Next Article in Journal
Detailed Characterization of Immune Cell Infiltrate and Expression of Immune Checkpoint Molecules PD-L1/CTLA-4 and MMR Proteins in Testicular Germ Cell Tumors Disclose Novel Disease Biomarkers
Next Article in Special Issue
Exosomes: Versatile Nano Mediators of Immune Regulation
Previous Article in Journal
17β-Estradiol Activates HSF1 via MAPK Signaling in ERα-Positive Breast Cancer Cells
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cancers
Volume 11
Issue 10
10.3390/cancers11101534
cancers-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Natural Killer Cell Therapy: A New Treatment Paradigm for Solid Tumors

by
Sooyeon Oh
1,2,
Joo-Ho Lee
3,
KyuBum Kwack
4,* and
Sang-Woon Choi
1,5
1
Chaum Life Center, CHA University School of Medicine, Seoul 06062, Korea
2
Graduate school of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Korea
3
Department of Gastroenterology and Hepatology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam 13496, Korea
4
Department of Biomedical Science, College of Life Science, CHA University, Seongnam 13488, Korea
5
School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA 01003, USA
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(10), 1534; https://doi.org/10.3390/cancers11101534
Submission received: 2 July 2019 / Revised: 29 September 2019 / Accepted: 6 October 2019 / Published: 11 October 2019
(This article belongs to the Special Issue Cancer Immunotherapy Using Natural Killer Cells: Successes and Challenges of the Field)
Versions Notes

Abstract

:
In treatments of solid tumors, adoptive transfer of ex vivo expanded natural killer (NK) cells has dawned as a new paradigm. Compared with cytotoxic T lymphocytes, NK cells take a unique position targeting tumor cells that evade the host immune surveillance by down-regulating self-antigen presentation. Recent findings highlighted that NK cells can even target cancer stem cells. The efficacy of allogeneic NK cells has been widely investigated in the treatment of hematologic malignancies. In solid tumors, both autologous and allogeneic NK cells have demonstrated potential efficacy. In allogeneic NK cell therapy, the mismatch between the killer cell immunoglobulin-like receptor (KIR) and human leukocyte antigen (HLA) can be harnessed to increase the antitumor activity. However, the allogeneic NK cells cause more adverse events and can be rejected by the host immune system after repeated injections. In this regard, the autologous NK cell therapy is safer. This article reviews the published results of clinical trials and discusses strategies to enhance the efficacy of the NK cell therapy. The difference in immunophenotype of the ex vivo expanded NK cells resulted from different culture methods may affect the final efficacy. Furthermore, currently available standard anticancer therapy, molecularly targeted agents, and checkpoint inhibitors may directly or indirectly enhance the efficacy of NK cell therapy. A recent study discovered that NK cell specific genetic defects are closely associated with the tumor immune microenvironment that determines clinical outcomes. This finding warrants future investigations to find the implication of NK cell specific genetic defects in cancer development and treatment, and NK cell deficiency syndrome should be revisited to enhance our understanding. Overall, it is clear that NK cell therapy is safe and promises a new paradigm for the treatment of solid tumors.

1. Introduction

During recent decades, significant strides have been made in the areas of immunology and immunotherapy. Following the success of adjuvant immunotherapy using cytokine induced killer (CIK) cells in the treatment of hepatocellular carcinoma (HCC) [1], natural killer (NK) cell therapy has been discussed as a promising candidate for the next important advance. The existence of NK cells was first suggested in 1964 when it was observed that irradiated mice rejected transplanted bone marrow cells without prior sensitization, depending on histocompatibility [2]. Later, in the 1970s, NK cells were described in more detail when the major histocompatibility complex (MHC) nonrestricted killer cells were found to be naturally cytotoxic to tumor cells, including leukemic cells [3,4,5,6]. After the discovery of NK cells, a great deal of research followed, which elucidated a critical role of NK cells in supporting the whole immune system, identified their association with many human diseases, and even attempted to use NK cells as a form of therapy [7]. Of note, it was demonstrated in more recent studies that NK cells can identify and selectively kill cancer stem cells [8,9,10]. This is particularly important, as it shows that NK cell-based therapy may become an effective method to target quiescent and nonproliferating cancer stem cells to prohibit relapse and metastasis [8]. This suggests that NK cell therapy could be considered as an adjuvant to standard cancer treatment. Currently, NK cell therapy is being discussed as a potential solution to unmet needs, not only in the treatment of cancer, but also that of other human diseases.

2. The Biological Background of NK Cell Therapy

NK cells, an important part of the innate immune system, are characterized by the expression of cluster of differentiation (CD) 56 and the absence of the T cell marker CD3. They comprise 5% to 15% of peripheral blood mononuclear cells (PBMCs), and the population of NK cells is divided into two subsets, CD56dim or CD56bright, based on the degree of CD56 fluorescence observed by flow cytometry. More than 90% of NK cells in the peripheral blood are CD56dimCD16+, while the majority of NK cells in the lymphoid tissues are CD56brightCD16− [11,12]. CD56dim NK cells are fully competent cytotoxic cells, while CD56bright NK cells are more suited for cytokine production. Therefore, CD56dim NK cells are considered cytotoxic while CD56bright NK cells are considered immune-regulatory [13]. CD16 is a low affinity Fcγ receptor which confers the ability to recognize antibody-coated target cells and is important for antibody-dependent cell cytotoxicity (ADCC). In this respect, NK cells play a role as effector cells in the adaptive immune system.
NK recognition of target cells depends on activating and inhibitory receptors expressed on the cell surface. These receptors recognize ligands on target cells. More specifically, the NK cell recognizes the ‘absence’ of a self-antigen through the interaction between its killer cell immunoglobulin-like receptors (KIRs) and MHC class I molecules expressed on the surface of the target cell [14,15]. Inhibitory KIRs are transmembrane molecules coded on chromosome 19 that interact with human leukocyte antigen (HLA)-A, HLA-B, and HLA-C, the MHC class I molecules [16]. When the right MHC class I molecule is recognized by a corresponding KIR, the KIR transmits an inhibitory signal. However, when the MHC class I molecule is missing, no inhibitory signal is generated, and the balance shifts towards activation. This ‘missing-self’ recognition is a vital process for the whole immune system. Cytotoxic T lymphocytes (CTLs), which perform a task similar to NK cells, recognize diseased cells when the cells present ‘altered’ self-antigens on MHC class I molecules. This process is highly dependent on antigen recognition, and CTLs fail to recognize diseased cells if the presentation of self-antigen in the context of self-MHC is lost. To evade host immune surveillance, some virally infected or malignantly transformed cells downregulate or altogether lose expression of MHC-peptide. This loophole in the adaptive immune system can be closed by NK cell activation, and this difference in recognition mechanisms is why NK cells have garnered significant attention and are expected to fill the holes left by CTLs in CIK cell therapy.
The interaction between KIR and HLA to determine target cell killing provides the scientific background for allogeneic NK cell therapy. Since tumor recognition by NK cells depends on the absence of self-antigen presentation, cancer cells with low HLA expression, especially leukemic cells, are susceptible to lysis by NK cells [17]. However, tumor cells with high expression of HLA such as lymphomas and some solid tumors tend to be more resistant [17]. If the KIR on an NK cell is mismatched with the HLA of a target cell, the chances of cytolysis rise [18,19,20]. Therefore, allogeneic NK cells with a KIR-HLA mismatch are expected to contribute to the killing of those tumor cells resistant to autologous NK cells. Broadly, KIR genes can be divided into two haplotypes, termed A and B. The A haplotype has a fixed number of KIR genes with several inhibitory KIRs and only one activating KIR. By contrast, the B haplotype has a greater number of genes and more than one activating KIR [21,22]. Therefore, the B haplotype is generally preferred as the donor for allogeneic NK cell therapy. The clinical benefit of allogeneic NK cells with a KIR-HLA mismatch has been actively investigated in the treatment of leukemia with or without hematopoietic stem cell transplantation (HSCT) [23].

3. Low NK Cell Activity and Cancer Development

Epidemiologic studies have indicated that decreased function of NK cells is related to cancer incidence. In 2000, the association between low NK cell cytotoxicity and development of cancer was demonstrated in a prospective cohort study conducted in a Japanese town including 3625 residents followed for 11 years [24]. Although this study demonstrated that NK cell cytotoxicity is a crucial component in immune surveillance of cancer cells, the chromium-51 release assay, which was used in this study to determine the NK cell cytotoxicity, could not be widely utilized in a clinical setting due to the technical difficulties associated with radioactive isotopes. Even without the use of radioactive isotope, a CD107a degranulation assay (another test for the NK cell cytotoxicity) is available, but was considered complicated and time-consuming. Recently, studies with similar aims have been conducted with a novel method. These studies tested the association between cancer incidence and NK cell activity as measured by IFN-γ release upon stimulation. It was shown that lower NK cell activity was associated with increased incidence of cancers in the stomach [25], colorectum [26], and prostate [27,28]. Measuring IFN-γ release to evaluate the functional state of NK cells is easily accomplished with a commercialized kit (NK Vue®, ATGen, Korea) with ‘PROMOCA™ (ATGen, Korea)’, an engineered recombinant cytokine that specifically stimulates NK cells [29]. Introduction of this new test for NK cell function in daily clinical practice increased social awareness that immunity matters in cancer prevention and treatment.
Upon unraveling the epidemiologic association between NK cells and cancer [24], research efforts ensued to use NK cells in the treatment of cancer via adoptive cellular transfer. In both in vitro and in vivo studies, NK cells have been shown to mediate direct killing of human cancer cells in acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma, glioblastoma, neuroblastoma, Ewing sarcoma, rhabdomyosarcoma, melanoma, and carcinomas of the breast, lung, ovary, colon, pancreas, renal cells, and stomach [17,30,31,32,33,34,35,36].

4. NK Cell Deficiency Syndrome (NKDS)

The role and importance of NK cells is the most pronounced in NKDS. NKDS is an isolated immune deficiency of NK cells in which other components of immune system are intact [37]. NKDS is characterized by a consistent and significant reduction in NK cell numbers, cytotoxic activity, or cytokine production [37]. According to differential findings of the named aspects, NKDS is divided into absolute, classical, and functional NKDS [37]. Patients with NKDS usually present severe and recurrent viral infections or atypical infections at adolescence or young adulthood [37]. The absence of NK cell immune surveillance in these patients was linked to increased susceptibility to development of malignant disease [38,39]. The cause of NKDS is attributed to genetic abnormality of NK cells [40,41,42]. In NKDS, NK cells could not be differentiated or modulated to have normal function with cytokine stimulation, which suggested that NKDS is a permanent condition [43,44]. Nevertheless, NKDS is rarely diagnosed. A recent study, however, suggested that genetic abnormality of NK cells may have higher prevalence than expected although the affected individuals do not present severe infectious disease as was described in NKDS. In this study, defects of NK cell specific genes compared with universal genes for immune system were more closely associated with tumor immune microenvironment that determines prognosis, clinical outcomes, and response to immunotherapy [45]. Depletion of NK cells resulted in failed recruitment of dendritic cells to the tumor microenvironment [46,47]. Genetic analysis suggested that NK cells could recruit not only dendritic cells but also 30 other immune cells and that NK cells are the first responders to detect and kill cancer cells and sequentially recruit many other immune cells, shaping tumor microenvironment into a certain pattern [45]. Therefore, it is highly likely that the NK cell specific genetic defect is closely associated with cancer development. Cancer patients with NK cell specific genetic abnormalities or NKDS may benefit from adoptive NK cell therapy with an allogeneic source.

5. Lymphokine Activated Killer (LAK) Cell Therapy: An Early Form of NK Cell Therapy

In the 1980s, autologous LAK cell therapy with concomitant administration of IL-2 was clinically applied in the treatment of advanced solid tumors for patients who were nonresponsive to standard therapy [48,49]. Lymphocytes obtained from cancer patients by repeated leukapheresis were incubated with IL-2 to generate LAK cells, which were administered to the patients in conjunction with IL-2. Clinical remission was observed in 31% (33/106) of the trial group treated with LAK cells and IL-2 and in 15% (7/47) of the control group treated only with IL-2 [48]. Moreover, complete remission (CR) was noted in eight patients, suggesting that autologous LAK cell therapy was an effective anticancer treatment [48]. In 1989, autologous LAK cells with IL-2 were given to 10 HCC patients, tumor regression was observed in two patients, and the rest maintained stable disease (SD) [50]. Furthermore, autologous LAK cells with IL-2 followed by surgical resection of HCC significantly decreased recurrence rate and increased recurrence-free survival [51,52]. A highlight study which demonstrated survival benefit was reported in 1997. In this phase III randomized trial for 174 primary lung carcinoma patients, autologous LAK cells (1–5 × 109 cells/1 shot) with IL-2 were given combined with or after standard cancer therapy every 2–3 months for 2 years, and the 5- and 9-year survival rates of the immunotherapy group were 54.5% and 52% respectively, compared to 33.4% and 24.2% in the control group (p < 0.001) [53]. Despite these encouraging results, autologous LAK cell therapy with IL-2 had critical limitations: the concomitant use of IL-2 was repeatedly noted to cause severe side effects including fever, hypotensive syncope, and vascular leak syndrome [48,53], and IL-2 was known to expand not only NK cells but also regulatory T cells (Tregs), potentiating immune suppression by Tregs [54] so that efficacy could not be proven consistently [55,56].

6. Ex Vivo Expansion of NK Cells to Increase the Number

To acquire a sufficiently large number of fully functional NK cells, various culture methods were developed [54]. Ex vivo expansion of NK cells into sufficiently large numbers made it possible to omit the use of exogenous cytokines, thus the moniker ‘LAK’ was dropped. Ex vivo expansion of NK cells used not only IL-2 but also combinations of cytokines with or without feeder cells. When feeder cells were used with cytokines, NK cells could be expanded 100- to 40,000-fold in 2–3 weeks [54]. This was a significant advance compared to 10- to 20-fold expansion when single cytokine was used. As feeder cells, many types of cells are employed including PBMCs, antigen presenting cells, modified K562 cells, and Epstein–Barr virus-transformed lymphoblastoid cell lines [54,57]. However, there are safety concerns in using feeder cells that the feeder cells may contaminate the final therapeutic cell product. Therefore, many groups have developed feeder-free culture system using stimulators instead. So far, many groups have developed good manufacturing practice (GMP) compliant and efficient ex vivo expansion systems [54,57]. Biotechnology has advanced to the point where NK cells can be generated directly from CD34+ hematopoietic stem cells (HSCs) [58]. Compared with NK cells harvested from PBMCs, NK cells generated directly from HSCs showed lower expression of inhibitory receptors (KIR2DL1, KIR2DL2/3, and KIR3DL1) and higher expression of activating receptors (NKp30, NKp44, and NKp46) [59]. Moreover, these NK cells exhibited cytotoxicity even without prior exposure to IL-2, while NK cells from PBMCs required IL-2 exposure to exhibit cytotoxicity [59]. More recently, a novel strategy to expand highly functional NK cells by using osteoclasts as feeder cells was proposed [9]. Expanded NK cells from cancer patients had decreased cytotoxicity and lower secretion of IFN-γ compared with those from healthy individuals [9] consistent with previous findings showing decreased expansion efficiency and altered cytokine production in cancer patients [60]. This phenomenon was correlated with increased expansion of T cells, for which the addition of anti-CD3 antibody served as an effective solution [9]. Despite these remarkable advances, different types of culture protocols developed by different groups pose a problem for standardization and generate difficulty in ensuring the reproducibility of results [54,61]. It is believed that different culture methods give rise to NK cells with different immunophenotypes. Researchers should move towards establishing a quality standard for the phenotype of manufactured NK cells because the immunophenotype may be a critical component in determining the function and therapeutic efficacy of NK cells [62].

7. Current NK Cell Therapy in Solid Tumors

In 2004, autologous NK cells expanded ex vivo with an irradiated human feeder cell-line and IL-2 were tested in patients with malignant glioma [63]. The NK cell infusion with IFN-β in nine patients revealed clinical responses [63]. The same year, another study reported SD in one of 12 patients with refractory colorectal cancer or non-small cell lung cancer (NSCLC) who received infusions of autologous NK cells ex vivo expanded and incubated with heat shock protein 70 (HSP70) [64]. HSP70 is a tumor-selective recognition structure, and NK cells incubated with HSP70 demonstrated enhanced cytolytic activity against HSP70 positive tumors in vitro and in vivo [64]. In 2011, a treatment result for autologous NK cell (expanded with irradiated autologous PBMC as feeder cells, IL-2 and OKT3; OKT3 stimulates the PBMC feeder cells) therapy with lymphodepleting but nonmyeloablative chemotherapy with cyclophosphamide and fludarabine was reported [65]. An average of 4.7 × 1010 cells was given to patients with metastatic melanoma or renal cell carcinoma, and no clinical responses were observed. The adoptively transferred NK cells persisted from one week to several months, but the persistent NK cells expressed significantly lower levels of NK group 2-member D (NKG2D, an activating receptor) and could not lyse tumor cells in vitro unless they were reactivated with IL-2 [65]. In 2015, a similar but more encouraging observation was reported. In this study, NK cells were expanded with OK432 (OK432 (Picibanil) is a streptococcal preparation [66] that activates NK cells better than in conventional LAK cells [67]), IL-2, and recombinant human fibronectin fragment (FN-CH296, RetroNectin®)-induced T-cells as a stimulator [68]. These expanded autologous NK cells were given to patients with unresectable, locally advanced digestive tract cancers at doses of 0.5 × 109, 1.0 × 109, and 2.0 × 109 cells/injection [68]. Although no clinical responses were observed in this study, cytotoxicity of patients’ peripheral blood increased two-fold [68]. The same group proceeded to a downstream study where immunoglobulin G (IgG) 1 antibody (trastuzumab or cetuximab) was combined with the same doses of autologous NK cells, and this study was published in 2018 [69]. Nine patients with advanced gastric or colorectal cancers received trastuzumab- or cetuximab-based chemotherapy with autologous NK cells [69]. Among six evaluable patients, four patients presented with SD and the other two with progressive disease (PD) [69]. A pilot prospective cohort study published in 2018 treated colon cancer patients (stage IIIa-c) after radical resection with chemotherapy (5-Fu and oxaliplatin according to the National Comprehensive Cancer Network (NCCN)) with or without autologous NK cell therapy [70]. The autologous NK cells were cultured in an anti-CD16 coated flask with IL-2 and OK432. The 5-year progression free survival (PFS, 51.1% vs. 35%, p = 0.044) and overall survival (OS) rate (72.5% vs. 51.6%, p = 0.037) were significantly higher in the group with NK cell therapy [70]. In 2019, a clinical trial reported the effect of autologous NK cell therapy administered to advanced lung cancer patients [71]. This therapy, called highly activated NK cell immunotherapy, cultured NK cells using an in vitro culture kit that contains membrane chimeric active cellular factors (HANK Bioengineering Co., Ltd, Shenzhen, China) [71]. A total of 13 patients received the NK cell therapy without other treatment. After 3 months, 11 patients (84.6%) were evaluated as SD and two patients (15.4%) as PD [71]. Another study reported in 2019 was conducted in one patient with NSCLC stage IIIb [72]. Autologous NK cells activated with HSP70 and IL-2 were combined with radiochemotherapy and anti-programmed death-1 (PD-1) antibody nivolumab. The patients exhibited an excellent OS that no viable tumor cells or signs of progression were detected up to 33 months after diagnosis [72].
Following the successes in hematologic malignancies [23], the safety and feasibility of allogeneic NK cells were also investigated in solid tumors. For HSCT in hematologic malignancies, HLA compatible donor availability only met around 60% of the demands [73]. Therefore, haplotype HSCT was adopted with T cell depletion strategies to avoid graft-versus-host disease (GVHD) [23]. Despite the worrisome anticipation that lack of mature graft T cells may jeopardize immune recovery and graft-versus-leukemia (GVL) effect, GVL effect was still present, and it was thanks to the graft NK cells matured in vivo after HSCT [23,74]. Following researches showed that a mismatch between donor NK cell KIRs and their cognate HLA class I ligands is an important factor to determine the presence of GVL without GVHD and to improve engraftment rates and survival time [75,76]. In a study conducted in 112 high risk acute leukemia patients undergoing haplotype mismatched HSCT, the probability of event-free survival at 5 years was significantly higher in KIR mismatched group compared to KIR matched group (60% vs. <5%, p < 0.0005) [77]. Thus, KIR mismatch was identified as a key factor to strengthen the antitumor effect by allogeneic NK cells. Based on this finding, infusion of allogeneic NK cells with a KIR-HLA mismatch has been widely tested as a monotherapy or as an adjuvant therapy after HSCT in hematologic malignancies, and the outcomes were favorable [23]. The early clinical trials of allogeneic NK cell therapy in solid tumors, therefore, strongly resembled those in hematologic malignancies. In 2005, it was reported that haploidentical allogeneic NK cells were safely transferred to patients with metastatic melanoma and renal cell carcinoma [78]. Three studies in advanced solid tumors reported that infusion of allogeneic NK cells followed by HSCT revealed minor signs of clinical response in 2009, 2011, and 2013 [79,80,81]. In another study reported in 2011, infusion of allogeneic NK cells was followed by lymphodepleting preconditioning chemotherapy (cyclophosphamide and fludarabine) with or without total body irradiation, where transient donor chimerism was observed but limited, likely by reconstituting recipient Tregs [82]. Leaving behind the framework of hematologic treatment, an attempt was made to combine allogeneic NK cell therapy with standard chemotherapy for solid tumors. In a study reported in 2010, patients with NSCLC received 1st or 2nd line chemotherapy and 2–4 doses of allogeneic NK cells (0.2–29 × 106 cells/kg/dose) donated by relatives, and premedication with corticosteroids and H1-antihistamine was allowed [83]. The results confirmed the safety and suggested potential clinical efficacy [83]. Another study published in 2016 evaluated the safety and efficacy of allogeneic NK cell monotherapy for advanced solid tumors as well as malignant lymphoma [84]. In this study, allogeneic NK cells, named MG 4101 (GC Pharma, Korea), were derived from random healthy unrelated donors and ex vivo expanded with irradiated autologous PBMC feeder cells, IL-2, and OKT3 [84]. MG4101 was tested for tolerability at dose ranges of 1 × 106 cells/kg to 3 × 107 cells/kg. A maximal tolerable dose (MTD) was not determined, but 3 × 107 cells/kg was found to be the maximal feasible dose. Although all the doses tested were well tolerated with grade one or two toxicities, the final cohort with 3 × 107 cells/kg presented the most frequent incidence of adverse events [84]. Patient antibodies specific for donor NK cells were observed more frequently in repeated injections than in a single injection [84]. Of 17 evaluable patients, eight presented SD and nine PD [84]. Signs of immune activation were observed including upregulation of NKG2D on CD8 T cells and increased production of chemokines, whereas counts for Tregs and myeloid derived suppressor cells (MDSCs) as well as transforming growth factor (TGF)-β production decreased [84]. Of note, patients who received NK cells expressing higher numbers of incompatible KIRs had remarkably enhanced survival [84]. On the contrary, there is one study reported in 2018 that could not identify a relationship between treatment response and KIR-HLA mismatch. In this study, haploidentical NK cells were incubated overnight with 500–1000 U/ml IL-2 after depleting T lymphocytes by anti-CD3 antibody-coated paramagnetic particles and enriching NK cells with the CliniMACS CD56 reagent [85]. A combination therapy of the allogeneic NK cells and anti-CD2 antibody 3F8 was given to 35 patients with high-risk neuroblastoma after lymphodepleting preconditioning chemotherapy [85]. The tested NK cell doses ranged <1 × 106 to 50 × 106 cells/kg. Adverse events of grade three hypertension and grade four pneumonitis in one patient precluded reaching an MTD [85]. Among the 35 patients, 10 patients (29%) had clinical response, 17 (47%) no response and eight (23%) PD. Patients receiving >10 × 106 cells/kg had improved PFS (HR 0.36, 95%CI 0.15-0.87, p = 0.022) [85]. No relationship between response and KIR-HLA mismatch or FcγRIII receptor polymorphisms was identified, which may have been due to small sample size [85]. In stage IV HCC, effectiveness of irreversible electroporation combined with allogeneic NK cell therapy was reported in 2018. The allogeneic NK cells were expanded using the Human HANK Cell in vitro Preparation Kit (HANK Bioengineering Co., Ltd, Shenzhen, China) that includes the lethally radiated K562-mb15-41BBL stimulatory cells, plasma treatment fluid, lymphocyte culture fluid additives, serum-free medium additives, and cell infusion additives [86]. In this study including 40 patients, increased OS was observed in the combination therapy group compared with irreversible electroporation monotherapy group (10.1 vs. 8.9 months, p = 0.0078) [86]. In 2019, a similar study conducted in 40 unresectable primary liver cancer patients reported that patients who received combination therapy exhibited superior median PFS and OS compared to those who received irreversible electroporation monotherapy (PFS 15.1 vs. 10.6 months, p  <  0.05; OS 17.9 vs. 23.2 months, p  <  0.05) [87]. In this study, the allogeneic NK cells were donated by KIR-HLA mismatching relatives and expanded using the in vitro preparation kit (HANK Bioengineering Co., Ltd, Shenzhen, China) [87]. ‘Off the shelf’ NK cells, the NK-92 cell line, were also tested in solid tumors. In studies reported in 2008 and 2013, ex vivo expanded NK-92 cells were infused as a monotherapy for advanced solid tumor patients. NK cell doses from 1 × 108 cells/m2 to 1 × 1010 cells/m2 were tested [88,89]. Although grade three/four side effects were reported [88], the incidence was rare, and they were generally evaluated to be safe [89]. The dose of 1 × 1010 cells/m2 was considered the maximum expandable cell dose with the use of an established culture bag system [89]. Three of 15 patients had some antitumor response, including all three patients with lung cancer [89]. One patient developed anti-HLA antibodies, and the persistence of NK-92 cells was confirmed in two patients [89].

8. Strategies to Enhance the Effect of NK Cell Therapy

In the treatment of solid tumors, both autologous and allogeneic NK cells have demonstrated potential efficacy, and therefore receive equal attention, but it has not yet been determined which is more effective, and each has its pros and cons. In a clinical trial reported in 2017, the efficacy of allogeneic NK cell therapy was directly compared to that of autologous NK cells in recurrent breast cancer [90]. Allogeneic NK cell therapy fully mismatched for KIR and HLA showed better efficacy in terms of tumor response, the number of circulating tumor cells, immune function, and quality of life, with no difference in adverse effects [90]. Moreover, only allogeneic sources should be considered as an option for cancer patients identified with NK cell specific genetic abnormalities or NKDS [43,44,45]. Even so, allogeneic NK cell therapy is known to have several limitations in comparison to autologous NK cell therapy. Allogeneic NK cells cause side effects that increase in severity linearly with cell doses, or require immunosuppressive pretreatments [83,84,85,89]. In addition, the generation of antibodies against transferred allogeneic NK cells potentially limits the possibility and efficacy of repetitive treatments [84,89]. A strategy to overcome these limitations may be developing autologous NK cells which are as effective as the allogeneic. In a xenograft animal model with ovarian cancer tumor grafts, autologous, or allogeneic NK cells expanded with IL-2 and K562 feeder cells expressing IL-21 were infused [62]. In this in vivo study, autologous NK cells were as effective as the allogeneic NK cells, and the phenotype of NK cells was predominantly CD56superbrightCD16+ [62]. The researchers suggested that CD56bright or CD56superbright subsets are superior to CD56dim subsets in antitumor function. A recent study supports this idea, where intratumoral CD56bright NK cells in bladder cancer showed increased cytokine production and cytotoxicity and were associated with improved survival compared to their CD56dim counterparts [91]. It is interesting that this finding is somewhat contrary to the general belief that more mature CD56dim NK cells may be better for antitumor function. Similarly, a study showed that NK cells with a less mature phenotype, NKG2A+CD57-NKG2C- (CD57+ is a marker of terminal differentiation), were associated with protection from leukemia relapse and improved OS [92]. This is also contrary to the conventional knowledge that mature and memory-like NKG2A−selfKIR+CD57+NKG2C+ NK cells generated by cytokine stimulation or CMV infection are more efficacious [93,94,95,96,97,98]. Although a unifying explanation for these seemingly contradictory findings is not yet available, recent observations suggest that the phenotype of NK cells determines the function, and CD56bright or CD56superbright NK cells may not only differentiate into mature cytotoxic NK cells, but also secrete enough cytokines to overcome the immunosuppressive tumor microenvironment [99]. Furthermore, those cytokines may induce the differentiation of cancer stem cells limiting their ability to expand and metastasize [100]. Thus, the limitations of autologous NK cell therapy may be overcome by converting patient NK cells into a CD56bright or CD56superbright phenotype, rather than CD56dim [62,99]. In addition, the conventional designation of maturity by the degree of CD56 fluorescence should be reconsidered. The CD56 fluorescence in this context represents the distinct functional status rather than the maturational status. Further studies are warranted to determine the clinical meaning of the final immunophenotypes of the ex vivo expanded NK cells according to different culture methods. In the long run, defining the optimal immunophenotype of therapeutic NK cells in terms of maturation markers, activating/inhibitory receptors and KIR-HLA mismatch will be extremely useful. Some experts say that ex vivo activation may give rise to KIR-HLA mismatching autologous NK cells, because previously silenced, self-reactive, mismatched NK cells could be reactivated. This is thought to be possible because KIR genes on chromosome 19 and HLA genes on chromosome 6 are inherited independently, in other words KIR expression is independent of HLA expression [101], and anergic NK cells with self-reactive KIRs do exist [102,103]. In an analysis of NK cell clones, CD56bright NK cells showed higher cloning efficiency compared with CD56dim or CD57+ subsets [104]. Furthermore, it was demonstrated that CD57+ subsets could reverse, and acquire a CD57- phenotype in specific conditions, which had previously been considered impossible [104]. These recent discoveries suggest that an era of generating therapeutic NK cells with an optimal immunophenotype may arrive sooner than expected.
Early trials have been conducted in advanced cancer patients with a high tumor burden. In those studies, signs of clinical response were observed as was indicated by preclinical models that NK cell therapy prevented migration and invasion of cancer cells contributing to prevention of systemic metastasis [36]. However, such response was not dramatic as it did not meet the expectation of the scientific community. The reason for the subdued response was attributed to the immunosuppressive microenvironment that accompanies advanced cancer with a high tumor burden. In severely immunosuppressive microenvironment, adoptively transferred immune cells are easily disengaged, losing their cytotoxic activity and ability to infiltrate into tumor tissues [53]. On the contrary, promising results came from phase III trials conducted in early stage cancer patients, who were left with minimal tumor burden after curative treatment [1,52,53]. In the early stage cancer patients, these studies clearly demonstrated survival benefit of adoptive immune cell therapy with autologous T cells or NK cells. These observations are supported by laboratory findings that NK cells play a more potent role in tumor initiation or prevention, as opposed to slowing tumor growth and progression, in a KRAS knock-in mouse lung cancer model [35], and that NK cells could identify and selectively kill quiescent cancer stem cells in many other studies [8]. Based on these findings, it can be inferred that solid tumor patients who would get the maximal benefit from NK cell therapy are likely to be the ones with a low or minimal tumor burden with a purpose to prohibit cancer relapse and metastasis.
For patients with a high tumor burden, combination therapy with standard anticancer therapy seems safe and feasible. Different adjunct treatments were tried along with NK cell therapy. For solid tumors, the use of high-intensity chemotherapy, as was done in hematologic malignancies, may not have enough benefit weighed against the anticipated risk. Immunosuppressive therapy using chemotherapy or corticosteroids may facilitate the survival and function of adopted NK cells, but may have the downside of suppressing the patient’s native immune system. In contrast, combination therapy with IgG antibodies, both as molecularly targeted agents and checkpoint inhibitors, may have potential benefit of utilizing CD16, the low affinity Fcγ receptor on NK cells, coupling NK cell cytotoxicity with ADCC [69]. In in vitro studies, trastuzumab and pertuzumab increased the cytotoxic level of IL-2 activated NK cells targeting ERBB2 positive cancer cell lines [105], and an anti-programmed cell death-ligand 1 (PD-L1) antibody avelumab increased ADCC by NK cells targeting triple negative breast cancer cells [106]. In a preclinical study, activated NK cells, in combination with the anti-GD2 antibody dinutuximab, improved survival of neuroblastoma mice after surgical resection [107]. In addition, avelumab could greatly enhance ADCC of the high-affinity NK cell line in meningioma in vitro and in vivo [108]. In particular, combination therapy with checkpoint inhibitors may have an additional benefit by unleashing exhausted immune cells [72]. In mouse models of cancer, NK cells expressed PD-1 and cancer cells expressed PD-L1, and a PD-1/PD-L1 blockade elicited a strong NK cell response [109]. In a preclinical ovarian cancer model, PM21-particle expanded NK cells had increased antitumor efficacy when combined with an anti-PD-L1 antibody [110]. Amongst multikinase inhibitors, sorafenib and regorafenib are predicted to have a potential synergistic effect when combined with NK cell therapy [111,112,113,114]. To evade host immune surveillance, certain tumor cells such as HCC express a disintegrin and metalloproteases 9 (ADAM9) protease that cleaves membrane bound MHC class I-related chain A (MICA), the ligand for NKG2D. Preclinical studies demonstrated that this MICA shedding can be inhibited by sorafenib and regorafenib [111,112,113,114]. In addition to immune modulatory and antitumor effects, sorafenib and regorafenib inhibit the expression of ADAM9 protease. This can directly restore antitumor NK cell activation and may enhance the efficacy of NK cell therapy.

9. Conclusions and Future Perspectives

Recently, immunological treatments have become a new paradigm in medicine. Immune check-point inhibitors significantly improved the life expectancy of cancer patients. Chimeric antigen receptor (CAR) T cell therapy provided a cure for some patients who were otherwise untreatable [115]. Compared to these dramatic successes, NK cell therapy is not yet satisfactory. There are numerous ongoing clinical trials on NK cell therapy all over the world. In ClinicalTrials.gov, 28 trials for solid tumors and 31 trials for hematologic malignancies were searched (search term: “NK cell” AND “Therapy”; recruitment status: “Recruiting” or “Active, not recruiting”; search date 30th Aug 2019). The search results for solid tumors were listed in Table 1. The trials are in phase I/II testing safety and efficacies as a monotherapy, an adjuvant therapy, and a combination therapy in addition to standard or trial anticancer therapy. The sources of allogeneic NK cells ranged from haploidentical donors, unrelated donors, umbilical cord blood, NK cell lines, to engineered NK cells including CAR-NK cells.
Since its first introduction to clinical research, NK cell therapy has slowly improved, both in quantity and quality, during the past 30 years. In the early years when ex vivo expansion of NK cells was not available, NK cells were acquired by repetitive leukapheresis, stimulated ex vivo and re-infused to patients with IL-2 in LAK cell therapy. In recent years, many institutes developed GMP compliant culture methods to expand NK cells ex vivo to a sufficiently large number, even from CD34+ HSCs. This advancement in biotechnology may accelerate the speed of research on NK cell therapy in the future. Allogeneic NK cell therapy is expected to be incorporated into the standard therapy of hematologic malignancies in the near future [23]. In solid tumors, autologous and allogeneic NK cell therapies both have demonstrated potential efficacy and are getting equal scientific attention. Both have pros and cons. In general, autologous NK cells are discouraged due to their low efficacy, whereas allogeneic NK cells produce more side effects and possess the potential for rejection, precluding repetitive treatments. A recent in vivo study suggested that these problems may be solved by developing autologous NK cells that mirror the allogeneic efficacy, and that the key to doing this is to modulate the final immunophenotype of the NK cell. In addition, currently available molecularly targeted agents and checkpoint inhibitors may directly facilitate the action of adoptively transferred NK cells by acting as a medium for ADCC, helping to overcome the immune exhaustion or inhibiting tumor immune evasion.
A recent study pointed out that NK cell specific genetic defects may contribute to cancer development and determine treatment outcome. In this regard, revisiting the NKDS and investigating the NK cell specific genetic defects that are subclinical may provide a new perspective in cancer prevention and treatment. Overall, NK cell therapy has been safely administered and demonstrated great potential to enhance clinical outcomes in cancer patients. In the long run, NK cell therapy is expected to provide solutions for unmet medical needs.

Funding

This research was funded by a grant of Basic Research Project in Science and Engineering, funded by the Ministry of Science, Technology and Information, Republic of Korea (Grant no. 2019R1F1A1054920).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Lee, J.H.; Lee, J.H.; Lim, Y.S.; Yeon, J.E.; Song, T.J.; Yu, S.J.; Gwak, G.Y.; Kim, K.M.; Kim, Y.J.; Lee, J.W.; et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology 2015, 148, 1383–1391. [Google Scholar] [CrossRef] [PubMed]
  2. Cudkowicz, G.; Stimpfling, J.H. Hybrid resistance to parental marrow grafts: Association with the k region of h-2. Science 1964, 144, 1339–1340. [Google Scholar] [CrossRef] [PubMed]
  3. Kiessling, R.; Klein, E.; Wigzell, H. “Natural” killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype. Eur. J. Immunol. 1975, 5, 112–117. [Google Scholar] [CrossRef] [PubMed]
  4. Kiessling, R.; Klein, E.; Pross, H.; Wigzell, H. “Natural” killer cells in the mouse. II. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Characteristics of the killer cell. Eur. J. Immunol. 1975, 5, 117–121. [Google Scholar] [CrossRef] [PubMed]
  5. Herberman, R.B.; Nunn, M.E.; Holden, H.T.; Lavrin, D.H. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. II. Characterization of effector cells. Int. J. Cancer 1975, 16, 230–239. [Google Scholar] [CrossRef] [PubMed]
  6. Herberman, R.B.; Nunn, M.E.; Lavrin, D.H. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. I. Distribution of reactivity and specificity. Int. J. Cancer 1975, 16, 216–229. [Google Scholar] [CrossRef] [PubMed]
  7. Suen, W.C.; Lee, W.Y.; Leung, K.T.; Pan, X.H.; Li, G. Natural Killer Cell-Based Cancer Immunotherapy: A Review on 10 Years Completed Clinical Trials. Cancer Investig. 2018, 36, 431–457. [Google Scholar] [CrossRef] [PubMed]
  8. Luna, J.I.; Grossenbacher, S.K.; Murphy, W.J.; Canter, R.J. Targeting Cancer Stem Cells with Natural Killer Cell Immunotherapy. Expert Opin. Biol. Ther. 2017, 17, 313–324. [Google Scholar] [CrossRef]
  9. Kaur, K.; Cook, J.; Park, S.H.; Topchyan, P.; Kozlowska, A.; Ohanian, N.; Fang, C.; Nishimura, I.; Jewett, A. Novel Strategy to Expand Super-Charged NK Cells with Significant Potential to Lyse and Differentiate Cancer Stem Cells: Differences in NK Expansion and Function between Healthy and Cancer Patients. Front Immunol. 2017, 8, 297. [Google Scholar] [CrossRef]
  10. Kaur, K.; Topchyan, P.; Kozlowska, A.K.; Ohanian, N.; Chiang, J.; Maung, P.O.; Park, S.H.; Ko, M.W.; Fang, C.; Nishimura, I.; et al. Super-charged NK cells inhibit growth and progression of stem-like/poorly differentiated oral tumors in vivo in humanized BLT mice; effect on tumor differentiation and response to chemotherapeutic drugs. Oncoimmunology 2018, 7, e1426518. [Google Scholar] [CrossRef]
  11. Fehniger, T.A.; Cooper, M.A.; Nuovo, G.J.; Cella, M.; Facchetti, F.; Colonna, M.; Caligiuri, M.A. CD56bright natural killer cells are present in human lymph nodes and are activated by T cell–derived IL-2: A potential new link between adaptive and innate immunity. Blood 2003, 101, 3052–3057. [Google Scholar] [CrossRef] [PubMed]
  12. Ferlazzo, G.; Thomas, D.; Lin, S.-L.; Goodman, K.; Morandi, B.; Muller, W.A.; Moretta, A.; Münz, C. The abundant NK cells in human secondary lymphoid tissues require activation to express killer cell Ig-like receptors and become cytolytic. J. Immunol. 2004, 172, 1455–1462. [Google Scholar] [CrossRef] [PubMed]
  13. Cooper, M.A.; Fehniger, T.A.; Caligiuri, M.A. The biology of human natural killer-cell subsets. Trends Immunol. 2001, 22, 633–640. [Google Scholar] [CrossRef]
  14. Ljunggren, H.G.; Karre, K. In search of the ‘missing self’: MHC molecules and NK cell recognition. Immunol. Today 1990, 11, 237–244. [Google Scholar] [CrossRef]
  15. Anfossi, N.; Andre, P.; Guia, S.; Falk, C.S.; Roetynck, S.; Stewart, C.A.; Breso, V.; Frassati, C.; Reviron, D.; Middleton, D.; et al. Human NK cell education by inhibitory receptors for MHC class I. Immunity 2006, 25, 331–342. [Google Scholar] [CrossRef] [PubMed]
  16. Hilton, H.G.; Parham, P. Missing or altered self: Human NK cell receptors that recognize HLA-C. Immunogenetics 2017, 69, 567–579. [Google Scholar] [CrossRef] [PubMed]
  17. Bachanova, V.; Miller, J.S. NK cells in therapy of cancer. Crit. Rev. Oncogen. 2014, 19, 1–2. [Google Scholar] [CrossRef]
  18. Ciccone, E.; Pende, D.; Viale, O.; Than, A.; Di Donato, C.; Orengo, A.M.; Biassoni, R.; Verdiani, S.; Amoroso, A.; Moretta, A. Involvement of HLA class I alleles in natural killer (NK) cell-specific functions: Expression of HLA-Cw3 confers selective protection from lysis by alloreactive NK clones displaying a defined specificity (specificity 2). J. Exp. Med. 1992, 176, 963–971. [Google Scholar] [CrossRef]
  19. Colonna, M.; Brooks, E.G.; Falco, M.; Ferrara, G.B.; Strominger, J.L. Generation of allospecific natural killer cells by stimulation across a polymorphism of HLA-C. Science 1993, 260, 1121–1124. [Google Scholar] [CrossRef]
  20. Moretta, A.; Tambussi, G.; Bottino, C.; Tripodi, G.; Merli, A.; Ciccone, E.; Pantaleo, G.; Moretta, L. A novel surface antigen expressed by a subset of human CD3-CD16+ natural killer cells. Role in cell activation and regulation of cytolytic function. J. Exp. Med. 1990, 171, 695–714. [Google Scholar] [CrossRef]
  21. Pyo, C.-W.; Guethlein, L.A.; Vu, Q.; Wang, R.; Abi-Rached, L.; Norman, P.J.; Marsh, S.G.; Miller, J.S.; Parham, P.; Geraghty, D.E. Different patterns of evolution in the centromeric and telomeric regions of group A and B haplotypes of the human killer cell Ig-like receptor locus. PLoS ONE 2010, 5, e15115. [Google Scholar] [CrossRef] [PubMed]
  22. Jiang, W.; Johnson, C.; Jayaraman, J.; Simecek, N.; Noble, J.; Moffatt, M.F.; Cookson, W.O.; Trowsdale, J.; Traherne, J.A. Copy number variation leads to considerable diversity for B but not A haplotypes of the human KIR genes encoding NK cell receptors. Genome Res. 2012, 22, 1845–1854. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Mavers, M.; Bertaina, A. High-Risk Leukemia: Past, Present, and Future Role of NK Cells. J. Immunol. Res. 2018, 2018, 1586905. [Google Scholar] [CrossRef] [PubMed]
  24. Imai, K.; Matsuyama, S.; Miyake, S.; Suga, K.; Nakachi, K. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: An 11-year follow-up study of a general population. Lancet 2000, 356, 1795–1799. [Google Scholar] [CrossRef]
  25. Lee, J.; Park, K.H.; Ryu, J.H.; Bae, H.J.; Choi, A.; Lee, H.; Lim, J.; Han, K.; Park, C.H.; Jung, E.S.; et al. Natural killer cell activity for IFN-gamma production as a supportive diagnostic marker for gastric cancer. Oncotarget 2017, 8, 70431–70440. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Jobin, G.; Rodriguez-Suarez, R.; Betito, K. Association Between Natural Killer Cell Activity and Colorectal Cancer in High-Risk Subjects Undergoing Colonoscopy. Gastroenterology 2017, 153, 980–987. [Google Scholar] [CrossRef] [PubMed]
  27. Koo, K.C.; Shim, D.H.; Yang, C.M.; Lee, S.B.; Kim, S.M.; Shin, T.Y.; Kim, K.H.; Yoon, H.G.; Rha, K.H.; Lee, J.M.; et al. Reduction of the CD16(-)CD56bright NK cell subset precedes NK cell dysfunction in prostate cancer. PLoS ONE 2013, 8, e78049. [Google Scholar] [CrossRef]
  28. Barkin, J.; Rodriguez-Suarez, R.; Betito, K. Association between natural killer cell activity and prostate cancer: A pilot study. Can. J. Urol. 2017, 24, 8708–8713. [Google Scholar]
  29. Lee, S.B.; Cha, J.; Kim, I.K.; Yoon, J.C.; Lee, H.J.; Park, S.W.; Cho, S.; Youn, D.Y.; Lee, H.; Lee, C.H.; et al. A high-throughput assay of NK cell activity in whole blood and its clinical application. Biochem. Biophys. Res. Commun. 2014, 445, 584–590. [Google Scholar] [CrossRef]
  30. Schmidt, S.; Tramsen, L.; Rais, B.; Ullrich, E.; Lehrnbecher, T. Natural killer cells as a therapeutic tool for infectious diseases—Current status and future perspectives. Oncotarget 2018, 9, 20891–20907. [Google Scholar] [CrossRef]
  31. Fang, F.; Xiao, W.; Tian, Z. Challenges of NK cell-based immunotherapy in the new era. Front. Med. 2018. [Google Scholar] [CrossRef] [PubMed]
  32. Grossenbacher, S.K.; Canter, R.J.; Murphy, W.J. Natural killer cell immunotherapy to target stem-like tumor cells. J. Immunother. Cancer 2016, 4, 19. [Google Scholar] [CrossRef] [PubMed]
  33. Oh, S.J.; Yang, J.I.; Kim, O.; Ahn, E.J.; Kang, W.D.; Lee, J.H.; Moon, K.S.; Lee, K.H.; Cho, D. Human U87 glioblastoma cells with stemness features display enhanced sensitivity to natural killer cell cytotoxicity through altered expression of NKG2D ligand. Cancer Cell Int. 2017, 17, 22. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Marrufo, A.M.; Mathew, S.O.; Chaudhary, P.; Malaer, J.D.; Vishwanatha, J.K.; Mathew, P.A. Blocking LLT1 (CLEC2D, OCIL)-NKRP1A (CD161) interaction enhances natural killer cell-mediated lysis of triple-negative breast cancer cells. Am. J. Cancer Res. 2018, 8, 1050–1063. [Google Scholar] [PubMed]
  35. Cong, J.; Wang, X.; Zheng, X.; Wang, D.; Fu, B.; Sun, R.; Tian, Z.; Wei, H. Dysfunction of Natural Killer Cells by FBP1-Induced Inhibition of Glycolysis during Lung Cancer Progression. Cell Metab. 2018. [Google Scholar] [CrossRef] [PubMed]
  36. Sun, Y.; Yao, Z.; Zhao, Z.; Xiao, H.; Xia, M.; Zhu, X.; Jiang, X.; Sun, C. Natural killer cells inhibit metastasis of ovarian carcinoma cells and show therapeutic effects in a murine model of ovarian cancer. Exp. Ther. Med. 2018, 16, 1071–1078. [Google Scholar] [CrossRef] [PubMed]
  37. Orange, J.S. Human natural killer cell deficiencies and susceptibility to infection. Microbes Infect. 2002, 4, 1545–1558. [Google Scholar] [CrossRef]
  38. Ballas, Z.K.; Turner, J.M.; Turner, D.A.; Goetzman, E.A.; Kemp, J.D. A patient with simultaneous absence of “classical” natural killer cells (CD3-, CD16+, and NKH1+) and expansion of CD3+, CD4-, CD8-, NKH1+ subset. J. Allergy Clin. Immunol. 1990, 85, 453–459. [Google Scholar] [CrossRef]
  39. Komiyama, A.; Kawai, H.; Yabuhara, A.; Yanagisawa, M.; Miyagawa, Y.; Ota, M.; Hasekura, H.; Akabane, T. Natural killer cell immunodeficiency in siblings: Defective killing in the absence of natural killer cytotoxic factor activity in natural killer and lymphokine-activated killer cytotoxicities. Pediatrics 1990, 85, 323–330. [Google Scholar]
  40. Grier, J.T.; Forbes, L.R.; Monaco-Shawver, L.; Oshinsky, J.; Atkinson, T.P.; Moody, C.; Pandey, R.; Campbell, K.S.; Orange, J.S. Human immunodeficiency-causing mutation defines CD16 in spontaneous NK cell cytotoxicity. J. Clin. Investig. 2012, 122, 3769–3780. [Google Scholar] [CrossRef]
  41. Jawahar, S.; Moody, C.; Chan, M.; Finberg, R.; Geha, R.; Chatila, T. Natural Killer (NK) cell deficiency associated with an epitope-deficient Fc receptor type IIIA (CD16-II). Clin. Exp. Immunol. 1996, 103, 408–413. [Google Scholar] [CrossRef] [PubMed]
  42. de Vries, E.; Koene, H.R.; Vossen, J.M.; Gratama, J.W.; von dem Borne, A.E.; Waaijer, J.L.; Haraldsson, A.; de Haas, M.; van Tol, M.J. Identification of an unusual Fc gamma receptor IIIa (CD16) on natural killer cells in a patient with recurrent infections. Blood 1996, 88, 3022–3027. [Google Scholar] [PubMed]
  43. Biron, C.A.; Byron, K.S.; Sullivan, J.L. Severe herpesvirus infections in an adolescent without natural killer cells. N. Engl. J. Med. 1989, 320, 1731–1735. [Google Scholar] [CrossRef] [PubMed]
  44. Fleisher, G.; Starr, S.; Koven, N.; Kamiya, H.; Douglas, S.D.; Henle, W. A non-x-linked syndrome with susceptibility to severe Epstein-Barr virus infections. J. Pediatr. 1982, 100, 727–730. [Google Scholar] [CrossRef]
  45. Xu, X.; Li, J.; Zou, J.; Feng, X.; Zhang, C.; Zheng, R.; Duanmu, W.; Saha-Mandal, A.; Ming, Z.; Wang, E. Association of Germline Variants in Natural Killer Cells with Tumor Immune Microenvironment Subtypes, Tumor-Infiltrating Lymphocytes, Immunotherapy Response, Clinical Outcomes, and Cancer Risk. JAMA Network Open 2019, 2, e199292. [Google Scholar] [CrossRef] [PubMed]
  46. Bottcher, J.P.; Bonavita, E.; Chakravarty, P.; Blees, H.; Cabeza-Cabrerizo, M.; Sammicheli, S.; Rogers, N.C.; Sahai, E.; Zelenay, S.; Reis e Sousa, C. NK Cells Stimulate Recruitment of cDC1 into the Tumor Microenvironment Promoting Cancer Immune Control. Cell 2018, 172, 1022–1037. [Google Scholar] [CrossRef] [PubMed]
  47. Barry, K.C.; Hsu, J.; Broz, M.L.; Cueto, F.J.; Binnewies, M.; Combes, A.J.; Nelson, A.E.; Loo, K.; Kumar, R.; Rosenblum, M.D.; et al. A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments. Nat. Med. 2018, 24, 1178–1191. [Google Scholar] [CrossRef] [PubMed]
  48. Rosenberg, S.A.; Lotze, M.T.; Muul, L.M.; Chang, A.E.; Avis, F.P.; Leitman, S.; Linehan, W.M.; Robertson, C.N.; Lee, R.E.; Rubin, J.T.; et al. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N. Engl. J. Med. 1987, 316, 889–897. [Google Scholar] [CrossRef]
  49. Rosenberg, S.A.; Lotze, M.T.; Muul, L.M.; Leitman, S.; Chang, A.E.; Ettinghausen, S.E.; Matory, Y.L.; Skibber, J.M.; Shiloni, E.; Vetto, J.T. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N. Engl. J. Med. 1985, 313, 1485–1492. [Google Scholar] [CrossRef]
  50. Onishi, S.; Saibara, T.; Fujikawa, M.; Sakaeda, H.; Matsuura, Y.; Matsunaga, Y.; Yamamoto, Y. Adoptive immunotherapy with lymphokine-activated killer cells plus recombinant interleukin 2 in patients with unresectable hepatocellular carcinoma. Hepatology 1989, 10, 349–353. [Google Scholar] [CrossRef]
  51. Une, Y.; Kawata, A.; Uchino, J. [Adopted immunochemotherapy using IL-2 and spleen LAK cell—Randomized study]. Nihon Geka Gakkai Zasshi 1991, 92, 1330–1333. [Google Scholar] [PubMed]
  52. Takayama, T.; Sekine, T.; Makuuchi, M.; Yamasaki, S.; Kosuge, T.; Yamamoto, J.; Shimada, K.; Sakamoto, M.; Hirohashi, S.; Ohashi, Y.; et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: A randomised trial. Lancet 2000, 356, 802–807. [Google Scholar] [CrossRef]
  53. Kimura, H.; Yamaguchi, Y. A phase III randomized study of interleukin-2 lymphokine-activated killer cell immunotherapy combined with chemotherapy or radiotherapy after curative or noncurative resection of primary lung carcinoma. Cancer 1997, 80, 42–49. [Google Scholar] [CrossRef]
  54. Fang, F.; Xiao, W.; Tian, Z. NK cell-based immunotherapy for cancer. Seminars Immunol. 2017, 31, 37–54. [Google Scholar] [CrossRef] [PubMed]
  55. Kawata, A.; Une, Y.; Hosokawa, M.; Wakizaka, Y.; Namieno, T.; Uchino, J.; Kobayashi, H. Adjuvant chemoimmunotherapy for hepatocellular carcinoma patients. Adriamycin, interleukin-2, and lymphokine-activated killer cells versus adriamycin alone. Am. J. Clin. Oncol. 1995, 18, 257–262. [Google Scholar] [CrossRef] [PubMed]
  56. Burns, L.J.; Weisdorf, D.J.; DeFor, T.E.; Vesole, D.H.; Repka, T.L.; Blazar, B.R.; Burger, S.R.; Panoskaltsis-Mortari, A.; Keever-Taylor, C.A.; Zhang, M.J.; et al. IL-2-based immunotherapy after autologous transplantation for lymphoma and breast cancer induces immune activation and cytokine release: A phase I/II trial. Bone Marrow Transp. 2003, 32, 177–186. [Google Scholar] [CrossRef] [PubMed]
  57. Hu, W.; Wang, G.; Huang, D.; Sui, M.; Xu, Y. Cancer Immunotherapy Based on Natural Killer Cells: Current Progress and New Opportunities. Front Immunol. 2019, 10, 1205. [Google Scholar] [CrossRef]
  58. Wang, K.; Han, Y.; Cho, W.C.; Zhu, H. The rise of human stem cell-derived natural killer cells for cancer immunotherapy. Expert Opin. Biol. Ther. 2018, 1–8. [Google Scholar] [CrossRef] [PubMed]
  59. Yoon, S.R.; Lee, Y.S.; Yang, S.H.; Ahn, K.H.; Lee, J.H.; Lee, J.H.; Kim, D.Y.; Kang, Y.A.; Jeon, M.; Seol, M.; et al. Generation of donor natural killer cells from CD34(+) progenitor cells and subsequent infusion after HLA-mismatched allogeneic hematopoietic cell transplantation: A feasibility study. Bone Marrow Transp. 2010, 45, 1038–1046. [Google Scholar] [CrossRef] [PubMed]
  60. Alves, P.C.M.; De Angelo Andrade, L.A.L.; Petta, C.A.; Lorand-Metze, I.; Derchain, S.F.; Guimaraes, F. Ex vivo expansion of CD56+ NK and NKT-like lymphocytes from peripheral blood mononuclear cells of patients with ovarian neoplasia. Scand. J. Immunol. 2011, 74, 244–252. [Google Scholar] [CrossRef]
  61. Veluchamy, J.P.; Kok, N.; van der Vliet, H.J.; Verheul, H.M.W.; de Gruijl, T.D.; Spanholtz, J. The Rise of Allogeneic Natural Killer Cells As a Platform for Cancer Immunotherapy: Recent Innovations and Future Developments. Front. Immunol. 2017, 8, 631. [Google Scholar] [CrossRef] [PubMed]
  62. Poznanski, S.M.; Nham, T.; Chew, M.V.; Lee, A.J.; Hammill, J.A.; Fan, I.Y.; Butcher, M.; Bramson, J.L.; Lee, D.A.; Hirte, H.W.; et al. Expanded CD56superbrightCD16+ NK cells from ovarian cancer patients are cytotoxic against autologous tumor in a patient-derived xenograft murine model. Cancer Immunol. Res. 2018. [Google Scholar] [CrossRef] [PubMed]
  63. Ishikawa, E.; Tsuboi, K.; Saijo, K.; Harada, H.; Takano, S.; Nose, T.; Ohno, T. Autologous natural killer cell therapy for human recurrent malignant glioma. Anticancer Res. 2004, 24, 1861–1871. [Google Scholar] [PubMed]
  64. Krause, S.W.; Gastpar, R.; Andreesen, R.; Gross, C.; Ullrich, H.; Thonigs, G.; Pfister, K.; Multhoff, G. Treatment of colon and lung cancer patients with ex vivo heat shock protein 70-peptide-activated, autologous natural killer cells: A clinical phase i trial. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2004, 10, 3699–3707. [Google Scholar] [CrossRef] [PubMed]
  65. Parkhurst, M.R.; Riley, J.P.; Dudley, M.E.; Rosenberg, S.A. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2011, 17, 6287–6297. [Google Scholar] [CrossRef] [PubMed]
  66. Ryoma, Y.; Moriya, Y.; Okamoto, M.; Kanaya, I.; Saito, M.; Sato, M. Biological effect of OK-432 (picibanil) and possible application to dendritic cell therapy. Anticancer Res. 2004, 24, 3295–3301. [Google Scholar] [PubMed]
  67. Sudo, T.; Aruga, A.; Shimizu, K.; Matsushita, N.; Takasaki, K. OK432-activated Natural Killer Cells Enhanced Trastuzumab (Herceptin®)-mediated Antibody-dependent Cellular Cytotoxicity in Patients with Advanced Cancer. Anticancer Res. 2006, 26, 4327–4333. [Google Scholar] [PubMed]
  68. Sakamoto, N.; Ishikawa, T.; Kokura, S.; Okayama, T.; Oka, K.; Ideno, M.; Sakai, F.; Kato, A.; Tanabe, M.; Enoki, T.; et al. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. J. Trans. Med. 2015, 13, 277. [Google Scholar] [CrossRef] [PubMed]
  69. Ishikawa, T.; Okayama, T.; Sakamoto, N.; Ideno, M.; Oka, K.; Enoki, T.; Mineno, J.; Yoshida, N.; Katada, K.; Kamada, K.; et al. Phase I clinical trial of adoptive transfer of expanded natural killer cells in combination with IgG1 antibody in patients with gastric or colorectal cancer. Int. J. Cancer 2018, 142, 2599–2609. [Google Scholar] [CrossRef]
  70. Li, L.; Li, W.; Wang, C.; Yan, X.; Wang, Y.; Niu, C.; Zhang, X.; Li, M.; Tian, H.; Yao, C.; et al. Adoptive transfer of natural killer cells in combination with chemotherapy improves outcomes of patients with locally advanced colon carcinoma. Cytotherapy 2018, 20, 134–148. [Google Scholar] [CrossRef]
  71. Xie, S.; Wu, Z.; Niu, L.; Chen, J.; Ma, Y.; Zhang, M. Preparation of highly activated natural killer cells for advanced lung cancer therapy. Oncol. Targets Ther. 2019, 12, 5077–5086. [Google Scholar] [CrossRef] [PubMed]
  72. Kokowski, K.; Stangl, S.; Seier, S.; Hildebrandt, M.; Vaupel, P.; Multhoff, G. Radiochemotherapy combined with NK cell transfer followed by second-line PD-1 inhibition in a patient with NSCLC stage IIIb inducing long-term tumor control: A case study. Strahlentherapie und Onkologie Organ der Deutschen Rontgengesellschaft 2019, 195, 352–361. [Google Scholar] [CrossRef] [PubMed]
  73. Locatelli, F.; Pende, D.; Falco, M.; Della Chiesa, M.; Moretta, A.; Moretta, L. NK Cells Mediate a Crucial Graft-versus-Leukemia Effect in Haploidentical-HSCT to Cure High-Risk Acute Leukemia. Trends Immunol. 2018, 39, 577–590. [Google Scholar] [CrossRef] [PubMed]
  74. Aversa, F.; Tabilio, A.; Velardi, A.; Cunningham, I.; Terenzi, A.; Falzetti, F.; Ruggeri, L.; Barbabietola, G.; Aristei, C.; Latini, P.; et al. Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. N. Engl. J. Med. 1998, 339, 1186–1193. [Google Scholar] [CrossRef] [PubMed]
  75. Ruggeri, L.; Capanni, M.; Casucci, M.; Volpi, I.; Tosti, A.; Perruccio, K.; Urbani, E.; Negrin, R.S.; Martelli, M.F.; Velardi, A. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. Blood 1999, 94, 333–339. [Google Scholar] [PubMed]
  76. Ruggeri, L.; Mancusi, A.; Capanni, M.; Urbani, E.; Carotti, A.; Aloisi, T.; Stern, M.; Pende, D.; Perruccio, K.; Burchielli, E.; et al. Donor natural killer cell allorecognition of missing self in haploidentical hematopoietic transplantation for acute myeloid leukemia: Challenging its predictive value. Blood 2007, 110, 433–440. [Google Scholar] [CrossRef] [PubMed]
  77. Ruggeri, L.; Capanni, M.; Urbani, E.; Perruccio, K.; Shlomchik, W.D.; Tosti, A.; Posati, S.; Rogaia, D.; Frassoni, F.; Aversa, F. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002, 295, 2097–2100. [Google Scholar] [CrossRef] [PubMed]
  78. Miller, J.S.; Soignier, Y.; Panoskaltsis-Mortari, A.; McNearney, S.A.; Yun, G.H.; Fautsch, S.K.; McKenna, D.; Le, C.; Defor, T.E.; Burns, L.J.; et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 2005, 105, 3051–3057. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  79. Brehm, C.; Huenecke, S.; Quaiser, A.; Esser, R.; Bremm, M.; Kloess, S.; Soerensen, J.; Kreyenberg, H.; Seidl, C.; Becker, P.S.; et al. IL-2 stimulated but not unstimulated NK cells induce selective disappearance of peripheral blood cells: Concomitant results to a phase I/II study. PLoS ONE 2011, 6, e27351. [Google Scholar] [CrossRef]
  80. Stern, M.; Passweg, J.R.; Meyer-Monard, S.; Esser, R.; Tonn, T.; Soerensen, J.; Paulussen, M.; Gratwohl, A.; Klingebiel, T.; Bader, P.; et al. Pre-emptive immunotherapy with purified natural killer cells after haploidentical SCT: A prospective phase II study in two centers. Bone Marrow Transp. 2013, 48, 433–438. [Google Scholar] [CrossRef] [PubMed]
  81. Barkholt, L.; Alici, E.; Conrad, R.; Sutlu, T.; Gilljam, M.; Stellan, B.; Christensson, B.; Guven, H.; Bjorkstrom, N.K.; Soderdahl, G.; et al. Safety analysis of ex vivo-expanded NK and NK-like T cells administered to cancer patients: A phase I clinical study. Immunotherapy 2009, 1, 753–764. [Google Scholar] [CrossRef] [PubMed]
  82. Geller, M.A.; Cooley, S.; Judson, P.L.; Ghebre, R.; Carson, L.F.; Argenta, P.A.; Jonson, A.L.; Panoskaltsis-Mortari, A.; Curtsinger, J.; McKenna, D.; et al. A phase II study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer. Cytotherapy 2011, 13, 98–107. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Iliopoulou, E.G.; Kountourakis, P.; Karamouzis, M.V.; Doufexis, D.; Ardavanis, A.; Baxevanis, C.N.; Rigatos, G.; Papamichail, M.; Perez, S.A. A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer. Cancer Immunol. Immunother. CII 2010, 59, 1781–1789. [Google Scholar] [CrossRef] [PubMed]
  84. Yang, Y.; Lim, O.; Kim, T.M.; Ahn, Y.O.; Choi, H.; Chung, H.; Min, B.; Her, J.H.; Cho, S.Y.; Keam, B.; et al. Phase I Study of Random Healthy Donor-Derived Allogeneic Natural Killer Cell Therapy in Patients with Malignant Lymphoma or Advanced Solid Tumors. Cancer Immunol. Res. 2016, 4, 215–224. [Google Scholar] [CrossRef] [PubMed]
  85. Modak, S.; Le Luduec, J.B.; Cheung, I.Y. Adoptive immunotherapy with haploidentical natural killer cells and Anti-GD2 monoclonal antibody m3F8 for resistant neuroblastoma: Results of a phase I study. Oncoimmunology 2018, 7, e1461305. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Alnaggar, M.; Lin, M.; Mesmar, A.; Liang, S.; Qaid, A.; Xu, K.; Chen, J.; Niu, L.; Yin, Z. Allogenic Natural Killer Cell Immunotherapy Combined with Irreversible Electroporation for Stage IV Hepatocellular Carcinoma: Survival Outcome. Cellular Physiol. Biochem. Int. J. Exp. Cellular Physiol. Biochem. Pharmacol. 2018, 48, 1882–1893. [Google Scholar] [CrossRef] [PubMed]
  87. Yang, Y.; Qin, Z.; Du, D. Safety and Short-Term Efficacy of Irreversible Electroporation and Allogenic Natural Killer Cell Immunotherapy Combination in the Treatment of Patients with Unresectable Primary Liver Cancer. Cardiovasc. Interv. Radiol. 2019, 42, 48–59. [Google Scholar] [CrossRef] [PubMed]
  88. Arai, S.; Meagher, R.; Swearingen, M.; Myint, H.; Rich, E.; Martinson, J.; Klingemann, H. Infusion of the allogeneic cell line NK-92 in patients with advanced renal cell cancer or melanoma: A phase I trial. Cytotherapy 2008, 10, 625–632. [Google Scholar] [CrossRef]
  89. Tonn, T.; Schwabe, D.; Klingemann, H.G.; Becker, S.; Esser, R.; Koehl, U.; Suttorp, M.; Seifried, E.; Ottmann, O.G.; Bug, G. Treatment of patients with advanced cancer with the natural killer cell line NK-92. Cytotherapy 2013, 15, 1563–1570. [Google Scholar] [CrossRef]
  90. Liang, S.; Xu, K.; Niu, L.; Wang, X.; Liang, Y.; Zhang, M.; Chen, J.; Lin, M. comparison of autogeneic and allogeneic natural killer cells immunotherapy on the clinical outcome of recurrent breast cancer. OncoTargets Ther. 2017, 10, 4273. [Google Scholar] [CrossRef]
  91. Mukherjee, N.; Ji, N.; Hurez, V.; Curiel, T.J.; Montgomery, M.O.; Braun, A.J.; Nicolas, M.; Aguilera, M.; Kaushik, D.; Liu, Q.; et al. Intratumoral CD56(bright) natural killer cells are associated with improved survival in bladder cancer. Oncotarget 2018, 9, 36492–36502. [Google Scholar] [CrossRef] [PubMed]
  92. Bjorklund, A.T.; Clancy, T.; Goodridge, J.P.; Beziat, V.; Schaffer, M.; Hovig, E.; Ljunggren, H.G.; Ljungman, P.T.; Malmberg, K.J. Naive Donor NK Cell Repertoires Associated with Less Leukemia Relapse after Allogeneic Hematopoietic Stem Cell Transplantation. J. Immunol. 2016, 196, 1400–1411. [Google Scholar] [CrossRef] [PubMed]
  93. Romee, R.; Rosario, M.; Berrien-Elliott, M.M.; Wagner, J.A.; Jewell, B.A.; Schappe, T.; Leong, J.W.; Abdel-Latif, S.; Schneider, S.E.; Willey, S.; et al. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Sci. Trans. Med. 2016, 8, 357ra123. [Google Scholar] [CrossRef] [PubMed]
  94. Foley, B.; Cooley, S.; Verneris, M.; Pitt, M.; Curtsinger, J.; Luo, X.; Lopez-Verges, S.; Lanier, L.L.; Weisdorf, D.; Miller, J.S. Cytomegalovirus reactivation after 494 allogeneic transplantation promotes a lasting increase in educated NKG2C+ natural 495 killer cells with potent function. Blood 2012, 119, 2665–2674. [Google Scholar] [CrossRef] [PubMed]
  95. Muccio, L.; Bertaina, A.; Falco, M.; Pende, D.; Meazza, R.; Lopez-Botet, M.; Moretta, L.; Locatelli, F.; Moretta, A.; Della Chiesa, M. Analysis of memory-like natural killer cells in human cytomegalovirus-infected children undergoing alphabeta+T and B cell-depleted hematopoietic stem cell transplantation for hematological malignancies. Haematologica 2016, 101, 371–381. [Google Scholar] [CrossRef] [PubMed]
  96. Della Chiesa, M.; Falco, M.; Muccio, L.; Bertaina, A.; Locatelli, F.; Moretta, A. Impact of HCMV infection on NK cell development and function after HSCT. Front. Immunol. 2013, 4, 458. [Google Scholar] [CrossRef] [PubMed]
  97. Cichocki, F.; Cooley, S.; Davis, Z.; DeFor, T.E.; Schlums, H.; Zhang, B.; Brunstein, C.G.; Blazar, B.R.; Wagner, J.; Diamond, D.J.; et al. CD56dimCD57+NKG2C+ NK cell expansion is associated with reduced leukemia relapse after reduced intensity HCT. Leukemia 2016, 30, 456–463. [Google Scholar] [CrossRef] [PubMed]
  98. Schuch, A.; Zecher, B.F.; Muller, P.A.; Correia, M.P.; Daul, F.; Rennert, C.; Tauber, C.; Schlitt, K.; Boettler, T.; Neumann-Haefelin, C.; et al. NK-cell responses are biased towards CD16-mediated effector functions in chronic hepatitis B virus infection. J. Hepatol. 2018. [Google Scholar] [CrossRef] [PubMed]
  99. Poznanski, S.M.; Ashkar, A.A. Shining light on the significance of NK cell CD56 brightness. Cell Mol. Immunol. 2018, 15, 1071–1073. [Google Scholar] [CrossRef] [PubMed]
  100. Kozlowska, A.K.; Kaur, K.; Topchyan, P.; Jewett, A. Adoptive transfer of osteoclast-expanded natural killer cells for immunotherapy targeting cancer stem-like cells in humanized mice. Cancer Immunol. Immunoth. CII 2016, 65, 835–845. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  101. Parham, P. MHC class I molecules and KIRs in human history, health and survival. Nat. Rev. Immunol. 2005, 5, 201–214. [Google Scholar] [CrossRef] [PubMed]
  102. Kim, S.; Poursine-Laurent, J.; Truscott, S.M.; Lybarger, L.; Song, Y.J.; Yang, L.; French, A.R.; Sunwoo, J.B.; Lemieux, S.; Hansen, T.H.; et al. Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature 2005, 436, 709–713. [Google Scholar] [CrossRef] [PubMed]
  103. Del Zotto, G.; Marcenaro, E.; Vacca, P.; Sivori, S.; Pende, D.; Della Chiesa, M.; Moretta, F.; Ingegnere, T.; Mingari, M.C.; Moretta, A.; et al. Markers and function of human NK cells in normal and pathological conditions. Cytometry Part B Clin. Cytometry 2017, 92, 100–114. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Streltsova, M.A.; Erokhina, S.A.; Kanevskiy, L.M.; Lee, D.A.; Telford, W.G.; Sapozhnikov, A.M.; Kovalenko, E.I. Analysis of NK cell clones obtained using interleukin-2 and gene-modified K562 cells revealed the ability of “senescent” NK cells to lose CD57 expression and start expressing NKG2A. PLoS ONE 2018, 13, e0208469. [Google Scholar] [CrossRef] [PubMed]
  105. Asgari, A.; Sharifzadeh, S.; Ghaderi, A.; Hosseini, A.; Ramezani, A. In vitro cytotoxic effect of Trastuzumab in combination with Pertuzumab in breast cancer cells is improved by interleukin-2 activated NK cells. Mol. Biol. Rep. 2019. [Google Scholar] [CrossRef] [PubMed]
  106. Julia, E.P.; Amante, A.; Pampena, M.B.; Mordoh, J.; Levy, E.M. Avelumab, an IgG1 anti-PD-L1 Immune Checkpoint Inhibitor, Triggers NK Cell-Mediated Cytotoxicity and Cytokine Production Against Triple Negative Breast Cancer Cells. Front. Immunol. 2018, 9, 2140. [Google Scholar] [CrossRef] [PubMed]
  107. Barry, W.E.; Jackson, J.R.; Asuelime, G.E.; Wu, H.W.; Sun, J.; Wan, Z.; Malvar, J.; Sheard, M.A.; Wang, L.; Seeger, R.C.; et al. Activated Natural Killer Cells in Combination with Anti-GD2 Antibody Dinutuximab Improve Survival of Mice after Surgical Resection of Primary Neuroblastoma. Clin. Cancer Res. 2019, 25, 325–333. [Google Scholar] [CrossRef] [PubMed]
  108. Giles, A.J.; Hao, S.; Padget, M.R.; Song, H.; Zhang, W.; Lynes, J.; Sanchez, V.E.; Liu, Y.; Jung, J.; Cao, X.; et al. Efficient ADCC-killing of meningioma by avelumab and a high-affinity natural killer cell line, haNK. JCI Insight 2019. [Google Scholar] [CrossRef] [PubMed]
  109. Hsu, J.; Hodgins, J.J.; Marathe, M.; Nicolai, C.J.; Bourgeois-Daigneault, M.C.; Trevino, T.N.; Azimi, C.S.; Scheer, A.K.; Randolph, H.E.; Thompson, T.W.; et al. Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade. J. Clin. Investig. 2018, 128, 4654–4668. [Google Scholar] [CrossRef] [PubMed]
  110. Oyer, J.L.; Gitto, S.B. PD-L1 blockade enhances anti-tumor efficacy of NK cells. Front. Immunol. 2018, 7, e1509819. [Google Scholar] [CrossRef] [PubMed]
  111. Kohga, K.; Takehara, T.; Tatsumi, T.; Ishida, H.; Miyagi, T.; Hosui, A.; Hayashi, N. Sorafenib inhibits the shedding of major histocompatibility complex class I-related chain A on hepatocellular carcinoma cells by down-regulating a disintegrin and metalloproteinase 9. Hepatology 2010, 51, 1264–1273. [Google Scholar] [CrossRef] [PubMed]
  112. Arai, J.; Goto, K.; Stephanou, A.; Tanoue, Y.; Ito, S.; Muroyama, R.; Matsubara, Y.; Nakagawa, R.; Morimoto, S.; Kaise, Y.; et al. Predominance of regorafenib over sorafenib: Restoration of membrane-bound MICA in hepatocellular carcinoma cells. J. Gastroenterol. Hepatol. 2018, 33, 1075–1081. [Google Scholar] [CrossRef] [PubMed]
  113. Zhang, Q.; Zhang, H.; Ding, J.; Liu, H.; Li, H.; Li, H.; Lu, M.; Miao, Y.; Li, L.; Zheng, J. Combination Therapy with EpCAM-CAR-NK-92 Cells and Regorafenib against Human Colorectal Cancer Models. J. Immunol. Res. 2018, 2018, 4263520. [Google Scholar] [CrossRef] [PubMed]
  114. Hosseinzadeh, F.; Verdi, J.; Ai, J.; Hajighasemlou, S.; Seyhoun, I.; Parvizpour, F.; Hosseinzadeh, F.; Iranikhah, A.; Shirian, S. Combinational immune-cell therapy of natural killer cells and sorafenib for advanced hepatocellular carcinoma: A review. Cancer Cell Int. 2018, 18, 133. [Google Scholar] [CrossRef] [PubMed]
  115. Daher, M.; Rezvani, K. Next generation natural killer cells for cancer immunotherapy: The promise of genetic engineering. Curr. Opin. Immunol. 2018, 51, 146–153. [Google Scholar] [CrossRef]
Table
Table 1. On-going clinical trials on natural killer (NK) cell therapy for solid tumors.
Table 1. On-going clinical trials on natural killer (NK) cell therapy for solid tumors.
IdentifierPhaseStatusStart YearTitleConditionNK Cell SourceCountryLocation
NCT00720785IRecruiting2008Natural Killer Cells and Bortezomib to Treat CancerChronic Myeloid Leukemia, Multiple Myeloma, Pancreatic/Colon/Rectal/Non-small Cell Lung CancerAutologousUSANational Institutes of Health Clinical Center
NCT01807468IIActive, not recruiting2013Haploidentical Stem Cell Transplantation and NK Cell Therapy in Patients with High-risk Solid TumorsNeuroblastoma, Ewing Sarcoma, Rhabdomyosarcoma, Osteosarcoma, Soft Tissue SarcomaHaploidenticalRepublic of KoreaSamsung Medical Center
NCT01857934IIRecruiting2013Therapy for Children with Advanced Stage NeuroblastomaNeuroblastomaAllogeneicUSASt. Jude Children’s Research Hospital
NCT02100891IIRecruiting2014Phase 2 STIR Trial: Haploidentical Transplant and Donor Natural Killer Cells for Solid TumorsEwing Sarcoma, Neuroblastoma, Rhabdomyosarcoma, Osteosarcoma, CNS TumorsHaploidenticalRepublic of KoreaSamsung Medical Center
NCT02271711IRecruiting2015Expanded Natural Killer Cell Infusion in Treating Younger Patients with Recurrent/Refractory Brain TumorsMedulloblastoma/Ependymoma/MedulloblastomaAutologousUSAM.D. Anderson Cancer Center
NCT02370017IIRecruiting2015Combined Effect of Natural Killer Cell and Doublet Chemotherapy in Advanced NSCLC as the 1st Line TreatmentNon-small Cell Lung CancerAutologousRepublic of KoreaDaejeon St. Mary’s Hospital
NCT02507154I/IIRecruiting2015Reactivating NK Cells in Treating Refractory Head and Neck CancerNasopharyngeal Cancer, Head and Neck Squamous Cell CarcinomaAutologousSingaporeNational University Hospital
NCT02409576I/IIRecruiting2015Pilot Study of Expanded, Activated Haploidentical Natural Killer Cell Infusions for SarcomasEwing Sarcoma, RhabdomyosarcomaAllogeneicSingaporeNational University Hospital
NCT02465957IIActive, not recruiting2015QUILT-3.009: Patients with Stage IIIB or Stage IV Merkel Cell CarcinomaStage IIIB Merkel Cell Carcinoma, Stage IV Merkel Cell CarcinomaNK-92USARobert H. Lurie Comprehensive Cancer Center and 2 more locations
NCT02734524IIRecruiting2016A Clinical Research of NK Cell Infusion Combined with Chemotherapy in the Treatment of Non-small Cell Lung CancerNon-small Cell Lung CancerAutologousChinaSouthwest Hospital of Third Millitary Medical University
NCT02650648IRecruiting2016Humanized Anti-GD2 Antibody Hu3F8 and Allogeneic Natural Killer Cells for High-Risk NeuroblastomaNeuroblastomaBlood-related and haploidenticalUSAMemorial Sloan Kettering Cancer Center
NCT03242603I/IIRecruiting2017Immunotherapy of Neuroblastoma Patients Using a Combination of Anti-GD2 and NK CellsNeuroblastomaHaploidenticalSingaporeNational University Hospital
NCT03213964IRecruiting2017Intraperitoneal Delivery of Adaptive Natural Killer Cells (FATE-NK100) with Intraperitoneal Interleukin-2 in Women with Recurrent Ovarian, Fallopian Tube, and Primary Peritoneal CancerEpithelial Ovarian Cancer, Fallopian Tube Cancer, Primary Peritoneal CancerHaploidentical or not fully HLA-matched related donorUSAXuzhu medical university Masonic Cancer Center
NCT03410368IIRecruiting2018NK Cell-based Immunotherapy as Maintenance Therapy for Small-Cell Lung Cancer.Small-Cell Lung CancerAutologousChinaThe First Hospital of Jilin University
NCT03420963IRecruiting2018Ex-Vivo Expanded Allogeneic NK Cells for The Treatment of Pediatric Solid TumorsRelapsed or Refractory Solid TumorsUmbilical cord bloodUSAM.D. Anderson Cancer Center
NCT02573896IRecruiting2018Immunotherapy of Relapsed Refractory Neuroblastoma with Expanded NK CellsNeuroblastomaAutologousUSAChildren’s Hospital Los Angeles and 11 more locations
NCT03619954IRecruiting2018NK Cells Infusion for Advanced MalignanciesAdvanced Malignant Tumors?ChinaAnhui Provincial cancer center
NCT03209869IRecruiting2018Treatment of Relapsed or Refractory Neuroblastoma with Expanded Haploidentical NK Cells and Hu14.18-IL2NeuroblastomaHaploidenticalUSAUniversity of Wisconsin Carbone Cancer Center
NCT03662477IRecruiting2018Effect of NK Cell Immunotherapy on Advanced Lung Adenocarcinoma Adenocarcinoma with EGFR MutationNon-small Cell Lung CancerAutologousChinaShenzhen Luohu Hospital
NCT03319459IRecruiting2018FATE-NK100 as Monotherapy and in Combination with Monoclonal Antibody in Subjects with Advanced Solid TumorsAdvanced Solid TumorsHaploidentical or not fully HLA-matched related donorUSAUCSD Moores Cancer Center and 3 more locations
NCT03634501I/IIRecruiting2018Clinical Study on Antitumor Effect Induced by Activated Primary Natural Killer CellsLung Cancer, Breast Cancer, Colon Cancer, Pancreatic Cancer, Ovarian CancerAutologous and/or umbilical cord bloodChinaXuanwu Hospital
NCT03882840I/IIRecruiting2019Induced-T Cell Like NK Cellular Immunotherapy for Cancer Lack of MHC-IAdvanced Cancer with Low or No Expression of MHC-IT-like NK cells (Engineered from patient T cells)ChinaThe Second Affiliated Hospital of Guangzhou Medical University
NCT03958097IIRecruiting2019A Pilot Study of NK Cell Combined with PD-1 Antibody as Second Line Therapy for Advanced Driver Mutation Negative Non-small Cell Lung CancerNon-small Cell Lung CancerAutologousChinaThe First Hospital of Jilin University
NCT03940820I/IIRecruiting2019Clinical Research of ROBO1 Specific CAR-NK Cells on Patients with Solid TumorsSolid TumorAnti-ROBO1 CAR-NK cellsChinaSuzhou Hospital Affiliated to Nanjing Medical University
NCT03941457I/IIRecruiting2019Clinical Research of ROBO1 Specific BiCAR-NK Cells on Patients with Pancreatic CancerPancreatic CancerAnti-ROBO1 CAR-NK cellsChinaDepartment of Radiology, Shanghai Ruijin Hospital
NCT03853317IIActive, not recruiting2019QUILT-3.063: A Study of N-803, haNK and Avelumab in Patients with Merkel Cell Carcinoma That Has Progressed after Checkpoint TherapyMerkel Cell CarcinomahaNK (an off-the-shelf CD16-targeted NK cells)USAChan Soon-Shiong Institute for Medicine
NCT03941262IRecruiting2019Autologous Natural Killer Cells in Participants with Pathologically Confirmed CancerRefractory CancerAutologousUSASarcoma Oncology Research Center
NCT03841110IRecruiting2019FT500 as Monotherapy and in Combination with Immune Checkpoint Inhibitors in Subjects with Advanced Solid TumorsAdvanced Solid TumorsFT500 (an off-the-shelf, iPSC-derived NK cells)USAUCSD Moores Cancer Center and 2 more locations

Share and Cite

MDPI and ACS Style

Oh, S.; Lee, J.-H.; Kwack, K.; Choi, S.-W. Natural Killer Cell Therapy: A New Treatment Paradigm for Solid Tumors. Cancers 2019, 11, 1534. https://doi.org/10.3390/cancers11101534

AMA Style

Oh S, Lee J-H, Kwack K, Choi S-W. Natural Killer Cell Therapy: A New Treatment Paradigm for Solid Tumors. Cancers. 2019; 11(10):1534. https://doi.org/10.3390/cancers11101534

Chicago/Turabian Style

Oh, Sooyeon, Joo-Ho Lee, KyuBum Kwack, and Sang-Woon Choi. 2019. "Natural Killer Cell Therapy: A New Treatment Paradigm for Solid Tumors" Cancers 11, no. 10: 1534. https://doi.org/10.3390/cancers11101534

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop