2011-02-336321","article-title":"Dual-functional capability of CD3+CD56+ CIK cells, a T-cell subset that acquires NK function and retains TCR-mediated specific cytotoxicity","volume":"118","author":"Pievani","year":"2011","journal-title":"Blood"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6503","DOI":"10.1158\/1078-0432.CCR-09-1605","article-title":"T cell-based immunotherapy of metastatic renal cell carcinoma: Modest success and future perspective","volume":"15","author":"Shablak","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1007\/s10875-007-9076-0","article-title":"CD4+CD25+ regulatory T cells decreased the antitumor activity of cytokine-induced killer (CIK) cells of lung cancer patients","volume":"27","author":"Li","year":"2007","journal-title":"J. Clin. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1097\/CJI.0b013e318255ada3","article-title":"Interleukin-6 inhibits regulatory T cells and improves the proliferation and cytotoxic activity of cytokine-induced killer cells","volume":"35","author":"Lin","year":"2012","journal-title":"J. Immunother."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5649","DOI":"10.4049\/jimmunol.1201286","article-title":"IL-7 abrogates suppressive activity of human CD4+CD25+FOXP3+ regulatory T cells and allows expansion of alloreactive and autoreactive T cells","volume":"189","author":"Heninger","year":"2012","journal-title":"J. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/sj.gt.3300560","article-title":"Increase of proliferation rate and enhancement of antitumor cytotoxicity of expanded human CD3+ CD56+ immunologic effector cells by receptor-mediated transfection with the interleukin-7 gene","volume":"5","author":"Finke","year":"1998","journal-title":"Gene Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"91","DOI":"10.3109\/14653249.2011.613931","article-title":"The cytotoxic potential of interleukin-15-stimulated cytokine-induced killer cells against leukemia cells","volume":"14","author":"Rettinger","year":"2012","journal-title":"Cytotherapy"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1097\/CJI.0000000000000001","article-title":"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","volume":"36","author":"Tao","year":"2013","journal-title":"J. Immunother."},{"key":"ref_25","first-page":"823","article-title":"Effects of humanized interleukin 21 on anti-leukemic activity of cytokine induced killer cells and the mechanism","volume":"33","author":"Zhao","year":"2012","journal-title":"Zhonghua Xue Ye Xue Za Zhi"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1007\/s00262-004-0554-4","article-title":"Dendritic cells reduce number and function of CD4+CD25+ cells in cytokine-induced killer cells derived from patients with pancreatic carcinoma","volume":"53","author":"Schmidt","year":"2004","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1097\/00002371-200111000-00007","article-title":"Interactions between dendritic cells and cytokine-induced killer cells lead to an activation of both populations","volume":"24","author":"Ziske","year":"2001","journal-title":"J. Immunother."},{"key":"ref_28","first-page":"3134","article-title":"Dendritic cells reduce the number and function of CD4+CD25+ cells in cytokine-induced killer cells","volume":"85","author":"Li","year":"2005","journal-title":"Zhonghua Yi Xue Za Zhi"},{"key":"ref_29","first-page":"39","article-title":"The cytotoxicity of CIK\/NK cells stimulated by K562-DC fusion vaccines in NOD\/SCID mice model for human erythroleukemia","volume":"29","author":"Li","year":"2008","journal-title":"Zhonghua Xue Ye Xue Za Zhi"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1016\/j.leukres.2011.05.005","article-title":"Combining cytokine-induced killer cells with vaccination in cancer immunotherapy: More than one plus one?","volume":"35","author":"Thanendrarajan","year":"2011","journal-title":"Leuk. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/S1083-8791(01)70014-6","article-title":"Engineering hematopoietic grafts: Purified allogeneic hematopoietic stem cells plus expanded CD8+ NK-T cells in the treatment of lymphoma","volume":"7","author":"Verneris","year":"2001","journal-title":"Biol. Blood Marrow Transplant."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2923","DOI":"10.1182\/blood.V97.10.2923","article-title":"Expansion of cytolytic CD8(+) natural killer T cells with limited capacity for graft-versus-host disease induction due to interferon gamma production","volume":"97","author":"Baker","year":"2001","journal-title":"Blood"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.bbmt.2004.11.019","article-title":"A phase I trial of autologous cytokine-induced killer cells for the treatment of relapsed Hodgkin disease and non-Hodgkin lymphoma","volume":"11","author":"Leemhuis","year":"2005","journal-title":"Biol. Blood Marrow Transplant."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1002\/hon.886","article-title":"Immunotherapy with cytokine induced killer cells in solid and hematopoietic tumours: A pilot clinical trial","volume":"27","author":"Olioso","year":"2009","journal-title":"Hematol. Oncol."},{"key":"ref_35","first-page":"1244","article-title":"Clinical study of autologous cytokine induced killer cells combined with IL-2 for therapy of elderly patients with B-cell malignant lymphoma","volume":"18","author":"Yang","year":"2010","journal-title":"Zhongguo Shi Yan Xue Ye Xue Za Zhi"},{"key":"ref_36","first-page":"787","article-title":"Clinical study of autologous cytokine induced killer cell infusion treating for elderly patients with myelodysplastic syndrome","volume":"19","author":"Liu","year":"2011","journal-title":"Zhongguo Shi Yan Xue Ye Xue Za Zhi"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1002\/hon.1012","article-title":"Repeated transfusions of autologous cytokine-induced killer cells for treatment of haematological malignancies in elderly patients: A pilot clinical trial","volume":"30","author":"Yang","year":"2012","journal-title":"Hematol. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1007\/s12013-011-9273-6","article-title":"Clinical study of autologous cytokine-induced killer cells for the treatment of elderly patients with diffuse large B-cell lymphoma","volume":"62","author":"Lu","year":"2012","journal-title":"Cell Biochem. Biophys."},{"key":"ref_39","first-page":"564","article-title":"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","volume":"20","author":"Cai","year":"2012","journal-title":"Zhongguo Shi Yan Xue Ye Xue Za Zhi"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.jcyt.2013.11.001","article-title":"Treatment of multiple solitary plasmacytomas with cytokine-induced killer cells","volume":"16","author":"Yang","year":"2014","journal-title":"Cytotherapy"},{"key":"ref_41","first-page":"58","article-title":"Clinical study of autologous cytokine induced killer cells combined with chemotherapy for elderly patients with acute myeloid leukemia","volume":"22","author":"Yang","year":"2014","journal-title":"Zhongguo Shi Yan Xue Ye Xue Za Zhi"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"952","DOI":"10.3324\/haematol.11132","article-title":"Repeated infusions of donor-derived cytokine-induced killer cells in patients relapsing after allogeneic stem cell transplantation: A phase I study","volume":"92","author":"Introna","year":"2007","journal-title":"Haematologica"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1679","DOI":"10.1016\/j.bbmt.2011.05.012","article-title":"Adoptive immunotherapy with cytokine-induced killer cells for patients with relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation","volume":"17","author":"Laport","year":"2011","journal-title":"Biol. Blood Marrow Transplant."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1016\/j.bbmt.2010.05.015","article-title":"Feasibility and safety of adoptive immunotherapy with CIK cells after cord blood transplantation","volume":"16","author":"Introna","year":"2010","journal-title":"Biol. Blood Marrow Transplant."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1038\/bmt.2011.202","article-title":"The anti-tumour activity of allogeneic cytokine-induced killer cells in patients who relapse after allogeneic transplant for haematological malignancies","volume":"47","author":"Linn","year":"2012","journal-title":"Bone Marrow Transplant."},{"key":"ref_46","first-page":"198","article-title":"The efficacy of chemotherapy in combination with auto-cytokine-induced killer cells in acute leukemia","volume":"44","author":"Jiang","year":"2005","journal-title":"Zhonghua Nei Ke Za Zhi"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"851","DOI":"10.3109\/14653249.2012.694419","article-title":"A phase I\/II clinical trial of autologous cytokine-induced killer cells as adjuvant immunotherapy for acute and chronic myeloid leukemia in clinical remission","volume":"14","author":"Linn","year":"2012","journal-title":"Cytotherapy"},{"key":"ref_48","first-page":"1000","article-title":"Clinical efficacy of immunotherapy of dendritic cell and cytokine-induced killer cell combined with chemotherapy for treatment of multiple myeloma","volume":"33","author":"Zhong","year":"2012","journal-title":"Zhonghua Xue Ye Xue Za Zhi"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/15\/8\/14632\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:15:02Z","timestamp":1760217302000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/15\/8\/14632"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,8,21]]},"references-count":48,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2014,8]]}},"alternative-id":["ijms150814632"],"URL":"https:\/\/doi.org\/10.3390\/ijms150814632","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,8,21]]}}}