nk cell therapy in solid tumorsnk cell therapy in solid tumors

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. Curr Opin Immunol. The signaling domains of CAR-NK cells are very similar to those in CAR-T cells, typically composed of the fusion of CD3 with one or two TCR co-stimulatory molecule (s), such as CD28, 4-1BB, 2B4, DNAM1, and NKG2D. 2016;22(14):344050. 2019;10:909. PubMed Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. Article 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). Biochem Biophys Res Commun. Lu C, et al. Stimulating antibodies is typically used along with irradiated allogeneic PBMC to further promote NK activation and expansion. The relative proportion of CD56bright and CD56dim NK cells in tissues can be very different from that observed in the peripheral blood [17]. IL-21 has cumulative activation effect in combination with IL-2 [119] or IL-15. Dev Cell. NK cells are also potent producers of chemokines and cytokines such as interferon gamma (IFN-) and tumor necrosis factor alpha (TNF-) and thereby are essential in modulating adaptive immune responses. The difficulty to obtain large quantity of NK cells, to expand to clinical scale ex vivo, and to sustain in vivo survival and activity of infused NK cells has encumbered the progress. CAR NK therapy offers experimental treatment option for blood cancers BY Devon Carter Natural killer cells or NK cells are part of our immune system. 2017;47(5):82033. Oberschmidt O, et al. Dhar P, Wu JD. An antibody designed to improve adoptive NK-cell therapy inhibits pancreatic cancer progression in a murine model. They have the ability to target and destroy tumor cells without prior sensitization, via activation of NK cell-activating receptors Int J Cancer. The natural cytotoxic receptor NKp46 is also often used to identify mouse and human NK cells in combination with the absence of CD3 expression. The Ruggeri group showed that KIR-mismatched alloreactive donor NK cells protected bone marrow-transplanted AML patients from AML relapse while sparing graft versus host diseases (GVHD) [31, 32]. 2015;15:1011. 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. IL-21 has various effects on human NK cells. 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]. Although lethal irradiation of feeder cells before use is required, for safety concern, the residual contamination of feeder cells should be assessed. 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]. Guerra N, et al. Table 5 summarizes the clinical trials of NK cell-based therapy for hematological malignancies to date. Necrotic core even the name sounds creepy. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Generation of BiKEs and TriKEs to improve NK cell-mediated targeting of tumor cells. 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 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 are CD49aEomes+, whereas ILC1s are CD49a+Eomes [15, 16]. NK cells possess advantageous characteristics, including non-MHC-restricted recognition, ability to infiltrate Emerging insights into natural killer cells in human peripheral tissues. PubMed Several groups have demonstrated in vitro derivation of functional NK cells from human embryonic stem cells (hESCs) and iPSCs [108,109,110]. 2016;7:504. 7 Potent 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]. Blood. WebAB-201 is our clinical-stage CAR-NK cell therapy candidate targeting HER2-positive solid tumors. Improved killing of ovarian cancer stem cells by combining a novel chimeric antigen receptor-based immunotherapy and chemotherapy. Through several preclinical studies, researchers have discovered new guardian immune cells called chimeric antigen receptor (CAR)-modified natural killer (NK) cells, which show cytotoxic activity against various solid tumor types. 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. The broad spectrum of human natural killer cell diversity. Cell. NK cells are mounted with a repertoire of inhibitory and activating surface receptors (Table 1) [25,26,27,28,29]. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. WebAdoptive cell therapy is a rapidly advancing approach to cancer immunotherapy that seeks to facilitate antitumor responses by introducing potent effector cells into the tumor Efforts are still ongoing to identify the most optimal cytokine combination for NK cell expansion. 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. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Google Scholar. 2018;67(4):57587. Wang W, et al. 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. Additional markers such as lack of c-kit can be used to distinguish human NK (c-kit-) from ILC3s (c-kit+) [14]. But cancer cells can make themselves invisible, making it much more difficult for NK cells to find them and do their job. PubMed 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]. 1975;5(2): 1127. Cancer Res. Production Process of CAR-NK Front Immunol. 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]. In mouse strains lacking NK1.1 expression (e.g., BALB/c), CD49b is used for NK cell identification. Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors. Miller et al. Cancer Manag Res. Lee et al. PubMed Central To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies. 2002;295(5562):2097100. In one study, Ng et al. 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]. 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]. Br J Haematol. 2013;3:118. Rosario M, et al. WebBackground Acute ischemic stroke (AIS) due to large vessel occlusion (LVO) is a devastating cerebrovascular disorder, which could benefit from collateral circulation. 2014;28(4):91727. 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. Childs RW, Berg M. Bringing natural killer cells to the clinic: ex vivo manipulation. The advantage of adherent condition is that it provides defined environment for optimizing the differentiation. Imai C, Iwamoto S, Campana D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. NKp44-NKp44 ligand interactions in the regulation of natural killer cells and other innate lymphoid cells in humans. Webwith a high chance of succeeding in solid cancer therapy. 2020;12:324755. Google Scholar. Engineering natural killer cells for cancer immunotherapy. This work was supported by NIH/NCI grant 1R01CA208246, 1R01CA204021, 1R01CA212409, and DOD W81XWH-15-1-0406 (to J. D. Wu). Application of small molecule CHIR99021 leads to the loss of hemangioblast progenitor and increased hematopoiesis of human pluripotent stem cells. All authors declare no conflict of interest. Mol Ther. Topfer K, 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. 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]. Zingoni A, et al. Development of automated separation, expansion, and quality control protocols for clinical-scale manufacturing of primary human NK cells and alpharetroviral chimeric antigen receptor engineering. Cytotherapy. 2015;2:93. Cancer Immunol Immunother. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. WebFurther pharmacodynamic studies in tumor-free mice revealed superior proliferative and cytotoxic functions on NK cells after RLI treatment compared with IL-15 alone. Zhang C., et al. Nham T, et al. Mehta RS, Shpall EJ, Rezvani K. Cord blood as a source of natural killer cells. Google Scholar. Article Journal of Hematology & Oncology Sci Rep. 2020;10(1):2815. It has been shown that freshly isolated, resting NK cells are generally less lytic as compared to NK cells primed via various strategies [82]. Front Immunol. Shah N, et al. Huijskens MJ, et al. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. Ciurea SO, et al. Cichocki F, Grzywacz B, Miller JS. 2013;53(2):41923. Continuously expanding CAR NK-92 cells display selective cytotoxicity against B-cell leukemia and lymphoma. Cytokines are the critical components of NK maintenance system and activation as discussed earlier. The presence of autologous feeder cells (typically CD3-depleted PBMCs) in culture additionally facilitates NK expansion [124]. Natural killer cells stimulated with PM21 particles expand and biodistribute in vivo: clinical implications for cancer treatment. The subjects of the study were patients with high-risk solid tumors, including Ewing Sarcoma, Neuroblastoma, Rhabdomyosarcoma, Osteosarcoma, and CNS tumors. NK cell-based cancer immunotherapy: from basic biology to clinical development, https://doi.org/10.1186/s13045-020-01014-w, http://creativecommons.org/licenses/by/4.0/, http://creativecommons.org/publicdomain/zero/1.0/, Emerging agents and regimens for cancer therapy 2020. 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. J Transl Med. 1995;1(6):60714. Lancet. Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity. 2016;16(5):31020. A novel chimeric PD1-NKG2D-41BB receptor enhances antitumor activity of NK92 cells against human lung cancer H1299 cells by triggering pyroptosis. Parkhurst MR, et al. Cytotherapy. 2012;3:319. WebEnded 2022 with Approximately $475 Million in Cash, Cash Equivalents, and Receivables. The combination of IL-2/IL-15/IL-21 can support up to eightfold expansion of NK cells [121]. Huang Y, et al. 2018;32(2):52031. However, NK92 is a transformed cell line that has limitations associated with its tumorigenic nature, and cytogenetic abnormalities, thus requiring irradiation for clinical use, which limits its life-time activity. Autologous natural killer cell therapy for human recurrent malignant glioma. 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 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. 2016;1441:34761. Galat Y, et al. The approach of using the modified NK cell line CAR-NK92, which can be easily expanded to large dose, has been in clinical trial. Markers and function of human NK cells in normal and pathological conditions. Article 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. It was shown that of CD3-depleted peripheral blood mononuclear cells (PBMC) with IL-21 and IL-15 for 1320days resulted in 3.7-fold expansion of NK cells with clinical activity in delaying leukemia progression [120]. 2020;122:2006. For hematological cancers, CD19 remains a major target. 2013;15(10):1297306. (3) NK cells act as a bridge between the anti-tumor antibodies IgG1 and IgG3, whereby Fab specifically recognizes the tumor while the Fc segment binds to the Stem Cells Transl Med. Mol Ther Oncolytics. Cells, 2020; 9(2). CAR-NK cell therapy has proven to kill hematological and solid tumor cells in preclinical and clinical trials, demonstrating its potential as an off-the-shelf product with In solid tumors, both autologous and allogeneic NK cells have demonstrated potential efficacy. Uherek C, et al. Front Oncol. 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. However, several studies have shown that intratumoral NK cells can also be associated with increased survival ( 6 Nat Rev Mol Cell Biol. Ex vivo-expanded natural killer cells demonstrate robust proliferation in vivo in high-risk relapsed multiple myeloma patients. 2019;10:3123. 2018;2018:4263520. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. 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 The ability of Natural Killer (NK) cells to kill tumor targets has been extensively studied in various hematological malignancies. 2017;23(2):489502. Barrow AD, Martin CJ, Colonna M. The natural cytotoxicity receptors in health and disease. Source: Liu, S., Galat, V., Galat4, Y. et al. To date, more than 350 Cordyceps-related species have been found worldwide based on fungus and/or insect host. Immunity. Blood. Spanholtz J, et al. PubMed Muller N, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. 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]. 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 Hemolytic anemia due to passenger lymphocyte syndrome in solid malignancy patients treated with allogeneic natural killer cell products. Romee, R., et al. 2012;16(3):56981. Cytotherapy. NKG2D and its ligands in cancer. Cancer Immunol Res. However, a more complex scenario has recently emerged. Upon ligation, these receptors transmit either inhibitory or activating signals to control NK activation. Cytotherapy. Lister J, et al. 2012;14(7):83040. Many efforts are emerging for developing and engineering NK cell-based cancer immunotherapy. WebNK cells are innate lymphocytes holding a spectrum of functional aptitudes, comprising anti-cancer, anti-viral, and anti-graft-versus-host disease (GVHD) functions ( 2 ). 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. Sci Rep. 2017;7(1):11075. 2015;13:277. 2006;107(1):15966. In the last years, natural killer (NK) cell-based immunotherapy has emerged as a promising therapeutic approach for solid tumors and hematological malignancies. 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 The deal gives Merck control of two off-the-shelf solid tumor cell Ascorbic acid promotes proliferation of natural killer cell populations in culture systems applicable for natural killer cell therapy. The expanded human NK cells showed potent ADCC activities in vitro and superior tumor control in a mouse xenograft model of ovarian cancer when combined with Herceptin, an anti-HER2 antibody [87]. Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. 1981;41(11 Pt 1):44205. further pioneered the use of NK cells in non-transplant settings. Highly efficient IL-21 and feeder cell-driven ex vivo expansion of human NK cells with therapeutic activity in a xenograft mouse model of melanoma. 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. Miller JS, et al. The following section summarizes the current pre-clinical efforts to enhance the efficacy of NK cell-based therapy. Although challenges exist, perspectives are enticed by currently approved NK cell-based therapies and emerging pre-clinical and clinical studies. 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. In vivo efficacy of umbilical cord blood stem cell-derived NK cells in the treatment of metastatic colorectal cancer. Immunity. Cancer Res. 2016;22(3):596608. Li Y, et al. PubMed Central Cookies policy. But what it does in the realm of cancer spread is creepier still. The linear model proposes that CD56 marks a transition from immature into a more mature status and that immature CD56bright NK cells further differentiate into mature CD56dim populations in human [19, 24]. Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor. 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]. Denman CJ, et al. Eur J Cancer. 2020;382(6):54553. WebOne of the most exciting developments in the fight against cancer is the advent of cell-based immunotherapy, a personalized treatment that kills cancer by using the patients WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. However, there are many challenges to overcome, such as difficulty to meet clinical-grade ex vivo expansion, limited in vivo persistence, limited infiltration to solid tumors, and tumor editing to evade NK cell activity. Blood. 2016;18(1):8090. A clinically adaptable method to enhance the cytotoxicity of natural killer cells against B-cell malignancies. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. CAR-engineered NK cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells. Clin Cancer Res. Cancer Res. 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. Exp Hematol. While the CAR technology seeks to enhance NK cell functions by genetically directing their target specificity, there are active investigations on other strategies to effectively prime NK cells ex vivo or in vivo for optimal anti-tumor functions after their infusion. NK cell dysfunction via altered activating receptor expression or tumor downregulation of NK cell receptor ligands is a common method of tumor immune escape. For example, the absence of NKG2D and other NCR ligands on leukemic blasts allows them to escape NK cell surveillance [86, 87]. showed that CAR-NK cells genetically modified to express the chemokine receptor CXCR1 had enhanced migration in vitro and in vivo as compared to control CAR-NK cells [54]. CAS Cell, 2019; 177(7): 17011713. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. 1985; 161(6): 146482. Phase 1 clinical trial using mbIL21 ex vivo-expanded donor-derived NK cells after haploidentical transplantation. 2006;66(1):51726. Shimasaki N, et al. J Exp Med, 1982; 155(6): 182341. Parodi M, et al. Privacy Merck has secured global licenses to two CAR-NK programs from Artiva Biotherapeutics. 2014;20(4):46373. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies. Parihar and colleagues designed CAR-NK cells expressing the activating receptor NKG2D as the antigen recognition to target human MDSCs. Cell Stem Cell. Genetically engineered CAR NK cells display selective cytotoxicity against FLT3-positive B-ALL and inhibit in vivo leukemia growth. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. Ni J, et al. Wang et al. 2018; 172(5): 10221037. Two CD19-targeting CAR-T products were approved by the FDA for treatment of B cell lymphomas and acute lymphoblastic leukemia (ALL). Shaping of natural killer cell antitumor activity by ex vivo cultivation. Exploring the NK cell platform for cancer immunotherapy. 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]. Clinical-scale derivation of natural killer cells from human pluripotent stem cells for cancer therapy. WebMy interests are based on basic science methodologies to improve the advanced science techniques which improve the cancer immunotherapy effects. Furthermore, IL-2, streptococcus A group, and zoledronate have all been approved for human use. 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. Cytotherapy. 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). The NKG2C+NK cells can be found in the circulation of HCMV-seropositive individuals [22]. 2013;2013(1):23446. Bjorkstrom NK, Ljunggren HG, Michaelsson J. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Zhang Q, et al. Killer (NK) cell activity against solid tumors. Sahm C, Schonfeld K, Wels WS. J Clin Oncol. 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 Granzin M, et al. Beyond directing CAR-NK cytotoxicity against tumor cells by targeting tumor antigens, it has been proposed that CAR-NK cells can be used to eliminate immunosuppressive immune cells in the tumor microenvironment that include myeloid-derived suppressor cells (MDSCs) and M2 tumor-associated macrophages (TAMs) [77, 78]. 2010;59(12):17819. Nat Rev Immunol. Immunotherapy. Tumor-primed human natural killer cells lyse NK-resistant tumor targets: evidence of a two-stage process in resting NK cell activation. 2018; 23(2): 181192. PubMed Central Most NK cells in the blood are CD56dim, whereas the CD56bright subset only represents less than 15% of total circulating NK cells [17]. Herberman RB, Nunn ME, Lavrin DH. But what it does in the realm of cancer spread is creepier still. Current preclinical development of NK cell-based therapy was largely inspired by early clinical studies. Berraondo P, et al. Provided by the Springer Nature SharedIt content-sharing initiative. 2013;15(2):231-241.e1. Oncotarget. Join us for this live, CME-certified symposium featuring an expert discussion of TROP2- and HER3-targeted antibody-drug conjugates and their current use in treating patients with solid tumors, including lung and breast cancers. Cytokine-mediated activation is frequently employed and currently under extensive investigation. Cancer Cell. Geller MA, et al. Freshly isolated, activated, or in vitro expanded NK cell populations display phenotypic and functional differences.
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