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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2018, Vol. 12 Issue (4) : 440-450
Challenges of NK cell-based immunotherapy in the new era
Fang Fang1, Weihua Xiao1(), Zhigang Tian1()
1. Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China
2. Hefei National Laboratory for Physical Sciences at Microscale, Hefei 230027, China
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Natural killer cells (NKs) have a great potential for cancer immunotherapy because they can rapidly and directly kill transformed cells in the absence of antigen presensitization. Various cellular sources, including peripheral blood mononuclear cells (PBMCs), stem cells, and NK cell lines, have been used for producing NK cells. In particular, NK cells that expanded from allogeneic PBMCs exhibit better efficacy than those that did not. However, considering the safety, activities, and reliability of the cell products, researchers must develop an optimal protocol for producing NK cells from PBMCs in the manufacture setting and clinical therapeutic regimen. In this review, the challenges on NK cell-based therapeutic approaches and clinical outcomes are discussed.

Keywords natural killer cells      immunotherapy      adoptive transfer      genetic modification      immune checkpoint inhibitor     
Corresponding Authors: Weihua Xiao,Zhigang Tian   
Just Accepted Date: 10 July 2018   Online First Date: 26 July 2018    Issue Date: 03 September 2018
 Cite this article:   
Fang Fang,Weihua Xiao,Zhigang Tian. Challenges of NK cell-based immunotherapy in the new era[J]. Front. Med., 2018, 12(4): 440-450.
Fig.1  Killing mechanisms of NK cell against tumor cells. Upon the formation of immunological synapse between activated NK cell and tumor cell, multiple killing mechanisms can be triggered, including direct killing of the tumor cell by the (A) release of granules containing perforin and granzymes and (B) induction of apoptosis through the ligation of Fas-FasL or TRAIL-TRAIL ligand, and indirect killing through (C) the secretion of factors that recruit and promote the activation of other inflammatory cells that indirectly kill a target cell.
Starting material Protocol features NK cell purity Expansion fold Properties References
NK92 Cytokine N/A N/A Additional irradiate step before use [81,103]
CB-MNC Allogeneic feeder cells 72%–95% 35–2389 [104,105]
Stem cell Cytokines and antibodies ≥70% 1000–2100 Lack in vivo “education” [106111]
PBMC CD3 depleted or/and CD56 enriched Cytokine combination 75%–99% 3–131 Additional purification step, low expansion rate [79,112115]
Allogeneic feeder cells plus cytokine or/and antibody ≥90% 16–3637 [116120]
PBMC Cytokines, antibodies, or/and other stimulators ≥70% 140–5712 Simple protocols of expansion, low purity [19,20,121]
Feeder cells 66%–99% 20–14 116 [21,22,122,123]
Tab.1  Manufacture of NK cells
Source of NK cells Patient characteristic Clinical outcome References
NK-92 Solid tumor (n = 31) CR= 0, PR= 4/31, SD= 5/31 [81,124,125]
Lymphoma (n = 3) CR= 1/3, PR= 1/3, SD= 0 [81,124]
Hematopoietic malignancy (n = 12) CR= 1/12, PR= 1/12, SD= 2/12 [103,124]
CD34+ cell-derived NK cells Hematopoietic malignancy, reached CR in previous therapy (n = 18) DFS≥12 months, 1-year OS 11/15, 2-year OS 4/15 [62,73,126]
Hematopoietic malignancy (NK cell combination therapy) (n = 20) CR= 9/20, PR= 9/20, SD= 0 [73,126]
Autologous PBNK Solid tumor (n = 36) CR= 0, PR= 1/36, SD= 10/36 [122,127,128]
Hematopoietic malignancy (n = 9) CR= 0, PR= 2/9, SD= 3/9 [129,130]
Allogeneic PBNK Solid tumor (n = 58) CR= 0, PR= 12/58, SD= 31/58 [78,79,128,131]
Lymphoma (n = 6) CR= 2/6, PR= 2/6, SD= 0 [55]
Hematopoietic malignancy, reached CR in previous therapy (n = 16) DFS≥18 months, 1-year OS 13/16, 2-year OS 12/16 [63,64]
Hematopoietic malignancy (n = 24) CR= 10/24, PR= 1/24, SD= 0 [58,64,132]
Tab.2  Clinical outcome of NK cell-based immunotherapy
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