To circumvent these challenges, Bi- and tri-specific killer engagers, BiKEs and TriKEs, are in development as a complemental approach. However, since 1964, only Cordyceps NK cell therapy in solid tumors, therefore, strongly resembled those in hematologic malignancies. Hammer Q, et al. IL-2 was used to induce lymphokine-activated killer (LAK) cells, a heterogeneous population of cells consisting primarily of NK, NKT, and T cell for autologous killer cell-based cancer therapy decades ago [115]. 2017;8:458. The expanded human NK cells showed potent ADCC activities in vitro and superior tumor control in a mouse xenograft model of ovarian cancer when combined with Herceptin, an anti-HER2 antibody [87]. Highly efficient IL-21 and feeder cell-driven ex vivo expansion of human NK cells with therapeutic activity in a xenograft mouse model of melanoma. 2016;7:504. Choi I, et al. Cerwenka A, Lanier LL. NK cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma and prolong animal survival. However, NK cell therapy directed against solid tumors is still in early development. WebExperienced R&D leader in pharmaceutical industry focusing on biologics and cell therapy drug discovery for immuno-oncology. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. BMC Immunol. Li Y, et al. The combination of IL-2/IL-15/IL-21 can support up to eightfold expansion of NK cells [121]. However, a more complex scenario has recently emerged. Galat Y, et al. Glyostems lead candidate NK cell therapy is currently being tested in a phase 1/2a trial for the treatment of the blood cancer acute myeloid leukemia. 2017;32(2):13554. Good manufacturing practice-compliant cell sorting and large-scale expansion of single KIR-positive alloreactive human natural killer cells for multiple infusions to leukemia patients. Here, we review advances in current approaches to optimizing the NK cell antitumor response including combination with other immunotherapies, cytokines, checkpoint inhibition, and engineering NK cells with chimeric antigen receptors (CARs) for the treatment of pediatric solid tumors. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. NK Cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy. Moreover, restricted expansion capacity poses a difficulty for improving the efficacy of NK cells through genetic engineering. N Engl J Med. Although lethal irradiation of feeder cells before use is required, for safety concern, the residual contamination of feeder cells should be assessed. Lee J, et al. 2007;178(1):8594. 2016;18(5):65363. NK cells are a key member of the innate immune system, and while they have some similarities to cytotoxic T lymphocytes (CTLs) in term of killing features, they have an extra intrinsic capability to detect and kill transformed/mutant cells independent of specific antigen recognition processes indicating MHC-unrestricted cytotoxicity done with CXCL16 positively correlated with M2-macrophage infiltration, enhanced angiogenesis, and poor prognosis in thyroid cancer. 2017;177(3):45766. Natural killer (NK) cell is a specialized immune effector cell type that plays a critical role in immune activation against abnormal cells. Cichocki F, et al. Google Scholar. The natural cytotoxic receptor NKp46 is also often used to identify mouse and human NK cells in combination with the absence of CD3 expression. Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity. Han J, et al. Blood. Join us for this live, CME-certified symposium featuring an expert discussion of TROP2- and HER3-targeted antibody-drug conjugates and their current use in treating patients with solid tumors, including lung and breast cancers. Among these TCR cell co-stimulatory molecules, 4-1BB, DNAM1, 2B4, and NKG2D were also expressed by NK cells as native activating receptors. Article We want to do better, and this NK cell therapy is a promising NK cells in the tumor microenvironment Conventional roles of NK cells in immunity Detection of aberrant cells by NK cells is determined by the intergradation of It was suggested that induced expression of CD69 on NK cells is important for the cytotoxicity of the CTV-1 tumor cell-activated NK [88]. The success has encouraged many ongoing clinical investigations of NK cell-based cancer therapy alone or in combination with other regimes. Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors. Ex vivo-expanded NK cells from blood and ascites of ovarian cancer patients are cytotoxic against autologous primary ovarian cancer cells. 2017;2017:6915912. Due to their innate ability to eliminate tumor cells, NK cell-based immunotherapies against cancer have been investigated for decades. NK CELL-BASED THERAPY IN SOLID. Phase I/II clinical trials are ongoing to evaluate the safety and efficacy of NK cell combined with nimotuzumab to treat late-stage malignancies (NCT03554889) and of NK cell infusion on patients with advanced malignant tumors following multi-line therapies (NCT03619954). Veluchamy JP, et al. 2018;65:38-48.e1. 7 Potent Methods Mol Biol. One study showed that overnight co-incubation with a leukemia cell line CTV-1 or its lysate without cytokines was sufficient to prime potent NK cells in vitro cytotoxicity against otherwise NK-insensitive tumor cells but not normal hemopoietic cells [88]. J Immunol. Transcription factors involved in the regulation of natural killer cell development and function: an update. The subjects of the study were patients with high-risk solid tumors, including Ewing Sarcoma, Neuroblastoma, Rhabdomyosarcoma, Osteosarcoma, and CNS tumors. Wang J, et al. Some investigations have sought to enhance NK migration toward the tumor by genetically modifying NK cells to overexpress chemokine receptors [54, 59, 94]. NKp44-NKp44 ligand interactions in the regulation of natural killer cells and other innate lymphoid cells in humans. Curr Opin Immunol. Tumor boron neutron capture therapy (BNCT) subcutaneousC26 tumor-bearing BALB/c mice were intrave- nously injected PEG-b-P(Glu-SS-BSH)respectively 100mg/kg BSHbasis, when Through several preclinical studies, researchers have discovered new guardian immune cells called chimeric antigen receptor (CAR)-modified natural killer (NK) cells, which show cytotoxic activity against various solid tumor types. statement and 2020;382(6):54553. A novel method to expand large numbers of CD56(+) natural killer cells from a minute fraction of selectively accessed cryopreserved cord blood for immunotherapy after transplantation. Imai C, Iwamoto S, Campana D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. Due to relatively unsophisticated cues for activation, NK cell has gained significant attention in the field of cancer immunotherapy. While the majority of investigation of ex vivo NK priming strategies rely on one or more cytokines, some studies indicate that cytokine supplement is not as critical for NK cell priming. Chapter 5 Cordyceps as an Herbal Drug Bao-qin Lin and Shao-ping Li. CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. 2008;44(1):4653. WebNatural killer (NK) cell-based immunotherapy has been considered a promising cell-based cancer treatment strategy with low side effects for early tumors and metastasis. further showed the impact of effective lymphodepleting pre-conditioning on in vivo NK cell expansion and persistence, as patients who received less intense pre-conditioning failed to display NK cell engraftment [5]. Google Scholar. Table 6 summarizes updated clinical trials of NK cell-based therapy for all solid tumors. The adoptive transfer of natural killer (NK) cells is an emerging therapy in the field of immuno-oncology. NK cells also play immunomodulatory functions by secreting chemokines and cytokines, such as RANTES and IFN- [12, 13]. This clearance for SNK02 is an important milestone in our pursuit to bring life-changing therapies to cancer patients and will be our second clinical NK cell therapy IL15 Trispecific Killer Engagers (TriKE) Make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced function. HIGHLIGHTS who: Ming-Yu Lai from the Department of Medical Oncology, Sun Yat-Sen University Cancer Center have published the paper: Comparison of response evaluation criteria in solid tumors and tumor regression grade in evaluating the effect of preoperative systemic therapy of gastric cancer, in the Journal: (JOURNAL) of Perform PBMCs apheresis from the patient and isolate NK cells, transfect the NK cells with Claudin6 targeting CAR, amplify the number of transfected NK cells as 2014;193(12):6192206. Cytotherapy. J Natl Cancer Inst. 2018;9:1869. Most recent studies showed that ex vivostimulation of human NK cells with the combination of IL-15/IL-18/IL-27 can achieve 17-fold expansion [122], and that the combination of IL-2 with IL-18 can achieve approximately 500-fold expansion over two-week period [123]. 2010;651:6177. J Transl Med. 2002;100(4):126573. Both UCB and placenta-derived cells contain some proportion of NK cell progenitors that have the capacity to differentiate into NK cells during maturation and expansion stages. BMC Biotechnol. Front Immunol. Blood. Front Immunol. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. Herberman RB, Nunn ME, Lavrin DH. 2015;13(3):46471. 2012;209(13):235165. Biol Blood Marrow Transpl. CNDO-109-NK cells were found well tolerated without occurrence of dose-limiting toxicities [89]. Effective against blood cancers, natural killer cells also may be effective against solid tumors. Mol Immunol. 2009;69(9):40107. Article Front Immunol. The BiKEs or TrikEs are composed of two or three linked single-chain antibody variable fragments of different antigen specificities [79]. A wide range of tumor antigens have been targeted by CAR-NK cells in pre-clinical studies for hematological malignancies and solid tumors [38, 39, 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76]. Immunity. Stem Cell Reports. This property, which is unique among immune cells, and their capacity to enhance antibody and T cell responses support a role for NK cells as anticancer agents. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. In mouse, the lack of CD3 and the presence of NK1.1 are canonical criterion for distinguishing NK cells. California Privacy Statement, There are great numbers of clinical trials on NK cell immunotherapy to treat solid tumors. WebThese antibodies are currently used in clinical trials in the treatment of both hematological and solid tumors. Oncoimmunology. 2018;67(4):57587. NK cell dysfunction via altered activating receptor expression or tumor downregulation of NK cell receptor ligands is a common method of tumor immune escape. For example, the absence of NKG2D and other NCR ligands on leukemic blasts allows them to escape NK cell surveillance [86, 87]. Effects of CSF1R-targeted chimeric antigen receptor-modified NK92MI & T cells on tumor-associated macrophages. Muller N, et al. A first-in-human clinical trial of CAR NK-92 cells in 3 patients with relapsed or refractory AML showed that CAR NK-92 can be infused at doses up to 5 billion cells per patient without causing significant adverse effects [149]. PubMed Ruggeri L, et al. 2016;1441:33346. A more simplified NK cell expansion method has been used by combining group Astreptococcus and zoledronate with IL-2 to stimulate UCB-derived mononuclear cells. 2013;13(2):1459. This strategy of GSK3 inhibition was used to generate FATE-NK100, which is being evaluated in an ongoing phase 1 clinical trial either as a monotherapy or in combination with monoclonal antibodies in patients with advanced solid tumors (NCT03319459). NK cells are infrequently seen in tumor biopsies. Cao B, et al. Cell, 2019; 177(7): 17011713. Cytokines are the critical components of NK maintenance system and activation as discussed earlier. 2017;77(20):566475. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies. In one study, Ng et al. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. ALT-803, an IL-15/IL-15Ra fusion complex, was shown to enhance NK cell functions both in vitro and in vivo [83]. Spanholtz J, et al. One approach to address the safety concern is the use of lysed cell product. Cell Stem Cell. 2017;92(2):10014. Carlsten M, et al. Eur J Immunol. Hemolytic anemia due to passenger lymphocyte syndrome in solid malignancy patients treated with allogeneic natural killer cell products. Myers JA, Miller JS. J Immunother Cancer. GSK3 inhibition drives maturation of NK cells and enhances their antitumor activity. 2016;7:105. Targeting immunosuppressive components in the TME to re-invigorate NK functions is also under investigation. Various strategies are being employed to overcome these challenges to improve the efficacy of NK cell-based therapy, such as ex vivo pre-conditioning with cytokines and/or small molecular drugs, engineering an off-the-shelf or iPSC-differentiated chimeric antigen receptor (CAR)-NK. 2013;15(10):1297306. further pioneered the use of NK cells in non-transplant settings. reported an approximately 1500-fold expansion of NK cells after PBMC stimulation with a combination of anti-CD3 and anti-CD56 mAbs [146]. Tanaka Y, et al. Nat Rev Immunol. Sci Transl Med. Clinical efficacy of this strategy has proven to be thus far be limited. Patients with advanced malignant solid tumors, histologically or cytologically confirmed, who had failed standard therapy, or had no standard therapy, or were not In the last 3 decades, NK cells have been utilized to harness Abel AM, et al. Tumor-primed human natural killer cells lyse NK-resistant tumor targets: evidence of a two-stage process in resting NK cell activation. 2015;2:93. PubMed Conceptually, iPSC-NK can provide a homogenously differentiated NK cell population that can be expanded to clinical scale as an off-the-shelf supply, overcoming the limitation of the NK-92 cell line. Compared with cytotoxic T lymphocytes, J Exp Med. 2017;9(6):1796812. WebHappy New Year to you! demonstrated a more than 500-fold NK expansion with over 98% purity within 2weeks and a greater than 5000-fold NK expansion over a 3-week period [147]. Blood. Natural killer cells produce T cell-recruiting chemokines in response to antibody-coated tumor cells. Front Immunol. Using patient samples and murine models, the potential of NK cell therapy is being realized in the lung. 2017;8(68):11278396. NKG2D and its ligands in cancer. In order to avoid critical side effects, such as GVHD caused by alloreactive T cells [98] or a passenger lymphocyte syndrome caused by donor-derived B cells [99], purification is recommended for allogeneic NK cells before the expansion to restrict contaminating total T cells to less than 15105/Kg. For hematological cancers, CD19 remains a major target. WebAB-201 is our clinical-stage CAR-NK cell therapy candidate targeting HER2-positive solid tumors. WebGiven the utility of NK cells in the control of tumor cell dissemination in solid tumors, it is likely that NK cells also play a key role in the control of lung cancer cells. Yang Y, et al. NK cell infiltration With the new tools of iPSC-NK and genetic engineering approach as well as new understandings of NK cell biology, it is the time to re-explore the therapeutic potentials of NK cells. NK cells expressing a chimeric activating receptor eliminate MDSCs and rescue impaired CAR-T cell activity against solid tumors. Ascorbic acid promotes proliferation of natural killer cell populations in culture systems applicable for natural killer cell therapy. 2019;9(1):6478. Ng YY, Tay JCK, Wang S. cxcr1 expression to improve anti-cancer efficacy of intravenously injected CAR-NK cells in mice with peritoneal xenografts. Combination therapy with EpCAM-CAR-NK-92 cells and regorafenib against human colorectal cancer models. Kim EK, et al. They are also summarized in Table 2. Lister J, et al. [2017][J Control Release][10.1016j.jconrel.2017.03. Sci Rep. 2019;9(1):13288. Tang X, et al. The broad spectrum of human natural killer cell diversity. Stem Cells. Oelsner S, et al. 2014;20(4):46373. Chemical stimuli such as Concanavalin A(ConA) [138], Phytohemagglutinin (PHA), and ionomycin [139] were also used in combination with irradiated allogeneic PBMCs to facilitate the activation. 2019;145(7):193545. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. Dhar P, Wu JD. This work was supported by NIH/NCI grant 1R01CA208246, 1R01CA204021, 1R01CA212409, and DOD W81XWH-15-1-0406 (to J. D. Wu). Cancers. All authors read and approved the final manuscript. Although challenges exist, perspectives are enticed by currently approved NK cell-based therapies and emerging pre-clinical and clinical studies. Immunity. Vasu S, et al. 2017;18(1):5667. Phillips JH, Lanier LL. On the other hand, it has limited viability support and can trigger proliferative arrest and apoptosis of NK cells at higher dosage (50ng/mL) [118]. Oncoimmunology. With the ongoing effort to improve the treatment response and new methods of generating more feasible clinical scales of NK cells, emerging clinical trials are being designed to evaluate these new modalities and to expand their indications. Bone marrow is considered to be the primary site of NK development. 2016;7(19):2776477. Clinicaltrials.gov currently lists over 100 clinical trials of NK cell-based cancer immunotherapy. Ni Z, et al. I. Article We are initiating the clinical evaluation of AB-201 at multiple centers in the US Additional markers such as lack of c-kit can be used to distinguish human NK (c-kit-) from ILC3s (c-kit+) [14]. In humans KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma prolong! On biologics and cell therapy california Privacy statement, There are great numbers of trials... In mouse, the residual contamination of feeder cells before use is required, for safety concern is use. 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