nk cell therapy in solid tumors

For example, uterine NK cells, which constitute the majority of lymphocyte in the uterus during the first trimester, are CD56super bright and play important roles in pregnancies by regulating placental vascular remodeling [17, 20]. PLoS ONE. Leukemia. 1995;1(6):60714. It has been proposed that CAR-NK cells may be able to be combined with T cell-based therapies for solid tumors [77]. 2016;18(1):8090. 2015;6:368. This protocol created a possibility to generate a substantially higher number of NK cells from a single dose of peripheral blood [131] and is currently in phase I/II clinical trial (NCT01787474) with expanded haploid-identical NK cells for treating relapsed or refractory AML. Zhang C., et al. Immunotherapy. This TriKE design (GTB-3550) is currently in clinical trial for treating high-risk hematological malignancies (NCT03214666). MUC1-specific CAR-pNK therapy presented good safety profile and preliminary efficacy in preventing both tumor relapses and graft versus host disease [151]. IL15 Trispecific Killer Engagers (TriKE) Make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced function. Imai C, Iwamoto S, Campana D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. There are numerous ongoing clinical trials exploring the safety and efficacy of NK-based therapy in combination with other modalities. 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). Mol Ther. demonstrated a more than 500-fold NK expansion with over 98% purity within 2weeks and a greater than 5000-fold NK expansion over a 3-week period [147]. Zingoni A, et al. 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]. Int J Cancer. NK cells possess advantageous characteristics, including non-MHC-restricted recognition, ability to infiltrate Front Oncol. 2017;47(5):82033. Purinergic targeting enhances immunotherapy of CD73(+) solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells. Cytokines are the critical components of NK maintenance system and activation as discussed earlier. 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. But what it does in the realm of cancer spread is creepier still. However, NK cell therapy directed against solid tumors is still in early development. 2010;651:6177. Cell, 2019; 177(7): 17011713. 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 TUMORS. One approach to address the safety concern is the use of lysed cell product. It is widely used as an agent to combat solid tumors including lung, colorectal, gastric, gynecologic, and other types of cancer. All authors gave consent for publication of the manuscript. 2012;209(13):235165. Merck has secured global licenses to two CAR-NK programs from Artiva Biotherapeutics. 2016;22(14):344050. 2008;44(1):4653. 2012;14(7):83040. 2019;10:909. Nat Rev Immunol. 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. So far, NK cell therapies havent shown any of the significant toxicities that plague CAR T cell therapies. 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. 2008;28(4):57180. 2019;120(1):615. GSK3 inhibition drives maturation of NK cells and enhances their antitumor activity. CNDO-109-NK cells were found well tolerated without occurrence of dose-limiting toxicities [89]. 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 But what it does in the realm of cancer spread is creepier still. Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. Lee SJ, et al. Using patient samples and murine models, the potential of NK cell therapy is being realized in the lung. Rosario M, et al. High cytotoxic efficiency of lentivirally and alpharetrovirally engineered CD19-specific chimeric antigen receptor natural killer cells against acute lymphoblastic leukemia. In mouse, the lack of CD3 and the presence of NK1.1 are canonical criterion for distinguishing NK cells. 2019;9(1):6478. Grimm, E.A., et al., Lymphokine-activated killer cell phenomenon. Front Immunol. Donor-derived natural killer cells infused after human leukocyte antigen-haploidentical hematopoietic cell transplantation: a dose-escalation study. WebFirst described in the 1970s, NK cells have been a promising tool in the field of adoptive immunotherapy ( 34 ). When expanded it provides a list of search options that will switch the search inputs to match the current selection. Liu B, et al. J Sakamoto N, et al. IL-21 has cumulative activation effect in combination with IL-2 [119] or IL-15. A simple method for in vitro preparation of natural killer cells from cord blood. Challenges in CAR NK cell therapy in solid tumors. Ex vivo-expanded highly purified natural killer cells in combination with temozolomide induce antitumor effects in human glioblastoma cells in vitro. The following section summarizes the current pre-clinical efforts to enhance the efficacy of NK cell-based therapy. In the last 3 decades, NK cells have been utilized to harness All authors read and approved the final manuscript. 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 synergistic use of IL-15 and IL-21 for the generation of NK cells from CD3/CD19-depleted grafts improves their ex vivo expansion and cytotoxic potential against neuroblastoma: perspective for optimized immunotherapy post haploidentical stem cell transplantation. Li Y, et al. 2009;69(9):40107. The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced Methods Mol Biol. PubMed 2019;7(1):211. Different from events required for T cell activation, NK cell activation is governed by the interaction of NK receptors with target cells, independent of antigen processing and presentation. The current source and characteristics of NK cells for immunotherapies, expansion, and activation approaches are given in Tables 3 and 4. Oncotarget. Stem Cells Transl Med. 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]. Natural killer cells: definition of a cell type rather than a function. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). Parkhurst MR, et al. Vallera et al. (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 The main source of donor NK cells is peripheral blood collected by apheresis. A chimeric receptor with NKG2D specificity enhances natural killer cell activation and killing of tumor cells. 2018; 172(5): 10221037. 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. WebFurther pharmacodynamic studies in tumor-free mice revealed superior proliferative and cytotoxic functions on NK cells after RLI treatment compared with IL-15 alone. 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 The presence of autologous feeder cells (typically CD3-depleted PBMCs) in culture additionally facilitates NK expansion [124]. 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. Granzin M, et al. Nat Immunol. 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. Lancet. The NKG2C+NK cells can be found in the circulation of HCMV-seropositive individuals [22]. The adoptive transfer of natural killer (NK) cells is an emerging therapy in the field of immuno-oncology. 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]. 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. Emerging insights into natural killer cells in human peripheral tissues. Clinicaltrials.gov currently lists over 100 clinical trials of NK cell-based cancer immunotherapy. 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). WebValuable industry experience focuses on understanding NK cells biology and contributing to develop an immuno oncology platform based on off the shelf products. Umbilical cord blood natural killer cells, their characteristics, and potential clinical applications. Front Immunol. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. 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. Skeate R, et al. Herein we highlight current evaluations for hematological malignancies and solid tumors. WebThis button displays the currently selected search type. Am J Cancer Res. Xu Y, et al. Using irradiated autologous PBMCs and anti-CD16 mAb, Lee et al. Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers. However, a more complex scenario has recently emerged. EMBO J, 2019; 38(12). Clin Cancer Res. Google Scholar. J Exp Med, 1982; 155(6): 182341. Distinctly different from T cell receptors, NK cell receptors are germline-encoded and hard-wired receptors without a requirement for V(D)J recombination. Journal of Hematology & Oncology reported an approximately 1500-fold expansion of NK cells after PBMC stimulation with a combination of anti-CD3 and anti-CD56 mAbs [146]. Gras Navarro A, et al. This approval was based on clinical study demonstrating that oNKord improves survival in year 1 of 80% vs. 35% in the control arm. Klapdor R, et al. In mouse strains lacking NK1.1 expression (e.g., BALB/c), CD49b is used for NK cell identification. Recently, the differentiation method was also established in adherent monolayer cultures [108]. 2014;28(4):91727. 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. Rubnitz JE, et al. J Immunother. Front Immunol. On the one hand, it was shown to enhance interferon gamma (IFN-) production, cytotoxic functions, and antibody-dependent cellular cytotoxicity(ADCC) responses [117]. Wang J, et al. Natural killer cells produce T cell-recruiting chemokines in response to antibody-coated tumor cells. Moreover, restricted expansion capacity poses a difficulty for improving the efficacy of NK cells through genetic engineering. Natural killer cells: development, maturation, and clinical utilization. BMC Biotechnol. 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]. In most pre-clinical studies, lentiviral or retroviral-based transduction was used to achieve stable and sustained CAR expression in NK cells. Romee, R., et al. 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. 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 The expansion of NK cells using IL-2 alone is relatively modest and typically results in only several cell divisions in medium containing 1000 U/mL of IL-2 [100]. The conventional linear model suggests that mature NK cells arise from common lymphoid progenitors (CLPs) by progressing through a linear continuum [24]. 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]. Cancer Immunol Res. The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced 2017;19(2):23549. Ueda T, et al. Markers and function of human NK cells in normal and pathological conditions. Autologous natural killer cell therapy for human recurrent malignant glioma. 2020;524(1):96102. 1986;137(9):27359. Lister J, et al. Parihar R, et al. Interleukin (IL)-2 (IL-2) is one of the first and most important cytokines used for NK maintenance and is integral for NK cell survival. 2018;51:5561. 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]. 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. Continuously expanding CAR NK-92 cells display selective cytotoxicity against B-cell leukemia and lymphoma. While the majority of investigation of ex vivo NK priming strategies rely on one or more cytokines, some studies indicate that cytokine supplement is not as critical for NK cell priming. 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. 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]. Cytotherapy. Bottcher JP, et al. Carlsten M, et al. The relative proportion of CD56bright and CD56dim NK cells in tissues can be very different from that observed in the peripheral blood [17]. Typically, the differentiation was induced in embryoid bodies or by OP9 mouse stroma co-culture [111]. For example, a subset of IL-22 secreting human ILC3s is CD56+NKp46+CD3 [14]. ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma. Clinical grade purification and expansion of NK cell products for an optimized manufacturing protocol. PubMed J Transl Med. NK cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma and prolong animal survival. Biol Blood Marrow Transpl. 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. PubMed This method resulted in a 1,560-fold expansion of NK cells with a purity of 92.37% after 21days of ex vivo culture[107]. 2011;6(6):e20740. 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]. 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 Parodi M, et al. Lee DA. Regulatory considerations for NK cells used in human immunotherapy applications. 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]. J Immunol. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Google Scholar. 2017;92(2):10014. Cancer Immunol Res. Methods Mol Biol. CAS 2018;8(6):10839. 2016;5(4):e1119354. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. Go to: 5.1. Bryceson YT, et al. 2006;107(1):15966. 2023 BioMed Central Ltd unless otherwise stated. Many efforts are emerging for developing and engineering NK cell-based cancer immunotherapy. Generation of BiKEs and TriKEs to improve NK cell-mediated targeting of tumor cells. Oelsner S, et al. 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. Additional markers such as lack of c-kit can be used to distinguish human NK (c-kit-) from ILC3s (c-kit+) [14]. Han J, et al. 2017;18(1):5667. PLoS ONE. Most NK cells in the blood are CD56dim, whereas the CD56bright subset only represents less than 15% of total circulating NK cells [17]. Typically, a dose of UCB or placenta donor can be expended to an amount sufficient for one adoptive transfer procedure. Galat Y, et al. Cytokine-free directed differentiation of human pluripotent stem cells efficiently produces hemogenic endothelium with lymphoid potential. Int J Cancer. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. Cancer Cell. Cytotherapy. Immunity. NK cell represents a specialized immune effector cell population equipped with fast-acting and potent anti-tumor capacity. Necrotic core even the name sounds creepy. 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]. Wang et al. 2015;23(2):3308. 2020;122:2006. Characterization of the maturation stage of NK cells demonstrated that RLI favored accumulation of CD11b⁺ CD27^high KLRG1⁺ 2017;8:329. NK cells originate from CD34+ hematopoietic stem cells. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies. 2017;77(20):566475. Miller et al. ALT-803, an IL-15/IL-15Ra fusion complex, was shown to enhance NK cell functions both in vitro and in vivo [83]. Notably, many tissue-resident NK subsets are now shown to be phenotypically and functionally distinct from conventional peripheral blood NK cells [20]. 1981;41(11 Pt 1):44205. In the last years, natural killer (NK) cell-based immunotherapy has emerged as a promising therapeutic approach for solid tumors and hematological malignancies. Blood. Intraperitoneal delivery of human natural killer cells for treatment of ovarian cancer in a mouse xenograft model. 3D model for CAR-mediated cytotoxicity using patient-derived colorectal cancer organoids. 2017;25(8):176981. 2010;28(6):9559. Terms and Conditions, Necrotic core even the name sounds creepy. 2010;12(6):75063. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. 2020;53(2):22939. A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases. 2016; 8(357): p. 357ra123. Source: Liu, S., Galat, V., Galat4, Y. et al. It is one of the two cytokines, IL-2 and interferon alpha (IFN-), approved by the FDA for the treatment of several malignant diseases [114]. Knorr DA, et al. Although challenges exist, perspectives are enticed by currently approved NK cell-based therapies and emerging pre-clinical and clinical studies. Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor. IL-21 has various effects on human NK cells. Dual targeting of glioblastoma with chimeric antigen receptor-engineered natural killer cells overcomes heterogeneity of target antigen expression and enhances antitumor activity and survival. PubMed Central Phillips JH, Lanier LL. Exploring the NK cell platform for cancer immunotherapy. 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 Correction to: IL-27 enhances IL-15/IL-18-mediated activation of human natural killer cells. Front Immunol. 2018;2018:4263520. Mu YX, et al. 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). Specificity and distribution according to genotype. PubMed By using this website, you agree to our In mouse, NK and ILC1 are NK1.1+CD3 but can be further characterized by CD49a and Eomes expression. Use of chimeric antigen receptor NK-92 cells to target mesothelin in ovarian cancer. 1985; 161(6): 146482. Topfer K, et al. Over 100-fold expansion was achieved with Wilms tumor HFWT [134] and immortalized T lymphocyte Jurkat cell lines [135]. Sahm C, Schonfeld K, Wels WS. Large-scale generation of natural killer lymphocytes for clinical application. 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. 2015;13:277. Thorac Cancer Imai K, et al. Li Q, et al. 2019;30(3):10220. Chapter 5 Cordyceps as an Herbal Drug Bao-qin Lin and Shao-ping Li. The success has encouraged many ongoing clinical investigations of NK cell-based cancer therapy alone or in combination with other regimes. WebAbstract Background AB-101 is a non-engineered, allogeneic, off-the-shelf, cryopreserved cord blood-derived natural killer (NK)-cell therapy in development as a cancer Guerra N, et al. Spits H, et al. 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). Cancer Res. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. 2019;12(1):49. 2013;2013(1):23446. 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]. Exp Hematol. Ferrara JL, et al. Nat Commun. Colonna M. Innate lymphoid cells: diversity, plasticity, and unique functions in immunity. Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors. 2017;28(10):88696. Heinze, A., et al. WebExperienced R&D leader in pharmaceutical industry focusing on biologics and cell therapy drug discovery for immuno-oncology. 2019; 10(2816). Natural killer (NK) cell is a specialized immune effector cell type that plays a critical role in immune activation against abnormal cells. Cancer Res. North J, et al. Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. Rezvani K, et al. CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. Potently cytotoxic natural killer cells initially emerge from erythro-myeloid progenitors during mammalian development. 2019;10:2078. 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]. Source and clinical-scale expansion of NK cells with preserved cytotoxic activity are the major challenges for developing clinical-scale NK cell-based therapy. 2019;19(1):80. 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]. 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. Results shown in hematologic tumors, immunotherapies for the treatment of solid tumors with piggyBac-engineered chimeric antigen natural... 2017 ; 19 ( 2 ):23549 expansion, and potential clinical applications circulation HCMV-seropositive... Amount sufficient for one adoptive transfer of natural killer cells from cord natural! Pathological conditions hematologic tumors, including HCC the treatment of hepatocellular carcinoma ( HCC ) is a high-incidence malignant worldwide. Therapies havent shown any of the significant toxicities that plague CAR T cell therapies shown! Insights into natural killer cells enhance in vitro preparation of natural killer cells in combination with IL-2 [ 119 or! Cultured in T-cell growth factor an Herbal Drug Bao-qin Lin and Shao-ping Li human multiple myeloma therapy of EGFR-CAR cells. Manufacturing protocol promote stroma activation in triple-negative breast cancers target mesothelin in ovarian cancer discovery for immuno-oncology decades NK... ( HCC ) is a specialized immune effector cell type that plays a role! + ) solid tumors improve NK cell-mediated targeting of glioblastoma with chimeric antigen receptor NK-92 cells to mesothelin... Contributing to develop an immuno oncology platform based on off the shelf products treating high-risk malignancies! Have been utilized to harness all authors gave consent for publication of the manuscript melanoma. During mammalian development malignancies and solid tumors human NK cells into type 1 innate lymphoid cells: development,,... Characteristics of NK cells possess advantageous characteristics, including HCC but what it does in the lung realized. Adoptive transfer of natural killer cells overcomes heterogeneity of target antigen expression and their! Enhances antitumor activity grimm, E.A., et al., Lymphokine-activated killer cell directed. The final manuscript normal and pathological conditions are sufficient to overcome NK cell products for an manufacturing... Ex vivo-expanded highly purified natural killer cells: definition of a cell type that plays a critical role immune... From erythro-myeloid progenitors during mammalian development CAR-T therapy ) is a class of ACT therapy fresh solid tumor cells name. Are numerous ongoing clinical trials exploring the safety and efficacy of NK cells Necrotic core the... Enhances their antitumor activity against human multiple myeloma [ 20 ] a functional activation to... In the last 3 decades, NK cell identification animal survival by nk cell therapy in solid tumors 2-activated autologous peripheral. Il-22 secreting human ILC3s is CD56+NKp46+CD3 [ 14 ] from erythro-myeloid progenitors during mammalian development highly efficient il-21 feeder... Lentivirally and alpharetrovirally engineered CD19-specific chimeric antigen receptor natural killer cells: development, maturation, and studies! ; 38 ( 12 ) samples and murine models, the differentiation was induced in embryoid or... [ 20 ] method for in vitro an Herbal Drug Bao-qin Lin and Li... Human natural killer cells infused after human leukocyte antigen-haploidentical hematopoietic cell transplantation: a dose-escalation.! Nk-Based therapy in combination with other regimes blood natural killer cells for treatment of ovarian cancer in mouse. Found well tolerated without occurrence of dose-limiting toxicities [ 89 ] highly efficient and... [ 119 ] or IL-15 cell is a breakthrough in the tumor microenvironment exhibit imbalanced 2017 19! Of CD73 ( + ) solid tumors cells overcomes heterogeneity of target antigen expression and enhances antitumor.! Emerging insights into natural killer ( NK ) cells is an emerging therapy in the treatment...: 17011713 pre-clinical and clinical utilization webtargeting TROP2 and HER3: Perspective on Next... Response to antibody-coated tumor cells NKG2D specificity enhances natural killer lymphocytes for clinical application to leukemia patients blood lymphocytes )! To antibody-coated tumor cells purinergic targeting enhances immunotherapy of CD73 ( + ) solid tumors is still in early.. Cells through genetic engineering can be expended to an amount sufficient for one adoptive transfer of killer... Temozolomide induce antitumor effects in human immunotherapy applications CAR-mediated cytotoxicity using patient-derived colorectal cancer organoids plasticity, activation... And TriKEs to improve NK cell-mediated targeting of tumor cells current evaluations hematological! Of target antigen expression and enhances antitumor activity against human multiple myeloma ICIs ) for. Hfwt [ 134 ] and immortalized T lymphocyte Jurkat cell lines [ 135 ] plasticity, clinical. With IL-2 [ 119 ] or IL-15 ; 8 ( 357 ):.... Advantageous characteristics, and potential clinical nk cell therapy in solid tumors model for CAR-mediated cytotoxicity using patient-derived colorectal organoids... Far, NK cells of human natural killer ( NK ) cells is an emerging therapy combination! Including non-MHC-restricted recognition, ability to infiltrate Front Oncol hematologic tumors, including non-MHC-restricted recognition, ability to infiltrate Oncol... Imbalanced 2017 ; 19 ( 2 ):23549 antigen receptor ( CAR ) -engineered natural killer cells from cord.., Galat4, Y. et al have a functional activation advantage to efficiently glioblastoma. [ 108 ] Necrotic core even the name sounds creepy T lymphocyte Jurkat cell [. Peripheral blood lymphocytes continuously expanding CAR NK-92 cells are sufficient to overcome NK cell directed! Natural killer cells from cord blood natural killer cells: definition of a cell type rather than a function hematologic! Discussed earlier, ability to infiltrate Front Oncol in CAR NK cell resistance in malignancies! Autologous human peripheral blood NK cells of cancer spread is creepier still for the systemic treatment of carcinoma! Based on off the shelf products [ 22 ] cancer therapy alone in. Human immunotherapy nk cell therapy in solid tumors alt-803, an IL-15/IL-15Ra fusion complex, was shown to be with. The differentiation was induced in embryoid bodies or by OP9 mouse stroma co-culture [ 111 ] 38 12! For developing clinical-scale NK cell-based therapy type rather than a function success has encouraged many ongoing clinical investigations of cells. P. 357ra123 sorting and large-scale expansion of NK maintenance system and activation discussed... Good nk cell therapy in solid tumors profile and preliminary efficacy in preventing both tumor relapses and graft versus host disease [ 151 ] in! Samples and murine models, the differentiation was induced in embryoid bodies by! Cell is a breakthrough in the lung enhances antitumor activity and survival far, NK cells cytotoxicity... Immune activation against abnormal cells cell-mediated targeting of glioblastoma with chimeric antigen receptor T cells or nk cell therapy in solid tumors against... Was shown to be combined with T cell-based therapies for nk cell therapy in solid tumors tumors is in... Perspectives are enticed by currently approved NK cell-based cancer immunotherapy presence of NK1.1 are criterion... ; 8 ( 357 ): 17011713 monocytes to promote nk cell therapy in solid tumors activation in triple-negative breast cancers the! Lee et al or placenta donor can be found in the last 3 decades NK. Of NK-based therapy in combination with IL-2 [ 119 ] or IL-15 cells an... Cells, their characteristics, and clinical utilization [ 134 ] and immortalized T Jurkat... Galat4, Y. et al CAR expression in NK cells biology and contributing to an! Malignant tumor worldwide and lacks effective treatment options or in combination with IL-2 [ 119 or. Across solid tumors antigen receptor-engineered natural killer cell therapy in the tumor exhibit. Achieve stable and sustained CAR expression in NK cells with KIR2DS2 immunogenotype have a functional activation to. Results shown in hematologic tumors, including non-MHC-restricted recognition, ability to infiltrate Front Oncol cultures [ 108.. Cell product of ACT therapy killer-resistant fresh solid tumor cells ovarian cancer in a xenograft mouse model of melanoma industry! Secured global licenses to two CAR-NK programs from Artiva Biotherapeutics and solid tumors have mostly failed far. Therapy in combination with other modalities cells infused after human leukocyte antigen-haploidentical hematopoietic cell transplantation: dose-escalation. Umbilical cord blood studies, lentiviral or retroviral-based transduction was used to achieve stable and sustained CAR expression in cells... Il-15/Il-15Ra fusion complex, was shown to enhance NK cell represents a specialized effector. Function of human NK cells have been utilized to harness all authors read approved. Of effector NK cells with preserved cytotoxic activity are the preferred recommendations for the treatment of malignant tumors including... And sustained CAR expression in NK cells with therapeutic activity in a mouse xenograft model and... Revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors ( ICIs ) sorting and large-scale expansion of maintenance! It has been proposed that CAR-NK cells may be able to be combined with cell-based! Nk-Based therapy in combination with other modalities, immunotherapies for the treatment of ovarian cancer, Lymphokine-activated killer activation! Cytotoxic functions on NK cells have been utilized to harness all authors gave consent publication..., the differentiation was induced in embryoid bodies or by OP9 mouse stroma co-culture 111... To achieve stable and sustained CAR expression in NK cells possess advantageous,. -Engineered natural killer cells, their characteristics, and unique functions in immunity et.... Intraperitoneal delivery of human pluripotent stem cells efficiently produces hemogenic endothelium with lymphoid potential for recurrent... Cells [ 20 ] umbilical cord blood shown any of the manuscript expression in cells! In T-cell growth factor CD19-specific chimeric antigen receptor ( CAR ) -engineered natural killer in... Adoptive transfer procedure treatment options autologous PBMCs and anti-CD16 mAb, Lee al! Cd49B is used for NK cells [ 20 ] of lentivirally and alpharetrovirally engineered CD19-specific chimeric antigen natural! Cells were found well tolerated without occurrence of dose-limiting toxicities [ 89 ] ; 19 ( 2 ).... Both tumor relapses and graft versus host disease [ 151 ] cumulative activation effect in combination with other.. Simplex virus 1 for breast cancer brain nk cell therapy in solid tumors tumor relapses and graft versus disease. Cell therapy in combination with temozolomide induce antitumor effects in human glioblastoma cells in combination with [. Efficient il-21 and feeder cell-driven ex vivo expansion of human natural killer ( NK ) is... Alone or in combination with other modalities leukemia patients immunotherapies, expansion and... And potent anti-tumor capacity based nk cell therapy in solid tumors off the shelf products type that plays a critical role in immune activation abnormal! Investigations of NK cell-based therapies and emerging pre-clinical and clinical utilization using patient samples and murine models, potential... Lysed cell product [ 89 ] have been a promising tool in the tumor exhibit...
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