nk cell therapy in solid tumors

Clin Cancer Res. Kim EK, et al. 2017;23(2):489502. 2016; 108(5). CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. Control of metastasis by NK Cells. 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. 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)). Heinze, A., et al. Natural killer (NK) cells are large granular lymphocytes with surface markers CD3 CD56 + NKp46 + in humans. Ishikawa E, et al. To date, more than 350 Cordyceps-related species have been found worldwide based on fungus and/or insect host. Article 2013;15(2):231-241.e1. Herein, we will provide an updated overview of the emerging endeavors for developing NK cell-based cancer immunotherapy from pre-clinical conceptual development, clinical grade expansion, and ongoing clinical development. Cao B, et al. Webwith a high chance of succeeding in solid cancer therapy. J Immunother Cancer. Instead, a combination of transcription factors, including T-bet, Eomes, E4BP4, Id2, and BLIMP, was identified to instruct NK development and maturation [23]. Cytokines are the critical components of NK maintenance system and activation as discussed earlier. NK cell therapy in solid tumors, therefore, strongly resembled those in hematologic malignancies. Kiessling R, Klein E, Wigzell H. Natural" killer cells in the mouse. The main source of donor NK cells is peripheral blood collected by apheresis. Tang X, et al. Webgeneration NK cell therapies. Klapdor R, et al. Parihar R, et al. Br J Cancer. In allogeneic transfer settings, the concept of KIR and HLA mismatches between donor and recipient was the original strategy aimed at enhancing the activation of donor NK cells to eradicate patients tumor cells. Nat Rev Mol Cell Biol. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. J Immunol Res. Nat Rev Immunol. Lee DA, Verneris MR, Campana D. Acquisition, preparation, and functional assessment of human NK cells for adoptive immunotherapy. This method was advantageous in that it did not require magnetic cell sorting, feeder cells, or multiple cytokines, potentially lowering the cost of production. BMC Cancer. Freshly isolated, activated, or in vitro expanded NK cell populations display phenotypic and functional differences. 2008;28(4):57180. 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 Wang et al. For instance, healthy cells express no or minimal level of ligands for NK cell activating receptors, but express high levels of the major histocompatibility complex class I molecules (MHC I), also known as human leukocyte antigen (HLA), that ligates to the killer immunoglobulin-like (KIR) family inhibitory receptors on NK cells to protect them from NK attack [29]. The conventional linear model suggests that mature NK cells arise from common lymphoid progenitors (CLPs) by progressing through a linear continuum [24]. PubMed Front Immunol. Ruggeri L, et al. Ex vivo-expanded NK cells from blood and ascites of ovarian cancer patients are cytotoxic against autologous primary ovarian cancer cells. Jennifer Wu supervised the study. Knorr DA, et al. 2012;3:319. Oncotarget. Additional markers such as lack of c-kit can be used to distinguish human NK (c-kit-) from ILC3s (c-kit+) [14]. 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]. Am J Cancer Res. IL-21 has various effects on human NK cells. In vivo efficacy of umbilical cord blood stem cell-derived NK cells in the treatment of metastatic colorectal cancer. This successful immunotherapy has led to a more complete view of cancer that now considers not only the cancer cells to be targeted and destroyed but also the immune environment of the cancer cells. Lopez-Soto A, et al. 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]. J Front Immunol. Hemolytic anemia due to passenger lymphocyte syndrome in solid malignancy patients treated with allogeneic natural killer cell products. Characterization of the maturation stage of NK cells demonstrated that RLI favored accumulation of CD11b⁺ CD27^high KLRG1⁺ Nat Immunol. J Exp Med, 1982; 155(6): 182341. We are initiating the clinical evaluation of AB-201 at multiple centers in the US 2010;28(6):9559. 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 2018; 23(2): 181192. Mol Immunol. Oncotarget. Two biotechs aim to broaden the reach of cancer immunotherapy by applying gene editing tools to an emerging form of cell therapy through a wide-ranging The combination of IL-2/IL-15/IL-21 can support up to eightfold expansion of NK cells [121]. Spits H, et al. Blood. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. Front Immunol. INTRODUCTION Cordyceps is the composite of a genus of fungus that grows on the larva of insects. WebThis page lists cancer drugs approved by the Food and Drug Administration (FDA) for the treatment of solid tumors based on their genetic and molecular features and not on PLoS ONE. Article 2015;38(5):197210. Spanholtz J, et al. Lotze MT, et al. A novel CD7 chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia. 2016;5(9):e1219007. Natural killer (NK) cell is a specialized immune effector cell type that plays a critical role in immune activation against abnormal cells. Recently, the FDA has approved the investigational new drug (IND) for the use of placenta-expanded NK cells (CYNK-001) against glioblastoma (GBM). They induce short-term activation of NK cells but do not support effective expansion without feeder cells. In the clinical setting, each batch requires validation, which results in additional lag time before a patient receives infusion. A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases. Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor. 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. In this review, we provide our current understandings of NK cell biology, ongoing pre-clinical and clinical development of NK cell-based therapies and discuss the progress, challenges, and future perspectives. Rosario M, et al. Non-clinical efficacy, safety and stable clinical cell processing of induced pluripotent stem cell-derived anti-glypican-3 chimeric antigen receptor-expressing natural killer/innate lymphoid cells. Cancer Res. Necrotic core even the name sounds creepy. Web- mWTX-330 is designed as a systemically delivered, conditionally activated IL-12 therapy and is a member of a novel class of INDUKINE therapeutics - - Preclinical data support 2014;20(4):46373. The safety of NK cell-based therapy has been demonstrated in both autologous and allogeneic haploidentical settings [4,5,6,7]. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Sci Rep. 2017;7(1):11075. Vasu S, et al. Methods Mol Biol. Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. Front Immunol. 2019;9(1):6478. Targeting immunosuppressive components in the TME to re-invigorate NK functions is also under investigation. WebIn this review, we provide our current understandings of NK cell biology, ongoing pre-clinical and clinical development of NK cell-based therapies and discuss the progress, challenges, and future perspectives. 2014;32(4):102131. demonstrated that antibody-mediated blockade of CD73 significantly enhanced the anti-tumor activities of NKG2D-enginneered CAR-NK92 in vitro and in vivo, with improved tumor infiltration by CAR-NK cells in vivo [43]. This work was supported by NIH/NCI grant 1R01CA208246, 1R01CA204021, 1R01CA212409, and DOD W81XWH-15-1-0406 (to J. D. Wu). Front Immunol. WebThese antibodies are currently used in clinical trials in the treatment of both hematological and solid tumors. J Clin Oncol. 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. Nat Commun. 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). Adenosine impairs the anti-tumor functions of both T and NK cells [43]. Cancer Immunol Res. NK cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma and prolong animal survival. et al. WebCancer immunotherapy has achieved great success in the past few years. When expanded it provides a list of search options that will switch the search inputs to match the current selection. WebMy interests are based on basic science methodologies to improve the advanced science techniques which improve the cancer immunotherapy effects. Mol Immunol. 2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. CXCL16 positively correlated with M2-macrophage infiltration, enhanced angiogenesis, and poor prognosis in thyroid cancer. Early clinical trials have demonstrated the overall safety of NK cell infusion, even in the allogeneic setting [4,5,6,7]. Li Y, et al. Front Immunol. With the subcutaneous hypopharyngeal tumor xenograft model, it was shown that CXCR1-expressing CAR-NK cells had enhanced tumor infiltration and tumor control as compared to control CAR-NK cells [54]. NK cells possess advantageous characteristics, including non-MHC-restricted recognition, ability to infiltrate DNAM1 and 2B4 costimulatory domains enhance the cytotoxicity of anti-GPC3 chimeric antigen receptor-modified natural killer cells against hepatocellular cancer cells in vitro. In most pre-clinical studies, lentiviral or retroviral-based transduction was used to achieve stable and sustained CAR expression in NK cells. Sci Transl Med. Roda JM, 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 WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. Privacy Preactivation with IL-12, IL-15, and IL-18 induces CD25 and a functional high-affinity IL-2 receptor on human cytokine-induced memory-like natural killer cells. Combination therapy with EpCAM-CAR-NK-92 cells and regorafenib against human colorectal cancer models. J Hematother Stem Cell Res. reported that a CD16/IL-15/CD33 TriKE not only enhances NK-mediated immunity against CD33+ targets, but also promotes the in vivo persistence, activation, and survival of NK cells by delivering IL-15 [80]. Due to relatively unsophisticated cues for activation, NK cell has gained significant attention in the field of cancer immunotherapy. Recently, several groups demonstrated that mouse and human NK cells pre-activated with a cocktail of IL-12/15/18 had enhanced and sustained anti-tumor effector functions in vitro and in vivo after infusion [84,85,86]. The concept of adoptive NK cell cancer immunotherapy was proven a decade ago from pioneering clinical studies against hematological malignancies. 2016;16(5):31020. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. 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. In mouse, NK and ILC1 are NK1.1+CD3 but can be further characterized by CD49a and Eomes expression. Bjorkstrom NK, Ljunggren HG, Michaelsson J. Cytometry B Clin Cytom. Nham T, et al. The emergence of this technology provided a completely new framework for clinical-scale NK cell production by allowing for the genetic modifications and unlimited expansion to be performed at the pluripotent cell state. Cytotherapy. The current in-development BiKEs or TrikEs simultaneously engage with CD16 and tumor antigens, thereby inducing the formation of immune synapses and NK-mediated ADCC [79]. Bottcher JP, et al. Phase I study of random healthy donor-derived allogeneic natural killer cell therapy in patients with malignant lymphoma or advanced solid tumors. PubMed Uherek C, et al. The cleavable CXCL16 containing NRPbody was shown to promote NK cell migration in vitro and infiltration into the tumor sites in vivo in xenografted mouse models of orthotopic and metastatic pancreatic cancer [90]. 2015;17(5):61320. Journal of Hematology & Oncology Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells. 2018;24(8):15819. Ex vivo expansion of highly cytotoxic human NK cells by cocultivation with irradiated tumor cells for adoptive immunotherapy. Springer Nature. Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor. It was proposed that the cytokine pre-activated NK cells were memory-like with an enhanced response to cytokine or activating receptor re-stimulation weeks or months after the initial pre-activation [84]. A clinically adaptable method to enhance the cytotoxicity of natural killer cells against B-cell malignancies. 2006;66(1):51726. Lee et al. Liu E, et al. 2017;19(2):23549. Chapter 5 Cordyceps as an Herbal Drug Bao-qin Lin and Shao-ping Li. Initial successes of adoptive NK cell transfer in treating hematological cancers prompted clinical endeavors in using the strategy against solid cancers. Killer (NK) cell activity against solid tumors. The current source and characteristics of NK cells for immunotherapies, expansion, and activation approaches are given in Tables 3 and 4. 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]. Abel AM, et al. J Immunol Res. Chang YH, et al. 2013;13(2):1459. Typically, a dose of UCB or placenta donor can be expended to an amount sufficient for one adoptive transfer procedure. Although challenges exist, perspectives are enticed by currently approved NK cell-based therapies and emerging pre-clinical and clinical studies. Retargeting of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction. 2015;6:368. Recent studies revealed that subset of mature NK cells can elicit long-lived adaptive-like nature in the specific context of CMV infection [21]. Hum Gene Ther Methods. 2013;73(6):177786. 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). 2019;145(7):193545. Szmania S, et al. Several groups have demonstrated in vitro derivation of functional NK cells from human embryonic stem cells (hESCs) and iPSCs [108,109,110]. Intraperitoneal delivery of human natural killer cells for treatment of ovarian cancer in a mouse xenograft model. NK cells also play a significant role in antibody-mediated cancer therapies by utilizing the Fc receptor to carry out antibody-dependent cellular cytotoxicity (ADCC) [30]. Sci Rep. 2019;9(1):13288. 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 Biol Blood Marrow Transpl. 2019;120(1):615. Biol Blood Marrow Transpl. 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 Stem Cell Reports. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. 2018;8(6):10839. Ojo EO, et al. 2017;8:458. To circumvent these challenges, Bi- and tri-specific killer engagers, BiKEs and TriKEs, are in development as a complemental approach. CAS Sci Rep. 2015;5:11483. 2017;130(16):185768. Liu, S., Galat, V., Galat4, Y. et al. So far, NK cell therapies havent shown any of the significant toxicities that plague CAR T cell therapies. Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers. Recent observations show that HMGB1 is a potent driver 2017;47(5):82033. Blood Transfus. Ex vivo-expanded natural killer cells demonstrate robust proliferation in vivo in high-risk relapsed multiple myeloma patients. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. However, CAR-T therapy has two major challenges: (i) requirement of a substantiate length of time to generate a therapeutic dose of autologous CAR-T cells which limits its feasibility to treat patients with rapidly progressing diseases; (ii) difficulty to obtain sufficient number of autologous T cells for CAR-T cell generation from heavily pre-treated and often lymphopenic cancer patients [37]. 2018;67(4):57587. 2013;15(10):1297306. Some investigations have sought to enhance NK migration toward the tumor by genetically modifying NK cells to overexpress chemokine receptors [54, 59, 94]. Luhm J, et al. Google Scholar. 2005;106(1):37683. PubMedGoogle Scholar. NK cell represents a specialized immune effector cell population equipped with fast-acting and potent anti-tumor capacity. 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. Geller MA, et al. Liu B, et al. They showed that infusion of NK cells from HLA-haploidentical donors combined with subcutaneous IL-2 administration after a pre-conditioning regimen of high-dose cyclophosphamide and fludarabine resulted in successful in vivo expansion of donor NK cells and the induction of complete remission in 5 out of 19 patients with poor-prognosis acute myeloid leukemia (AML) [5]. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. The mechanism of CTV-1-mediated NK priming is unclear. Human NK cell development: one road or many? 2017;18(9):100415. Rezvani K, et al. Handgretinger R, Lang P, Andre MC. Bioactive principles from Cordyceps sinensis: A potent food supplement A review M.G. Front Med (Lausanne). 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]. 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 They have the ability to target and destroy tumor cells without prior sensitization, via activation of NK cell-activating receptors In 2005, it was reported that haploidentical allogeneic NK cells GSK3 inhibition drives maturation of NK cells and enhances their antitumor activity. Miller et al. The feasibility of utilizing allogeneic NK cells, the established safety profiles, and the fast-acting nature of NK cells largely have led to the emerging effort to develop off-the-shelf NK cell-based cancer immunotherapy. On the one hand, it was shown to enhance interferon gamma (IFN-) production, cytotoxic functions, and antibody-dependent cellular cytotoxicity(ADCC) responses [117]. Short-term (1820h) pre-activation with ALT-803 augmented cytotoxicity and ADCC of NK cells in vitro. Bone marrow is considered to be the primary site of NK development. 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 Front Oncol. Overall, these results indicate that NK cells can invade some solid tumors. When NK cells infiltrate solid tumors, high numbers of NK cells may be associated with better survival. However, in most cases, anti-tumor properties of NK cells are attenuated at the tumor bed. Ascorbic acid promotes proliferation of natural killer cell populations in culture systems applicable for natural killer cell therapy. Using allogeneic NKs for adoptive transfer without expansion after a short overnight incubation with cytokines was shown to be sufficient to activate NK cells and enhance their cell cytotoxicity against tumor targets [86]. NK cells are found both in blood at levels of 5%-15% of circulating lymphocytes and in various lymphoid and non-lymphoid organs such as the spleen, lung, and liver [17, 18]. 2013;73(8):2598607. 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. 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. EMBO J, 2019; 38(12). 2019;10:909. An antibody designed to improve adoptive NK-cell therapy inhibits pancreatic cancer progression in a murine model. Lee HR, et al. CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have Hambach, J., et al., Targeting CD38-expressing multiple myeloma and Burkitt lymphoma cells in vitro with nanobody-based chimeric antigen receptors (Nb-CARs). In the last 3 decades, NK cells have been utilized to harness Due to their innate ability to eliminate tumor cells, NK cell-based immunotherapies against cancer have been investigated for decades. The advantage of adherent condition is that it provides defined environment for optimizing the differentiation. Miller et al. NK cells are CD49aEomes+, whereas ILC1s are CD49a+Eomes [15, 16]. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. Although CAR-NK cells hold great promise as a future off-the-shelf drug, there are NK cell-specific challenges, such as potential loss of viability and/or activity with freezethaw process and lack of in vivo persistence. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Rubnitz JE, et al. Natural killer cells: development, maturation, and clinical utilization. reported an approximately 1500-fold expansion of NK cells after PBMC stimulation with a combination of anti-CD3 and anti-CD56 mAbs [146]. The adoptive transfer of natural killer (NK) cells is an emerging therapy in the field of immuno-oncology. Anti-tumor activities of adoptively transferred NK cells in vivo have been demonstrated as well in pre-clinical xenograft mouse models of ovarian cancer, glioblastoma, and metastatic colorectal cancer [33,34,35,36]. NK cell progenitors progress through distinct developmental stages and gradually acquire the expression of surface receptors that define NK cell identity such as NK1.1 and CD56 and/or regulate their effector functions such as CD16 and NKp46 [19]. Potently cytotoxic natural killer cells initially emerge from erythro-myeloid progenitors during mammalian development. Romee, R., et al. 2002;100(4):126573. CAR-engineered NK cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells. NKG2D and DNAM-1 activating receptors and their ligands in NK-T cell interactions: role in the NK cell-mediated negative regulation of T cell responses. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. More recent evidence had indicated that NK cells can also develop and mature at secondary lymphoid organs, including tonsils, spleen, and lymph nodes [19]. Effects of CSF1R-targeted chimeric antigen receptor-modified NK92MI & T cells on tumor-associated macrophages. The differences also arise from activation approaches, such as the choice of interleukins, their combinations, type of feeder cells, and some other factors [95,96,97]. 2018; 172(5): 10221037. The success has encouraged many ongoing clinical investigations of NK cell-based cancer therapy alone or in combination with other regimes. Production Process of CAR-NK Front Immunol. Shah N, et al. Ex vivo expansion of natural killer cells from human peripheral blood mononuclear cells co-stimulated with anti-CD3 and anti-CD52 monoclonal antibodies.

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