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Frontiers of Medicine

Front Med    2012, Vol. 6 Issue (1) : 56-66     DOI: 10.1007/s11684-012-0177-7
Natural killer cell lines in tumor immunotherapy
Min Cheng1, Jian Zhang2, Wen Jiang2, Yongyan Chen1, Zhigang Tian1()
1. Institute of Immunology, Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China; 2. Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China
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Natural killer (NK) cells are considered to be critical players in anticancer immunity. However, cancers are able to develop mechanisms to escape NK cell attack or to induce defective NK cells. Current NK cell-based cancer immunotherapy is aimed at overcoming NK cell paralysis through several potential approaches, including activating autologous NK cells, expanding allogeneic NK cells, usage of stable allogeneic NK cell lines and genetically modifying fresh NK cells or NK cell lines. The stable allogeneic NK cell line approach is more practical for quality-control and large-scale production. Additionally, genetically modifying NK cell lines by increasing their expression of cytokines and engineering chimeric tumor antigen receptors could improve their specificity and cytotoxicity. In this review, NK cells in tumor immunotherapy are discussed, and a list of therapeutic NK cell lines currently undergoing preclinical and clinical trials of several kinds of tumors are reviewed.

Keywords natural killer cell      natural killer cell line      tumor immunotherapy      genetic modification     
Corresponding Authors: Tian Zhigang,   
Issue Date: 05 March 2012
 Cite this article:   
Min Cheng,Jian Zhang,Wen Jiang, et al. Natural killer cell lines in tumor immunotherapy[J]. Front Med, 2012, 6(1): 56-66.
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Min Cheng
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Yongyan Chen
Zhigang Tian
NK cell lineInstrumentCulture mediumCytokine in mediumStarting cell numberCulture time (days)Harvested cell numberViability
NK-921-L Vuelife culture bag [74,105]X-Vivo 10 serum-free media amino acids and 2.5% human AB plasmaIL-2 (500IU/ml)(2.5 × 105/ml) × 25ml/bag15-17> 1 × 109/bag≥ 80%
Controlled stirred bioreactor [56]Optimized clinical-grade mediaIL-2 (100-500IU/ml)1 × 107/bioreactor11-16> 1010/bioreactor> 95%
NKG* [59]WAVE Bioreactorα-MEM medium 10% fetal bovine serum + 10% horse serumIL-2 (100IU/ml)(1 × 105/ml) × 200ml/bag12-14> 1010/bag> 90%
NKL [63,81]Plates or FlasksRPMI 1640 medium 10% heat-inactivated human AB serumIL-2 (100 pM)
KHYG-1 [67,78,79]Plates or FlasksRPMI 1640 medium 2% human low-toxicity AB serumIL-2 (450 IU/ml)
Tab.1  Large-scale expansion of NK cell lines for clinical application
NK cell lineTumor cells killed by NK cell lines in vitroExperimental therapyClinical trials
Animal modelTreatmentEffectsPatientsTreatmentEffects
NK-92Daudi, K562, OKM-2T, KG1, HL60, Raji, NALM6, CEM-S, CEM-T, primary patient-derived leukemic cells [62,68,71-73,106,107].malignant melanoma in a SCID mouse model [69]5 × 106 or 1 × 107 NK-92 cells i.v.,one doseprolonged survival significantly; reduced tumor growthPhase I/II [56] 4 sarcoma, 2 medulloblastoma, 1 PNET, 1 B cell ALL1-3 × 109 NK-92 cells/m2 body surface; i.v. two doseswithout any significant side effects; no conclusions as to the efficacy can be drawn
xenografted primary human leukemia in SCID mouse model [68]2 × 107 NK-92 cells i.p.,one dose or five doses every other dayprolonged survival significantly; lead to cure in some micePhase I [74] 11 advanced renal cell cancer, 1 melanoma1 × 108 or 3 × 108 or 1 × 109 or 3 × 109 NK-92 cells/m2 body surface; i.v. three doses (3 patients/group)no severe hemodynamic or hematologic toxicities
Phase I (a)Acute Myeloid Leukemia1 × 109 or 3 × 109 or 5 × 109 NK-92 cells/m2 body surface; i.v. two dosesstatus: suspended
Phase I (b) Leukemia, Lymphoma, Myeloma, Hodgkin's Disease1 × 109 or 3 × 109 or 5 × 109 NK-92 cells/m2 body surface; i.v. on days 1, 3 and 5 of each cycle; 6 cycles monthlystatus: suspended
NKG [59]Ho8910, K562, SGC7901, A549, Hep2, HepG2, HCT116, SBKR3, LoVo, and DaudiXenografted human ovarian cancer in nude mouse model1 × 107 NKG cells i.p., one dose or 6.67 × 105 NKG cell/g bodyweight i.p., nine dosesprolonged survival significantly; inhibited the tumor growth; decreased mortality rateNo
NKLK562, Daudi, and U937 [81,82]NoNo
KHYG-1K562, Daudi, Raji, HL60, EM2 and EM3 [67,78,79];NoNo
Tab.2  Experimental therapy and clinical trials of NK cell line for tumor immunotherapy
NK cell lineGenes transferredMethod of gene transferEffects
NK-92IL-2 [84]RetrovirusIncreased proliferation; increased cytotoxicity against target tumor cells; increased secretion of IFN-γ and TNF-α; enhanced antitumor activity in human tumor-bearing SCID mice.
IL-15 [91]Transfection (Lipofectamine 2000)Increased proliferation; inhibited apoptosis of NK cell line; increased cytotoxicity via increasing expression of perforin, FasL and IFN-γ.
SCF [93]Transfection (Lipofectamine 2000)Increased proliferation; increased cytotoxicity; increased expression of perforin and FasL.
Anti-CD19-CD3ξ [104]ElectroporationIncreased cytotoxicity to CD19+tumor cell lines and CD19+ primary tumor cells.
Anti-CD20-CD3ξ [100]RetrovirusIncreased cytotoxicity to CD20+ tumor targets.
Anti-ErbB2-CD3ξ [103]RetrovirusIncreased cytotoxicity to erbB2+ T cell lymphoma cells, breast, ovarian and squamous cell carcinomas.
NKLIL-15 [92]ElectroporationIncreased proliferation; inhibited apoptosis of NK cell line; increased cytotoxicity via increased expression of perforin, FasL and IFN-γ.
IFN-α*ElectroporationPromoted expression of perforin, grazyme, TNF-α and IFN-γ; increased cytotoxicity; enhanced anti-tumor activity in human tumor-bearing SCID mice.
Tab.3  Genetic modification of NK cell lines
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