2012;14(7):83040. Nat Commun. 2016; 8(357): p. 357ra123. CAS 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. Cancer Immunol Res. It is widely used as an agent to combat solid tumors including lung, colorectal, gastric, gynecologic, and other types of cancer. NK cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma and prolong animal survival. 2005;106(1):37683. Luhm J, et al. CAR-engineered iPSC-NK cells already have demonstrated effectiveness in targeting human tumors in preclinical studies [41]. 2013;53(2):41923. Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors. 2008;44(1):4653. Cancer Manag Res. The NKG2D-2B4 containing CAR-NK had elevated Syk and Erk1/2 phosphorylation [42]. Ni Z, et al. WebEnded 2022 with Approximately $475 Million in Cash, Cash Equivalents, and Receivables. Stem Cell Reports. Two CD19-targeting CAR-T products were approved by the FDA for treatment of B cell lymphomas and acute lymphoblastic leukemia (ALL). For instance, in the use of CD19-modified K562 to propagate NK cells, the contamination was assessed by flow cytometry detection of surface expression of the NK cell endogenous molecule CD32 and the K562 transgene CD19 to distinguish NK cells from the feeder cells [140]. Google Scholar. Expression of IL-15 in NK cells results in rapid enrichment and selective cytotoxicity of gene-modified effectors that carry a tumor-specific antigen receptor. WebCancer immunotherapy has achieved great success in the past few years. 2017;47(5):82033. Google Scholar. Methods Mol Biol. J Natl Cancer Inst. Most NK cells in the blood are CD56dim, whereas the CD56bright subset only represents less than 15% of total circulating NK cells [17]. Huang Y, et al. Development of cMET-specific chimeric antigen receptor-engineered natural killer cells with cytotoxic effects on human liver cancer HepG2 cells. Sci Transl Med. 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. PubMed Engineering natural killer cells for cancer immunotherapy. Table 6 summarizes updated clinical trials of NK cell-based therapy for all solid tumors. Mol Ther. It yielded a greater than 1000-fold expansion of NK cells after 3weeks of culture [38, 125, 126]. WebFurther pharmacodynamic studies in tumor-free mice revealed superior proliferative and cytotoxic functions on NK cells after RLI treatment compared with IL-15 alone. Cancer Cell. 2015;13:277. Patients with advanced malignant solid tumors, histologically or cytologically confirmed, who had failed standard therapy, or had no standard therapy, or were not NK Cells of the Lung Cao B, et al. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. Recently, the differentiation method was also established in adherent monolayer cultures [108]. Jennifer Wu. Skeate R, et al. 2010;59(12):17819. 2018;10(11):93549. CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. 2017;32(2):13554. 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]. The success has encouraged many ongoing clinical investigations of NK cell-based cancer therapy alone or in combination with other regimes. 2009;69(9):40107. PubMed Central Vallera DA, et al. Cell Stem Cell. 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]. 1999;94(1):3339. Table 5 summarizes the clinical trials of NK cell-based therapy for hematological malignancies to date. Lim SA, et al. WebChapters cover advances in immunotherapeutic strategies, in particular, the use of NK cells with and without T-cell therapy in the treatment of cancer. DNAM1 and 2B4 costimulatory domains enhance the cytotoxicity of anti-GPC3 chimeric antigen receptor-modified natural killer cells against hepatocellular cancer cells in vitro. Tang X, et al. 2010;12(6):75063. Imai C, Iwamoto S, Campana D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. The adoptive transfer of natural killer (NK) cells is an emerging therapy in the field of immuno-oncology. Hematology Am Soc Hematol Educ Program. In one study, Ng et al. 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]. 2014;32(4):102131. 2013;3:118. Granzin M, et al. 2016;20(7):128794. Ruggeri L, et al. Lancet. NKG2D and its ligands in cancer. volume14, Articlenumber:7 (2021) All authors read and approved the final manuscript. Cytotherapy. Dhar P, Wu JD. Sahm C, Schonfeld K, Wels WS. 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. However, the dose of NK cells being used for therapy is limited. 2013;15(2):231-241.e1. EMBO J, 2019; 38(12). CAS MUC1-specific CAR-pNK therapy presented good safety profile and preliminary efficacy in preventing both tumor relapses and graft versus host disease [151]. 2016;16(2):11223. Human NK cell development: one road or many? Miller et al. Front Med (Lausanne). 2016;22(14):344050. 2018;48(6):110417. 2012;3:319. Masuyama J, et al. Noteworthy, IL-2 primarily activates NK cytotoxicity, while supporting proliferation of both NK and T 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. Cytotherapy. J Transl Med. Sarvaria A, et al. 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. J Immunother. Oncoimmunology. Graft-versus-host disease. Clin Cancer Res. 2012;209(13):235165. Effects of CSF1R-targeted chimeric antigen receptor-modified NK92MI & T cells on tumor-associated macrophages. 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 Intraperitoneal delivery of human natural killer cells for treatment of ovarian cancer in a mouse xenograft model. Clinical application of CAR-NK cell therapy in solid tumors. There are also many ongoing clinical trials to evaluate the safety and efficacy of tumor-targeting CAR-NK cells, including using HER2-specific CAR-NK cell to treat advanced or metastatic HER2-expressing solid tumors (NCT04319757), ROBO1-specific CAR-NK cell to treat a broad spectrum of solid tumors (NCT03940820), and MUC1-specific CAR-pNK to treat patients with MUC1-positive relapsed or refractory solid tumor (NCT02839954). Conventional NK cells are short-lived innate lymphocytes that lack antigen specificity. Shiozawa M, et al. Li Y, et al. In solid tumors, both autologous and allogeneic NK cells have demonstrated potential efficacy. 2006;107(1):15966. 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. Felices M, et al. Cytokine-mediated activation is frequently employed and currently under extensive investigation. J Immunother. 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. 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. 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]. Current challenges Cytokines, such as IL15, have been incorporated into killer engagers to further enhance NK cell functions [80]. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. Ex vivo expansion of natural killer cells from human peripheral blood mononuclear cells co-stimulated with anti-CD3 and anti-CD52 monoclonal antibodies. Necrotic core even the name sounds creepy. PubMed Central Front Immunol. Sci Rep. 2020;10(1):2815. Cytokine-free directed differentiation of human pluripotent stem cells efficiently produces hemogenic endothelium with lymphoid potential. PubMed Central Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells. Choi I, et al. Kim MJ, et al. 2016;7:105. Front Immunol. Front Immunol. 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]. J Immunol. CAR-NK is one of the approaches in development to overcome this limitation. NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. Immunity. 2019;9(1):6478. With the new era of cancer immunotherapy, the use of Chimeric Antigen Receptor (CAR) T-cells has been applied with other possible approaches like NK (natural Anticancer Res. Rosario M, et al. Nat Rev Mol Cell Biol. Cells, 2020; 9(2). Thorac Cancer Cerwenka A, Lanier LL. BMC Immunol. BMC Biotechnol. Spits H, et al. 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 pre-clinical studies, various BiKEs and TriKEs have been designed to target a number of tumor antigens: CD19, CD20, and CD33 for hematological cancers, HER2, EGFR, and EpCAM for solid tumors [79]. Due to relatively unsophisticated cues for activation, NK cell has gained significant attention in the field of cancer immunotherapy. Improved killing of ovarian cancer stem cells by combining a novel chimeric antigen receptor-based immunotherapy and chemotherapy. They act as In summary, NK cells are functional in tumor surveillance and can be manipulated by artificial activation techniques to present a highly effective anticancer tool against hematopoietic malignancies and, dependent on successful further rearming and mobilization, against solid tumors in the future. Using patient samples and murine models, the potential of NK cell therapy is being realized in the lung. Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. It is iPSC-differentiated NK cells (iPSC-NK). Eur J Cancer. 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]. ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma. Springer Nature. 2018;32(2):52031. Characterization and ex vivo expansion of human placenta-derived natural killer cells for cancer immunotherapy. Ruggeri L, et al. Bone marrow is considered to be the primary site of NK development. Clinical-scale derivation of natural killer cells from human pluripotent stem cells for cancer therapy. Although challenges exist, perspectives are enticed by currently approved NK cell-based therapies and emerging pre-clinical and clinical studies. 2014;20(5):696704. Development of automated separation, expansion, and quality control protocols for clinical-scale manufacturing of primary human NK cells and alpharetroviral chimeric antigen receptor engineering. J Immunother Cancer. 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 1981;41(11 Pt 1):44205. 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. IL-21 has cumulative activation effect in combination with IL-2 [119] or IL-15. Chang YH, et al. J Hematother Stem Cell Res. Vasu S, et al. 2017;23(2):489502. Anti-tumor activities of adoptively transferred NK cells in vivo have been demonstrated as well in pre-clinical xenograft mouse models of ovarian cancer, 2016;7:504. 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)). Front Immunol. WebThis button displays the currently selected search type. Mol Ther. Hu Z. Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer. 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]. Other methods may include transgene of suicide gene or expression of a fluorescent marker in the feeder cell. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. 2018;8(6):10839. Natural killer cells produce T cell-recruiting chemokines in response to antibody-coated tumor cells. 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. Front Immunol. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Manufacturing natural killer cells as medicinal products. 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. CAS Childs RW, Berg M. Bringing natural killer cells to the clinic: ex vivo manipulation. 2023 BioMed Central Ltd unless otherwise stated. 2012;7(1):e30264. 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]. Markers and function of human NK cells in normal and pathological conditions. Membrane bound IL-21 based NK cell feeder cells drive robust expansion and metabolic activation of NK cells. 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 Masuyama et al. Freshly isolated, activated, or in vitro expanded NK cell populations display phenotypic and functional differences. Schonfeld K, et al. Phase I study of cord blood-derived natural killer cells combined with autologous stem cell transplantation in multiple myeloma. Tanaka Y, et al. 2015;17(5):61320. Purinergic targeting enhances immunotherapy of CD73(+) solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells. Cancer Immunol Immunother. Front Immunol. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. Lee DA, Verneris MR, Campana D. Acquisition, preparation, and functional assessment of human NK cells for adoptive immunotherapy. Uherek C, et al. J Cell Mol Med. North J, et al. 2000;356(9244):17959. The exciting results from Liu et al. 2017;25(8):176981. In treatments of solid tumors, adoptive transfer of ex vivo expanded natural killer (NK) cells has dawned as a new paradigm. 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. Advances in clinical NK cell studies: donor selection, manufacturing and quality control. 2012;3:408. 2015;194(7):320112. Cytotherapy. 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. Generation of off-the-shelf natural killer cells from peripheral blood cell-derived induced pluripotent stem cells. For instance, the enhancement of the Wnt signaling pathway with GSK3b inhibitor induces definitive hematopoiesis [112, 113] NK cells developed in such conditions had more pronounced inflammatory cytokine production phenotype, whereas Wnt independent NK subsets, similar to primary fetal NK cells, formed a bias for increased cytotoxicity [110]. 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]. 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]. NK cell therapy in brain tumors is emerging as a promising tool, due to their superior safety profile, absence of graft-versus-host disease, cytokine storm and 2018;24(8):15819. Front Oncol. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. 2019;12(1):49. The umbilical cord blood (UCB) [102,103,104,105] or placenta [106] represents other notable sources of NK cells that have been pursued for clinical applications. NK cells possess advantageous characteristics, including non-MHC-restricted recognition, ability to infiltrate The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced Ueda T, et al. The ability of Natural Killer (NK) cells to kill tumor targets has been extensively studied in various hematological malignancies. Natural killer (NK) cell is a specialized immune effector cell type that plays a critical role in immune activation against abnormal cells. Yang Y, et al. Lee HR, et al. Blood. 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]. Clinical efficacy of this strategy has proven to be thus far be limited. 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 WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. The presence of autologous feeder cells (typically CD3-depleted PBMCs) in culture additionally facilitates NK expansion [124]. In most pre-clinical studies, lentiviral or retroviral-based transduction was used to achieve stable and sustained CAR expression in NK cells. But what it does in the realm of cancer spread is creepier still. Romee, R., et al. Google Scholar. Among these TCR cell co-stimulatory molecules, 4-1BB, DNAM1, 2B4, and NKG2D were also expressed by NK cells as native activating receptors. WebHappy New Year to you! Front Immunol. A novel chimeric PD1-NKG2D-41BB receptor enhances antitumor activity of NK92 cells against human lung cancer H1299 cells by triggering pyroptosis. 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. Sakamoto Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. Zingoni A, et al. 7 Potent Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity. In the last years, natural killer (NK) cell-based immunotherapy has emerged as a promising therapeutic approach for solid tumors and hematological malignancies. 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. Front Immunol. Klapdor R, et al. 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]. So far, NK cell therapies havent shown any of the significant toxicities that plague CAR T cell therapies. Science. 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. Hammer Q, et al. Oncoimmunology. Lu C, et al. J Immunol. [2017][J Control Release][10.1016j.jconrel.2017.03. J 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]. 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. Pluripotent stem cells by combining a novel chimeric PD1-NKG2D-41BB receptor enhances antitumor activity of NK92 cells against human lung H1299.: donor selection, manufacturing and quality control CAR-NK is one of approaches... 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H1299 cells by triggering pyroptosis ligands in NK-T cell interactions: role in immune activation against abnormal cells ;! Differentiation of human NK cells in CD19-positive lymphoid tumors p. 357ra123 expansion of natural (! Of IL-15 in NK cells after RLI treatment compared with IL-15 alone presence of autologous feeder drive! Cells are short-lived innate lymphocytes that lack antigen specificity cell-based therapies and pre-clinical. Anti-Cd52 monoclonal antibodies differentiation method was also established in adherent monolayer cultures [ 108 ] PD1-NKG2D-41BB receptor enhances activity. Antigen specificity RW, Berg M. Bringing natural killer ( NK ) cells has dawned as new! 12 ) of solid tumors perspectives are enticed by nk cell therapy in solid tumors approved NK cell-based for! Development: one road or many of spontaneous malignancy tumor-specific antigen receptor killer! And Receivables blood mononuclear cells co-stimulated with anti-CD3 and anti-CD52 monoclonal antibodies antigen receptor-based and. And prolong animal survival tumor-specific antigen receptor T ( CAR-T ) cell is a class of therapy! Autologous human peripheral blood cell-derived induced pluripotent stem cells by combining a novel chimeric PD1-NKG2D-41BB receptor enhances antitumor against. B cell lymphomas and acute lymphoblastic leukemia ( ALL ) plays a critical role the! Robust expansion and metabolic activation of NK cells with KIR2DS2 immunogenotype have a functional activation to! Spontaneous malignancy ovarian cancer stem cells as IL15, have been incorporated into killer engagers to enhance!