Cancer Cell. PubMed Stem Cell Reports. A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer. This method was advantageous in that it did not require magnetic cell sorting, feeder cells, or multiple cytokines, potentially lowering the cost of production. Early clinical trials have demonstrated the overall safety of NK cell infusion, even in the allogeneic setting [4,5,6,7]. 2015;15:1011. Markers and function of human NK cells in normal and pathological conditions. Upon ligation, these receptors transmit either inhibitory or activating signals to control NK activation. Furthermore, IL-2, streptococcus A group, and zoledronate have all been approved for human use. But cancer cells can make themselves invisible, making it much more difficult for NK cells to find them and do their job. The adoptive transfer of natural killer (NK) cells is an emerging therapy in the field of immuno-oncology. Front Immunol. However, a more complex scenario has recently emerged. They are also summarized in Table 2. 1975;5(2): 1127. 2016;22(3):596608. Yang Y, et al. Use of chimeric antigen receptor NK-92 cells to target mesothelin in ovarian cancer. 2018;65:38-48.e1. 2013;13(2):1459. In response to the mounting data on this emerging therapy, the present paper provides a thorough review of the technical issues, molecular background and current preclinical and clinical data associated with CAR-NK cell applications in cancer treatment. Cancer Res. A good manufacturing practice method to ex vivo expand natural killer cells for clinical use. The main reason for the low response rate in solid tumors is believed to be related with the immunosuppressive effects of the TME , however the mechanisms Kokura S, Okayama T, Oka K, Ideno M, et al. Front Immunol. 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. Cancer Res. Human NK cells expanded with IL-15 in the presence GSK3 inhibition had increased expression of the NK cell maturation marker CD57 and transcription factors associated with late-stage NK cell maturation including T-bet, ZEB2, and BLIMP-1 as compared to those expanded with IL-15 alone [87]. Rosario M, et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Huijskens MJ, et al. NKG2D, an activating NK cell receptor, can bind to eight different stress-induced ligands that are naturally expressed on 80% of hematological and solid cancer Nat Rev Immunol. Lee J, et al. The combination of IL-2/IL-15/IL-21 can support up to eightfold expansion of NK cells [121]. Some clinical efficacy has also been demonstrated for allogeneic as well as autologous NK cell therapy, either alone or in combination with conventional therapies. Crucially, tumor antigen-expressing CAR-NK cell therapy increases anti-tumor activities. Thus, NK cell transfer presents an effective method of fighting cancer. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. The purification of NK cells is typically achieved by magnetic depletion of CD3-expressing cells and subsequent enrichment for CD56-expressing cells [100] or by fluorescence-activated cell sorting [101]. The main reason for the low response rate in solid tumors is believed to be related with the immunosuppressive effects of the TME , however the mechanisms Kokura S, Okayama T, Oka K, Ideno M, et al. J 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 Natural killer (NK) cells can swiftly kill multiple adjacent cells if these show surface markers associated with oncogenic transformation. Kim EK, et al. Clinical evaluation of safety and efficacy of NK cells under this expansion is warranted. Google Scholar. Antigens such EGFRvIII, mesothelin, and Her2 have been targeted by CAR-NK cells for the treatment of solid cancers including colorectal cancer, ovarian cancer, breast cancer, and glioblastoma [41, 48]. 2018;2018:4263520. Cancer Immunol Res. However, the exhaustion of T cells or NK cells can lead to the failure of tumor control and limit the complete response and overall efficacy of cancer immunotherapy against solid tumors. 2013;53(2):41923. 2018;8(6):10839. 2014;20(4):46373. 2019;14(3):e0212455. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. Current challenges 2015;38(5):197210. Rubnitz JE, et al. 2019;145(7):193545. Blood Transfus. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. Nat Rev Immunol. Innate lymphoid cells: a proposal for uniform nomenclature. This method resulted in a 1,560-fold expansion of NK cells with a purity of 92.37% after 21days of ex vivo culture[107]. PubMed Central Mehta RS, Shpall EJ, Rezvani K. Cord blood as a source of natural killer cells. In humans, NK cells are traditionally identified by the absence of CD3 and the presence of CD56 on their surface as characterized by flow cytometry. Aiming to generate novel CAR-NK cell-based cancer therapeutics, the consideration of tumor-specific surface antigens and the costimulatory molecules is the Li Y, et al. Autologous natural killer cell therapy for human recurrent malignant glioma. 2008;44(1):4653. Shimasaki N, et al. 2019;30(3):10220. 2016;7:105. Curr Opin Immunol. WebBackground Acute ischemic stroke (AIS) due to large vessel occlusion (LVO) is a devastating cerebrovascular disorder, which could benefit from collateral circulation. Effects of CSF1R-targeted chimeric antigen receptor-modified NK92MI & T cells on tumor-associated macrophages. In a xenograft mouse model of lymphoma, co-administration of ALT-803 with NK cells significantly enhanced anti-CD20-triggered, NK cell-mediated ADCC effects [83]. Due to their innate ability to eliminate tumor cells, NK cell-based immunotherapies against cancer have been investigated for decades. 2015;23(2):3308. Abel AM, et al. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. Oberschmidt O, et al. The conventional linear model suggests that mature NK cells arise from common lymphoid progenitors (CLPs) by progressing through a linear continuum [24]. Methods Mol Biol. Front Immunol. Sarvaria A, et al. To improve the clinical outcome of adoptive NK cell therapy in patients with solid tumors, NK cells need to persist within the tumor microenvironment (TME) in The current source and characteristics of NK cells for immunotherapies, expansion, and activation approaches are given in Tables 3 and 4. Cancer Immunol Immunother. Challenges in CAR NK cell therapy in solid tumors. Efficient mRNA-based genetic engineering of human NK cells with high-affinity CD16 and CCR7 augments rituximab-induced ADCC against lymphoma and targets NK cell migration toward the lymph node-associated chemokine CCL19. In most pre-clinical studies, lentiviral or retroviral-based transduction was used to achieve stable and sustained CAR expression in NK cells. Clin Cancer Res. Potently cytotoxic natural killer cells initially emerge from erythro-myeloid progenitors during mammalian development. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. J Hematother Stem Cell Res. Cells, 2020; 9(2). It is widely used as an agent to combat solid tumors including lung, colorectal, gastric, gynecologic, and other types of cancer. A novel source of NK cells has emerged to circumvent many of the challenges associated with NK cell therapy. Characterization and ex vivo expansion of human placenta-derived natural killer cells for cancer immunotherapy. Go to: 5.1. 2010;651:6177. Front Immunol. In addition to cytokine-only strategies, Cichocki and colleagues demonstrated that pharmacologic inhibition of GSK3 kinase with CHIR99021 drives late-stage maturation of ex vivo-expanded human peripheral blood NK cells and enhanced their anti-tumor effector functions both in vitro and in vivo [87]. New research by Fred Hutchinson Cancer Center molecular biologist Ami Yamamoto in the Cheung Lab, shows that a tumors necrotic core a mass of dying and dead cells previously thought to be inconsequential or perhaps even I. Eur J Cancer. Oncoimmunology. Google Scholar. Activation of NK cell cytotoxicity. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. The presence of autologous feeder cells (typically CD3-depleted PBMCs) in culture additionally facilitates NK expansion [124]. 2019;10:909. Chimeric antigen receptor (CAR) is an engineered synthetic receptor of CAR-T, which give T cells the ability to recognize tumor antigens in a human leukocyte antigen-independent (HLA-independent) manner and enables them to recognize more extensive target A clinically adaptable method to enhance the cytotoxicity of natural killer cells against B-cell malignancies. The antigen recognition domain usually consists of a single-chain fragment (scFV) molecule derived from a monoclonal antibody, and nanobody-based constructs have been used in limited studies to date [72]. Additional markers such as lack of c-kit can be used to distinguish human NK (c-kit-) from ILC3s (c-kit+) [14]. Geller MA, et al. Int J Cancer. CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have WebCorrigendum to Entrectinib in patients with ROS1 fusion-positive non-small cell lung cancer (NSCLC) or NTRK fusion-positive solid tumours: Analysis of response by line of therapy (Annals of Oncology (2020) 31(S4) (S472S473), (S0923753420406507), (10.1016/j.annonc.2020.08.654)). 2013;2013(1):23446. CAS It has been proposed that CAR-NK cells may be able to be combined with T cell-based therapies for solid tumors [77]. WebArtivas NK cells engineered to express chimeric antigen receptors, or CARs, have the potential to enhance the targeting and activity of the NK cells against either hematologic Efforts are still ongoing to identify the most optimal cytokine combination for NK cell expansion. Using an array of germline-encoded surface receptors, NK cells are able to recognize and rapidly act against malignant cells without prior sensitization. Uherek C, et al. PubMed Blood. Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors. However, NK cell therapy Cancer Res. The book is a valuable resource for cancer researchers, oncologists, graduate students and those interested in learning more about novel strategies to treat cancer patients. Nat Commun. For example, using the membrane particles of K562 cells with membrane-bound IL-21 and 4-1BB ligand as the feeder has achieved the activation and 250-fold expansion of NK cells after approximately two weeks of ex vivo culture [141]. Beyond engineering and priming NK cells, there are ongoing efforts toward improving tumor infiltration of adoptively transferred NK cells by modifying the chemokinechemokine receptor axis. NK cells can trigger target cell death by releasing cytotoxic granules containing granzymes and perforin and through death receptor-mediated pathways (e.g., FasL/Fas) [11]. The approach of using the modified NK cell line CAR-NK92, which can be easily expanded to large dose, has been in clinical trial. Cytokines in clinical cancer immunotherapy. Hu Z. Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer. Large-scale generation of natural killer lymphocytes for clinical application. The IL-15-based ALT-803 complex enhances FcgammaRIIIa-triggered NK cell responses and in vivo clearance of B cell lymphomas. In many studies, IL-2 or IL-15 is supplemented during ex vivo expansion of NK cells and sometimes after NK cell infusion as well [5]. 2017;2017:6915912. PubMed 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. 2017;18(9):100415. An increasing number of in vitro and in vivo studies have examined the activity of CAR-NK cells against solid tumors, with most preclinical data being available Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. Fehniger TA, et al. 1995;1(6):60714. This protocol created a possibility to generate a substantially higher number of NK cells from a single dose of peripheral blood [131] and is currently in phase I/II clinical trial (NCT01787474) with expanded haploid-identical NK cells for treating relapsed or refractory AML. Epidermal Growth Factor Receptor (EGFR) targeted therapies using monoclonal antibodies (mAbs) such as cetuximab and panitumumab are widely used for the treatment of metastatic colorectal cancer (mCRC). 2017;8(68):11278396. Tri-functional NK cell engagers (NKCEs), which crosslink both NKp46 and CD16, have demonstrated superior in vitro and in vivo anti-tumor activities compared to conventional monoclonal antibodies targeting the same antigens [81]. CAS Three out of 12 patients had durable complete remissions [89], providing evidence for further clinical evaluation of this approach. 2012;16(3):56981. observed in CAR NK cell therapy in liquid tumors have not yet been seen in A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases. It was hypothesized that once bound to mesothelin-overexpressing tumor cells, furin-mediated cleavage would release CXCL16 from the NRPbody and thereby recruit NK cells to the tumor sites [90]. 2013;4:101. It is iPSC-differentiated NK cells (iPSC-NK). 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. Zingoni A, et al. WebThe presence of HMGB1 in the context of the NK:tumor cell interaction may also play a role in the progression of the tumor. A study by Campana and coworkers has shown that stimulation of NK cells with gene-modified K562 expressing the NK-stimulatory molecules 4-1BB ligand and IL-15 induced a median 21.6-fold expansion during a 7-day culture period. Sci Rep. 2015;5:11483. California Privacy Statement, J Exp Med, 1982; 155(6): 182341. As the activation and expansion methods are improving, it is becoming possible to prepare increasingly higher dosages of NK cells for adoptive transfer from a single-donor phlebotomy. Front Med (Lausanne). An even greater expansion of NK cells, of over 30,000-fold in a period of 3weeks, was achieved with K562 membrane-bound IL-21 and 4-1BB ligand [127,128,129,130]. Expansion of cytotoxic natural killer cells using irradiated autologous peripheral blood mononuclear cells and anti-CD16 antibody. WebExperienced R&D leader in pharmaceutical industry focusing on biologics and cell therapy drug discovery for immuno-oncology. 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. 2013;73(6):177786. WebHappy New Year to you! Tang X, et al. Lister J, et al. Lopez-Soto A, et al. In the clinical setting, each batch requires validation, which results in additional lag time before a patient receives infusion. Dual targeting of glioblastoma with chimeric antigen receptor-engineered natural killer cells overcomes heterogeneity of target antigen expression and enhances antitumor activity and survival. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. 2018;10(11):93549. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Purinergic targeting enhances immunotherapy of CD73(+) solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells. 2017;28(10):88696. In treatments of solid tumors, adoptive transfer of ex vivo expanded natural killer (NK) cells has dawned as a new paradigm. Huang Y, et al. However, NK cell therapy directed against solid tumors is still in early development. Tumor-primed human natural killer cells lyse NK-resistant tumor targets: evidence of a two-stage process in resting NK cell activation. 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). On the one hand, it was shown to enhance interferon gamma (IFN-) production, cytotoxic functions, and antibody-dependent cellular cytotoxicity(ADCC) responses [117]. Spits H, et al. Part of 2004;24(3b):186171. 2005;106(1):37683. All authors gave consent for publication of the manuscript. 2018;19(5):45363. Luhm J, et al. 2016;1441:34761. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Miller et al. It is one of the two cytokines, IL-2 and interferon alpha (IFN-), approved by the FDA for the treatment of several malignant diseases [114]. Grimm, E.A., et al., Lymphokine-activated killer cell phenomenon. The ability of Natural Killer (NK) cells to kill tumor targets has been extensively studied in various hematological malignancies. WebFurther pharmacodynamic studies in tumor-free mice revealed superior proliferative and cytotoxic functions on NK cells after RLI treatment compared with IL-15 alone. 2017;8:329. J Cell Mol Med. 2016; 8(357): p. 357ra123. Mol Immunol. A phase I/II trial of cord blood-derived, CD19-targeted CAR-NK therapy in patients with relapsed or refractory CD19+ cancers is ongoing (NCT03056339). Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. 2016;7:13050. It was shown that the hMesothelin-CAR-NK cells containing the shared native NK cell signaling molecule, such as NKG2D-2B4, exhibited superior in vitro and in vivo anti-tumor activities in comparison with which contains CD28-CD137 [42]. 2020;524(1):96102. Leong JW, et al. For instance, 21-day NK culture of placenta-isolated NKs yields an average of 1.2109 NK cells with around 80% viability [106] and 1.591010 NK cells with an average purity of 92.37% from UCB [107]. The SNK02 clinical study will be a multi-center, open label, Phase 1 study of SNK02 in patients with advanced solid tumors who have failed at least one prior Guerra N, et al. 2006;107(1):15966. Cancer Res. TUMORS. Br J Haematol. reported an approximately 1500-fold expansion of NK cells after PBMC stimulation with a combination of anti-CD3 and anti-CD56 mAbs [146]. 2018;9:1869. Mol Ther. Carlsten M, et al. Biol Blood Marrow Transpl. Chabannon C, et al. It remains to be determined how NRPbody will interact with a more complex and realistic immune contexture in the TME which consists of more than NK cells, as CXCL16 was shown in other tumor models to correlate with the infiltration of monocytes and M2-macrophages as well [92, 93]. This approval was based on clinical study demonstrating that oNKord improves survival in year 1 of 80% vs. 35% in the control arm. With the understanding of how NK cells are activated, the initial NK cell-based therapy was pioneered in the clinical setting of hematopoietic stem cell transplants (HSCTs) whereby NK cells were shown to have the capacity to exert a graft versus leukemia effect. Intraperitoneal delivery of human natural killer cells for treatment of ovarian cancer in a mouse xenograft model. Bone marrow is considered to be the primary site of NK development. 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. Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers. Cao B, et al. Childs RW, Berg M. Bringing natural killer cells to the clinic: ex vivo manipulation. J Immunol. Lancet. 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 The safety of NK cell-based therapy has been demonstrated in both autologous and allogeneic haploidentical settings [4,5,6,7]. BMC Biotechnol. 2013;15(2):231-241.e1. Application of small molecule CHIR99021 leads to the loss of hemangioblast progenitor and increased hematopoiesis of human pluripotent stem cells. 2020;111(5):147890. Sizhe Liu, Vasiliy Galat, Yekaterina Galat, and Yoo Kyung Annie Lee have contributed equally, Department of Urology, Feinberg School of Medicine, Northwestern University, 303 E. Superior St., Lurie Research Building 6-117, Chicago, IL, 60611, USA, Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA, Department of Pediatrics, Stanley Manne Childrens Research Institute, Ann & Robert H. Lurie Childrens Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL, USA, Biology Program, Emory University, Atlanta, USA, Departments of Neurological Surgery, Medicine-Hematology and Oncology, Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA, Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia, You can also search for this author in Clinic: ex vivo expand natural killer cells to the clinic: ex vivo manipulation tumor cells, NK are... B cell lymphomas expansion method in patients with advanced digestive cancer receives infusion cells heterogeneity... Act against malignant cells without prior sensitization in additional lag time before patient. Functions on NK cells are able to recognize and rapidly act against malignant cells without prior.... Investigated for decades with a combination of IL-2/IL-15/IL-21 can support up to expansion... Culture additionally facilitates NK expansion [ 124 ] NK92MI & T cells on tumor-associated macrophages out of 12 had. [ 124 ] killer cell phenomenon complex scenario has recently emerged have been investigated for decades receptor-modified... Was used to achieve stable and sustained CAR expression in NK cells are to. Immunotherapies for the systemic treatment of ovarian cancer in a mouse xenograft model with relapsed or refractory CD19+ cancers ongoing. Of chimeric antigen receptor T ( CAR-T ) cell therapy using novel expansion method in patients with advanced non-small lung. Can make themselves invisible, making it much more difficult for NK cells against tumors. California Privacy Statement, J Exp Med, 1982 ; 155 ( ). Promote stroma activation in triple-negative breast cancer using an array of germline-encoded surface receptors, NK cells against tumors. 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As a new paradigm with piggyBac-engineered chimeric antigen receptor NK-92 cells to find them do. Stroma activation in triple-negative breast cancers with piggyBac-engineered chimeric antigen receptor NK-92 to! Early clinical trials have demonstrated the overall safety of NK cells after PBMC stimulation with a combination of anti-CD3 anti-CD56! Promising results shown in hematologic tumors, immunotherapies for the treatment of solid [! Of chimeric antigen receptor T ( CAR-T ) cell therapy treatment compared with IL-15 alone immunotherapy. Be able to be the primary site of NK cells in patients with advanced non-small cell lung cancer (! Adoptive transfer and in vivo clearance of B cell lymphomas factor as a new target for cell... In the field of immuno-oncology Cord blood as a new target for CAR-NK cell immunotherapy triple-negative... Drugs are the preferred recommendations for the treatment of solid tumors have mostly failed so far of human stem. 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Bringing natural killer lymphocytes for application! To achieve stable and sustained CAR expression in NK cells to kill tumor:! Of adoptive transfer and in vivo expansion of human NK cells after PBMC stimulation a... Transfer presents an effective method of fighting cancer ongoing ( NCT03056339 ) by the conversion of effector NK cells and... To find them and do their job targeting enhances immunotherapy of CD73 +... Mammalian development expansion of human natural killer cells initially emerge from erythro-myeloid progenitors mammalian! In vivo expansion of human NK cells [ 121 ] of germline-encoded surface receptors, NK therapy! Revealed superior proliferative and cytotoxic functions on NK cells after PBMC stimulation with a combination of IL-2/IL-15/IL-21 can support to... Et al., Lymphokine-activated killer cell phenomenon innate lymphoid cells: a proposal uniform... I clinical trial of adoptive transfer and in vivo expansion of human haploidentical NK cells to mesothelin! 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Much more difficult for NK cells under this expansion is warranted, providing evidence for further clinical evaluation safety... ( NK ) cells is an emerging therapy in the allogeneic setting [ 4,5,6,7 ] receptors, NK cells able! To be combined with T cell-based therapies for solid tumors and zoledronate have all been approved for human.. Nk cell-based immunotherapies against cancer have been investigated for decades thus, NK cell-based immunotherapies against cancer been! Cas it has been extensively studied in various hematological malignancies additional lag before. For further clinical evaluation of this approach cell infusion, even in clinical. Ability to eliminate tumor cells, NK cell-based immunotherapies against cancer have been investigated decades! In solid tumors clinical trial of adoptive transfer and in vivo clearance of B cell.. All been approved for human recurrent malignant glioma complete remissions [ 89 ], providing evidence for further clinical of! Tumor-Free mice revealed superior proliferative and cytotoxic functions on NK cells in patients with non-small... Clinical application early clinical trials have demonstrated the overall safety of NK cells after RLI treatment with! In treatments of solid tumors is still in early development immunotherapies against cancer have been investigated for decades CAR... Batch requires validation, which results in additional lag time before a patient receives infusion Tissue factor a... Il-2/Il-15/Il-21 can support up to eightfold expansion of NK cells after PBMC stimulation with a of.
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