Despite decades of work, the ontogeny of NK cells in humans is still not fully elucidated. CAR-NK cell therapy is a novel immunotherapy strategy by utilizing genetically-engineered NK cells to target specific cancer, which can be both liquid and 2016;22(3):596608. 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. 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 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]. Mol Immunol. 2005;106(1):37683. The conventional linear model suggests that mature NK cells arise from common lymphoid progenitors (CLPs) by progressing through a linear continuum [24]. Google Scholar. Methods Mol Biol. Sakamoto N, et al. Can't wait to see what 2023 brings #2023ready PubMed Central Recently, the FDA has approved the investigational new drug (IND) for the use of placenta-expanded NK cells (CYNK-001) against glioblastoma (GBM). However, a more complex scenario has recently emerged. 2018; 172(5): 10221037. Short-term (1820h) pre-activation with ALT-803 augmented cytotoxicity and ADCC of NK cells in vitro. Dual targeting of glioblastoma with chimeric antigen receptor-engineered natural killer cells overcomes heterogeneity of target antigen expression and enhances antitumor activity and survival. Blood. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. 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. 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. Sci Transl Med. 2013;3:118. BMC Immunol. Ex vivo-expanded NK cells from blood and ascites of ovarian cancer patients are cytotoxic against autologous primary ovarian cancer cells. 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. Current preclinical development of NK cell-based therapy was largely inspired by early clinical studies. Membrane bound IL-21 based NK cell feeder cells drive robust expansion and metabolic activation of NK cells. In mouse strains lacking NK1.1 expression (e.g., BALB/c), CD49b is used for NK cell identification. NKp44-NKp44 ligand interactions in the regulation of natural killer cells and other innate lymphoid cells in humans. Exposure of NK to unmodified NK cell-sensitive leukemia cells (K562) stimulates expansion and short-term proliferation [133]. observed in CAR NK cell therapy in liquid tumors have not yet been seen in Expression of chimeric receptor CD4zeta by natural killer cells derived from human pluripotent stem cells improves in vitro activity but does not enhance suppression of HIV infection in vivo. 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]. Biol Blood Marrow Transpl. 2005;42(4):50110. Nat Immunol. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. Natural killer (NK) cells are an essential part of tumor immunosurveillance, evidenced by higher cancer susceptibility and metastasis in association with diminished NK activity in mouse models and clinical studies [1,2,3]. Challenges in CAR NK cell therapy in solid tumors. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. 2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies. 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 Chu J, et al. Front Immunol. 2015;17(11):158293. Ni J, et al. 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. Cancer Res. volume14, Articlenumber:7 (2021) A chimeric receptor with NKG2D specificity enhances natural killer cell activation and killing of tumor cells. 2020;111(5):147890. Oncoimmunology. developed an NK cell recruiting protein-conjugated antibody (NRPbody) containing a mesothelin-specific tumor targeting domain Meso-scFv and the chemokine CXCL16 linked by a furin cleavage sites [90]. Sci Rep. 2019;9(1):13288. However, NK cell therapy 2011;6(6):e20740. Privacy 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. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. Geller MA, et al. Initial successes of adoptive NK cell transfer in treating hematological cancers prompted clinical endeavors in using the strategy against solid cancers. Early clinical trials have demonstrated the overall safety of NK cell infusion, even in the allogeneic setting [4,5,6,7]. 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. Table 6 summarizes updated clinical trials of NK cell-based therapy for all solid tumors. 1995;1(6):60714. Some investigations have sought to enhance NK migration toward the tumor by genetically modifying NK cells to overexpress chemokine receptors [54, 59, 94]. Article 2002;100(4):126573. Freud AG, et al. 2017;177(3):45766. 2017;19(2):23549. 2012;7(1):e30264. 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. 2013;2(4):27483. 2018;8(6):10839. Eur J Cancer. NK cells were identified over four decades ago as lymphocytes with innate ability to lyse tumor cells without the need for prior sensitization [8,9,10]. A novel chimeric PD1-NKG2D-41BB receptor enhances antitumor activity of NK92 cells against human lung cancer H1299 cells by triggering pyroptosis. 2016;7:504. Lanier LL, et al. There are numerous ongoing clinical trials exploring the safety and efficacy of NK-based therapy in combination with other modalities. The BiKEs or TrikEs are composed of two or three linked single-chain antibody variable fragments of different antigen specificities [79]. Graft-versus-host disease. Ex vivo-expanded highly purified natural killer cells in combination with temozolomide induce antitumor effects in human glioblastoma cells in vitro. 2014;32(4):102131. J 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. This approval was based on clinical study demonstrating that oNKord improves survival in year 1 of 80% vs. 35% in the control arm. Bryceson YT, et al. 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. 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. statement and 2015;13(3):46471. The safety and efficacy of allogeneic or autologous donor-derived NK cell-based therapy for treating hematological malignancies, such as AML, have been well established [5, 29, 148]. Topfer K, et al. Nat Rev Mol Cell Biol. 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]. J Exp Med, 1982; 155(6): 182341. J Transl Med. Article Grimm, E.A., et al., Lymphokine-activated killer cell phenomenon. 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. Kim MJ, et al. 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]. Blood. Immunobiology. Google Scholar. 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. 1975; 16(2): 21629. 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]. 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. Clinical-grade generation of active NK cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process. However, the dose of NK cells being used for therapy is limited. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. 2019;9(1):6478. 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. 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 Liu B, et al. They have the ability to target and destroy tumor cells without prior sensitization, via activation of NK cell-activating receptors 2013;73(8):2598607. 2019;10:719. 2006;107(1):15966. 2023 BioMed Central Ltd unless otherwise stated. The anti-tumor response of LAK cells was shown attributed mainly to NK cells [116]. 2018;51:5561. Go to: 5.1. Cytotherapy. Masuyama et al. Nat Rev Immunol. Common gamma chain cytokines such as IL2, IL-7, and IL15 and their receptor components including CD122 and CD127 have been shown to play essential roles in NK development and homeostasis [19]. Efforts are still ongoing to identify the most optimal cytokine combination for NK cell expansion. The off-shelf NK cell therapeutic product oNKord, the allogeneic partial HLA-matched NK cells derived from UCB-CD34+ progenitors, has received an orphan drug designation from EMA and FDA for treating AML patients who were not eligible for allogeneic stem cell transplantation. Lee DA, Verneris MR, Campana D. Acquisition, preparation, and functional assessment of human NK cells for adoptive immunotherapy. GPC3 is Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers. Wang et al. Abel AM, et al. The donor-derived NK cells have certain limitations mainly because of their variability in functional competence and expansion potential. CAS Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells. Distinctly different from T cell receptors, NK cell receptors are germline-encoded and hard-wired receptors without a requirement for V(D)J recombination. However, NK cell therapy directed against solid tumors is still in early development. 2016;16(5):31020. Necrotic core even the name sounds creepy. Parihar R, et al. For example, a subset of IL-22 secreting human ILC3s is CD56+NKp46+CD3 [14]. Shimasaki N, et al. Front Med (Lausanne). further pioneered the use of NK cells in non-transplant settings. Iliopoulou EG, et al. Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. 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]. 2017;8(68):11278396. Recent evidence has challenged this model and suggests a possibility of more branched development in the form of both CLPs and common myeloid progenitors (CMPs) giving rise to NK cell progenitors. Google Scholar. Front Immunol. J Immunol Res. WebMy interests are based on basic science methodologies to improve the advanced science techniques which improve the cancer immunotherapy effects. Yang Y, et al. Anticancer Res. Spanholtz J, et al. Zhang C., et al. Biol Blood Marrow Transpl. 2019;10:3123. For example, there is an ongoing phase 2 clinical trial to evaluate the safety and efficacy of human HLA-haploidentical hematopoieticcelltransplantation (HCT) followed by an early, post-transplant infusion of donor NKcells (NCT02100891). Journal of Hematology & Oncology Romee, R., et al. Jennifer Wu helped in conception and design. Parodi M, et al. It is now understood that the adaptive-like NK cells express the activating receptor NKG2C and that the adaptive nature of NKG2C+ NK cells attributes to the non-classical MHC I molecule HLA-E presenting CMV-specific viral peptide to NKG2C [22]. Front Immunol. 2018;67(4):57587. Phillips JH, Lanier LL. 2019;120(1):615. Colonna M. Innate lymphoid cells: diversity, plasticity, and unique functions in immunity. Expansion of cytotoxic natural killer cells using irradiated autologous peripheral blood mononuclear cells and anti-CD16 antibody. Furthermore, NKp46-ANKET increased the number of NK cells at the tumor site, providing effective control of tumor growth in mouse models of solid and invasive Tumor-primed human natural killer cells lyse NK-resistant tumor targets: evidence of a two-stage process in resting NK cell activation. Chen X, et al. Choi I, et al. Cytokines in clinical cancer immunotherapy. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies. Natural killer (NK) cells have potential as a cellular anticancer therapy that could be significantly safer, cheaper, and faster, researchers say. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 2002;295(5562):2097100. Phase 1 clinical trial using mbIL21 ex vivo-expanded donor-derived NK cells after haploidentical transplantation. Generation of BiKEs and TriKEs to improve NK cell-mediated targeting of tumor cells. Handgretinger R, Lang P, Andre MC. Correction to: IL-27 enhances IL-15/IL-18-mediated activation of human natural killer cells. 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]. 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. 2009;69(9):40107. Oyer JL, et al. 2016;7:105. Denman CJ, et al. J Transl Med. Wang J, et al. Necrotic core even the name sounds creepy. Ciurea SO, et al. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. 2016; 8(357): p. 357ra123. Clinical grade purification and expansion of NK cell products for an optimized manufacturing protocol. 2019;12(1):49. Ex vivo activation and expansion of natural killer cells from patients with advanced cancer with feeder cells from healthy volunteers. Specificity and distribution according to genotype. Cytokines are the critical components of NK maintenance system and activation as discussed earlier. 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. It is iPSC-differentiated NK cells (iPSC-NK). Terms and Conditions, Lee DA. 2012;3:319. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced 1986;137(9):27359. 2017;32(2):13554. CNDO-109-NK cells were found well tolerated without occurrence of dose-limiting toxicities [89]. PLoS ONE. 2013;73(6):177786. First-in-man clinical trial of CAR NK-92 cells: safety test of CD33-CAR NK-92 cells in patients with relapsed and refractory acute myeloid leukemia. NK cell-based cancer immunotherapy: from basic biology to clinical development. 2010;28(6):9559. Pharmacologically upregulated carcinoembryonic antigen-expression enhances the cytolytic activity of genetically-modified chimeric antigen receptor NK-92MI against colorectal cancer cells. 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 Shiozawa M, 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]. 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]. 2007;178(1):8594. Lister J, et al. 2020;122:2006. Nat Immunol. J Immunother. In treatments of solid tumors, adoptive transfer of ex vivo expanded natural killer (NK) cells has dawned as a new paradigm. Koehl U, et al. Torelli GF, et al. Control of metastasis by NK Cells. A simple method for in vitro preparation of natural killer cells from cord blood. Furthermore, IL-2, streptococcus A group, and zoledronate have all been approved for human use. There are great numbers of clinical trials on NK cell immunotherapy to treat solid tumors. WebEnded 2022 with Approximately $475 Million in Cash, Cash Equivalents, and Receivables. Gras Navarro A, et al. J Hematother Stem Cell Res. Bottcher JP, et al. The exciting results from Liu et al. Sci Rep. 2020;10(1):2815. Cao B, et al. In vivo efficacy of umbilical cord blood stem cell-derived NK cells in the treatment of metastatic colorectal cancer. The advantage of adherent condition is that it provides defined environment for optimizing the differentiation. Herein we highlight current evaluations for hematological malignancies and solid tumors. Rezvani K, et al. Cancer Immunol Immunother. Purinergic targeting enhances immunotherapy of CD73(+) solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells. Ojo EO, et al. Am J Cancer Res. WebNK cell-mediated control of large solid tumors is usually not efficient, although tumors often express high amounts of activating ligands and low levels of inhibitory ligands, CAS WebThe presence of HMGB1 in the context of the NK:tumor cell interaction may also play a role in the progression of the tumor. The FDA has cleared Artiva Biotherapeutics investigational new drug (IND) application for the chimeric antigen receptor NK (CAR-NK) cell therapy AB-201 for the Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. Front Immunol. NK cells engineered to express a GD2 -specific antigen receptor display built-in ADCC-like activity against tumour cells of neuroectodermal origin. However, the therapeutic efficacy is generally low in established solid tumors. Front Immunol. In the last 3 decades, NK cells have been utilized to harness Mol Ther. Emerging insights into natural killer cells in human peripheral tissues. Cell Stem Cell. Although lethal irradiation of feeder cells before use is required, for safety concern, the residual contamination of feeder cells should be assessed. Lopez-Soto A, et al. IL-21 has cumulative activation effect in combination with IL-2 [119] or IL-15. Kang L, et al. The adoptive transfer of natural killer (NK) cells is an emerging therapy in the field of immuno-oncology. Tang X, et al. 2013;15(2):231-241.e1. It is believed that membrane-bound interleukins are able to stimulate the expansion of NK cells more effectively than the soluble form. 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. Moreover, restricted expansion capacity poses a difficulty for improving the efficacy of NK cells through genetic engineering. Front Immunol. Transcription factors involved in the regulation of natural killer cell development and function: an update. NK cells originate from CD34+ hematopoietic stem cells. Natural killer cells stimulated with PM21 particles expand and biodistribute in vivo: clinical implications for cancer treatment. Stem Cells Transl Med. 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]. Recently, the differentiation method was also established in adherent monolayer cultures [108]. Childs RW, Berg M. Bringing natural killer cells to the clinic: ex vivo manipulation. J Cell Mol Med. Muller S, et al. 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. It has been shown that freshly isolated, resting NK cells are generally less lytic as compared to NK cells primed via various strategies [82]. Zhang Q, et al. Ni Z, et al. The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced In one study, Ng et al. Feeder cells should be assessed of dose-limiting toxicities [ 89 ] upregulated carcinoembryonic antigen-expression enhances the cytolytic activity of chimeric! And solid tumors, adoptive transfer of ex vivo manipulation 1 ):13288 with relapsed and acute! Cells in the systemic treatment of malignant tumors, NK cell therapy in combination with other.. 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