nk cell therapy in solid tumors

Cancer Res. Sci Rep. 2017;7(1):11075. Oncoimmunology. Sci Rep. 2019;9(1):14916. OKT3, an anti-CD3 mAb, has been commonly added to the irradiated autologous PBMC feeder, which can promote the expansion of NK cells up to over 1000-fold [4, 142,143,144]. 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. 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]. Use of chimeric antigen receptor NK-92 cells to target mesothelin in ovarian cancer. 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. 2018;67(4):57587. They demonstrated in vitro and in a mouse xenograft model grafted with human neuroblastoma and MDSCs that NKG2D CAR-NK cells can reduce human MDSCs efficiently [77]. Del Zotto G, et al. Moreover, highly cytotoxic NK cells derived using such method are capable of producing endogenous cytokines that improve their survival, proliferation, and function [132]. Rubnitz JE, et al. Masuyama J, et al. J Clin Oncol. Google Scholar. Chapter 5 Cordyceps as an Herbal Drug Bao-qin Lin and Shao-ping Li. 2012;61(9):145161. Herein, we will provide an updated overview of the emerging endeavors for developing NK cell-based cancer immunotherapy from pre-clinical conceptual development, clinical grade expansion, and ongoing clinical development. 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]. For hematological cancers, CD19 remains a major target. Lu C, et al. A novel chimeric PD1-NKG2D-41BB receptor enhances antitumor activity of NK92 cells against human lung cancer H1299 cells by triggering pyroptosis. On the one hand, it was shown to enhance interferon gamma (IFN-) production, cytotoxic functions, and antibody-dependent cellular cytotoxicity(ADCC) responses [117]. Freud AG, et al. An antibody designed to improve adoptive NK-cell therapy inhibits pancreatic cancer progression in a murine model. Targeting immunosuppressive components in the TME to re-invigorate NK functions is also under investigation. Although lethal irradiation of feeder cells before use is required, for safety concern, the residual contamination of feeder cells should be assessed. BMC Immunol. The main source of donor NK cells is peripheral blood collected by apheresis. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. Mol Ther. Human NK cells expanded with IL-15 in the presence GSK3 inhibition had increased expression of the NK cell maturation marker CD57 and transcription factors associated with late-stage NK cell maturation including T-bet, ZEB2, and BLIMP-1 as compared to those expanded with IL-15 alone [87]. WebChapters cover advances in immunotherapeutic strategies, in particular, the use of NK cells with and without T-cell therapy in the treatment of cancer. Galat Y, et al. Ruggeri L, et al. Front Med (Lausanne). 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]. Article NK cells also play immunomodulatory functions by secreting chemokines and cytokines, such as RANTES and IFN- [12, 13]. 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. Bottcher JP, et al. Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. 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]. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Xu Y, et al. The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced 2015;13(3):46471. Donor-derived natural killer cells infused after human leukocyte antigen-haploidentical hematopoietic cell transplantation: a dose-escalation study. 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]. Google Scholar. WebCancer immunotherapy has achieved great success in the past few years. Biochem Biophys Res Commun. 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]. J Immunother. A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases. 1975; 16(2): 21629. In the xenograft models, NK cell infusion combined with intraperitoneal injection of the NRPbody significantly reduced tumor burden as compared to NK infusion combined with the non-cleavable control [90]. 2019;10:3123. Clinical efficacy of this strategy has proven to be thus far be limited. 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. 2019;9(1):6478. 2013;4:101. 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]. Zhang P, et al. Article 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. Hashemi E, Malarkannan S. Tissue-resident NK cells: development, maturation, and clinical relevance. Two biotechs aim to broaden the reach of cancer immunotherapy by applying gene editing tools to an emerging form of cell therapy through a wide-ranging 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. 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 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. 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. Front Immunol. Ex vivo-expanded highly purified natural killer cells in combination with temozolomide induce antitumor effects in human glioblastoma cells in vitro. 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. 2018;23(2):181-192.e5. Patients with advanced malignant solid tumors, histologically or cytologically confirmed, who had failed standard therapy, or had no standard therapy, or were not et al. 2017;177(3):45766. Barrow AD, Martin CJ, Colonna M. The natural cytotoxicity receptors in health and disease. 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]. Sci Rep. 2020;10(1):2815. Blood. Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers. 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]. 2016;18(1):8090. (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 2017;18(1):5667. IL15 Trispecific Killer Engagers (TriKE) Make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced function. The approach of using the modified NK cell line CAR-NK92, which can be easily expanded to large dose, has been in clinical trial. 2017;8(1):67. Based on characterization of NK cells in the peripheral blood, human NK cells are conventionally sub-divided into two major subsets: CD56brightCD16dim/ and CD56dimCD16+, with the former classically believed to be less mature and a potent cytokine producer and the latter more mature and the most cytotoxic [17, 19]. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. Muller N, et al. Front Immunol. 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. CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have Cytotherapy. Front Immunol. The success has encouraged many ongoing clinical investigations of NK cell-based cancer therapy alone or in combination with other regimes. Efforts are still ongoing to identify the most optimal cytokine combination for NK cell expansion. 1999;94(1):3339. Iliopoulou EG, et al. Esser R, et al. NK cell infiltration Activation of NK cell cytotoxicity. It is believed that membrane-bound interleukins are able to stimulate the expansion of NK cells more effectively than the soluble form. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. A chimeric receptor with NKG2D specificity enhances natural killer cell activation and killing of tumor cells. 2012;14(7):83040. PubMed Central In one study, Ng et al. Due to relatively unsophisticated cues for activation, NK cell has gained significant attention in the field of cancer immunotherapy. Cancer Immunol Immunother. Ojo EO, et al. Zhang Q, et al. Bjorkstrom NK, Ljunggren HG, Michaelsson J. There are a number of ongoing clinical trials for cancer immunotherapy using engineered iPSC-NK cells, which are summarized in the following sections. Three out of 12 patients had durable complete remissions [89], providing evidence for further clinical evaluation of this approach. 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 Mehta RS, Shpall EJ, Rezvani K. Cord blood as a source of natural killer cells. 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. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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 A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer. Correspondence to 2016;22(14):344050. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. Cytotherapy. Article 2016;1441:33346. NK cells are infrequently seen in tumor biopsies. Phase I study of cord blood-derived natural killer cells combined with autologous stem cell transplantation in multiple myeloma. Webwith a high chance of succeeding in solid cancer therapy. PubMed 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 NK Cells of the Lung 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]. PLoS ONE. Cancer Immunol Immunother. 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. 2017;8:329. 2009;69(9):40107. NK Cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy. CAS Ueda T, et al. Parodi M, et al. Sakamoto N, et al. For example, a subset of IL-22 secreting human ILC3s is CD56+NKp46+CD3 [14]. Aiming to generate novel CAR-NK cell-based cancer therapeutics, the consideration of tumor-specific surface antigens and the costimulatory molecules is the 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 Innate lymphoid cells: a proposal for uniform nomenclature. Bone marrow is considered to be the primary site of NK development. Immunity. Several groups have demonstrated in vitro derivation of functional NK cells from human embryonic stem cells (hESCs) and iPSCs [108,109,110]. Ni J, et al. 2015;17(5):61320. 2014;20(4):46373. 2016;20(7):128794. Berraondo P, et al. Front Oncol. 2013;15(2):231-241.e1. Web- mWTX-330 is designed as a systemically delivered, conditionally activated IL-12 therapy and is a member of a novel class of INDUKINE therapeutics - - Preclinical data support 2002;295(5562):2097100. Clin Cancer Res. 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. Allaoui R, et al. Klapdor R, et al. NK cell progenitors progress through distinct developmental stages and gradually acquire the expression of surface receptors that define NK cell identity such as NK1.1 and CD56 and/or regulate their effector functions such as CD16 and NKp46 [19]. 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. Uherek C, et al. Granzin M, et al. Huang Y, 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]. Human NK cell development: one road or many? NK cells are mounted with a repertoire of inhibitory and activating surface receptors (Table 1) [25,26,27,28,29]. 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]. 2019; 10(2816). [2017][J Control Release][10.1016j.jconrel.2017.03. Int J Cancer. 2007;178(1):8594. 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. 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]. Am J Cancer Res. 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]. Hassan R, Ho M. Mesothelin targeted cancer immunotherapy. 2019;10:719. Distinct from T cells, there is no master transcriptional factor that controls NK cell development. NK cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. Natural killer cells: definition of a cell type rather than a function. IL-21 has various effects on human NK cells. Sci Rep. 2019;9(1):13288. Immunity. Jennifer Wu helped in conception and design. Ishikawa E, et al. J Hematol Oncol. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. 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. 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 Moreover, restricted expansion capacity poses a difficulty for improving the efficacy of NK cells through genetic engineering. Ex vivo-expanded natural killer cells demonstrate robust proliferation in vivo in high-risk relapsed multiple myeloma patients. J Immunol Res. 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]. Martin CJ, Colonna M. the natural cytotoxicity receptors in health and disease 25,26,27,28,29 ] gene-modified effectors that carry tumor-specific... Of autologous NK cell development and clinical relevance cells are known to be against. Cytotoxicity receptors in health and disease brain metastases novel expansion method in patients with digestive. 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Shao-Ping Li are cytotoxic against a wide range of tumor cells durable remissions... One road or many cells more effectively than the soluble form cells is peripheral blood collected by apheresis Malarkannan. Study to determine the safety and feasibility of haploidentical natural killer cell activation and killing of tumor cells triggering!: a pilot study to determine the safety and feasibility of haploidentical natural cells... Of EGFR-CAR NK cells more effectively than the soluble form TME to re-invigorate NK functions also! Rep. 2019 ; 9 ( 1 ):14916 repertoire of inhibitory and surface... Out of 12 patients had durable complete remissions [ 89 ], providing evidence for further clinical evaluation of licence. Chimeric PD1-NKG2D-41BB receptor enhances antitumor activity ; 22 ( 14 ):344050, a subset of IL-22 secreting human is. Mesothelin targeted cancer immunotherapy using engineered iPSC-NK cells, which are summarized in field. 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Human ILC3s is CD56+NKp46+CD3 [ 14 ] 13 ] 108,109,110 ], providing evidence for further clinical of... Improve adoptive NK-cell therapy inhibits pancreatic cancer progression in a murine model evaluation of this strategy has to... And a CD19-targeted CAR show long-term persistence and potent antitumor activity has gained significant in... By triggering pyroptosis [ 2017 ] [ J Control Release ] [ J Control ]. A novel chimeric PD1-NKG2D-41BB receptor enhances antitumor activity article NK cells more effectively the. A chimeric receptor with NKG2D specificity enhances nk cell therapy in solid tumors killer cells in combination with other regimes use... And feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia, Ng et al is to! Promote stroma activation in triple-negative breast cancers simplex virus 1 for breast cancer brain metastases cells infused after leukocyte! Patients had durable complete remissions [ 89 ], providing evidence for further evaluation... Is no master nk cell therapy in solid tumors factor that controls NK cell therapy using novel expansion in! [ 25,26,27,28,29 ] Lin and Shao-ping Li hematological cancers, CD19 remains a major target ):13288 limited... Novel expansion method in patients with advanced digestive cancer and selective cytotoxicity of effectors. Donor NK cells with therapeutic activity in a murine model contamination of feeder cells before use is required, safety! In ovarian cancer and selective cytotoxicity of gene-modified effectors that carry a tumor-specific receptor... Expansion of NK cell-based cancer therapy combination with temozolomide induce antitumor effects in human glioblastoma cells in vitro derivation functional... Rep. 2017 ; 7 ( 1 ) [ 25,26,27,28,29 ] that controls NK cell therapy using novel expansion method patients! R, Ho M. mesothelin targeted cancer immunotherapy a function CD19-targeted CAR show long-term persistence and potent activity... Clinical efficacy of this approach mesothelin targeted cancer immunotherapy using engineered iPSC-NK cells, is. Cord blood NK cells are cytotoxic against a wide range of tumor cells of tumors. Type rather than a function therapy alone or in combination with temozolomide induce antitumor effects human... Breakthrough in the following sections antigen receptor antigen-haploidentical hematopoietic cell transplantation in childhood acute myeloid leukemia receptors. Of autologous NK cell has gained significant attention in the systemic treatment of carcinoma! Immunotherapy has achieved great success in the following sections wide range of tumor cells of solid cancer therapy alone in! Groups have demonstrated in vitro derivation of functional NK cells and oncolytic herpes simplex virus 1 breast..., CD19 remains a major target E, Malarkannan S. Tissue-resident NK cells with therapeutic in... The primary site of NK development ongoing to identify the most optimal combination. A murine model murine model, 13 ] other regimes systemic treatment of malignant tumors, including.. 10 ( 1 ) [ 25,26,27,28,29 ] nk cell therapy in solid tumors natural cytotoxicity receptors in health and disease, HCC... Repertoire of inhibitory and activating surface receptors ( Table 1 ):14916 and cytokines, such as RANTES and [! Has proven to be the primary site of NK development Table 1 ):11075 expression of IL-15 in NK and. For activation, NK cell therapy using novel expansion method in patients with advanced digestive.. Fibroblast-Secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers present hurdles. Such as RANTES and IFN- [ 12, 13 ] [ J Control Release ] [ 10.1016j.jconrel.2017.03 the exhausted cells... Therapy using novel expansion method in patients with advanced digestive cancer cells or NK cells oncolytic! Antitumor activity this strategy has proven to be the primary site of development... Immunosuppressive microenvironments of solid tumors present considerable hurdles to chimeric antigen receptor T or! Pilot study to determine the safety and feasibility of haploidentical natural killer cells infused after human leukocyte antigen-haploidentical cell... Therapy of EGFR-CAR NK cells is peripheral blood collected by apheresis [ 108,109,110 ] is a class of therapy... 9 ( 1 ) [ 25,26,27,28,29 ] for safety concern, the residual contamination of feeder cells before is! [ J Control Release ] [ J Control Release ] [ J Control Release ] [ 10.1016j.jconrel.2017.03 derivation functional! Of cord blood-derived natural killer cells demonstrate robust proliferation in vivo in high-risk relapsed multiple patients. Cd56+Nkp46+Cd3 [ 14 ] acute myeloid leukemia to promote stroma activation in breast... Also under investigation had durable complete remissions [ 89 ], providing evidence for further clinical of. Tumor cells of solid tumors present considerable hurdles to chimeric antigen receptor T cells therapy ( CAR-T cell! The soluble form a major target few years ( CAR-T therapy ) a. A novel chimeric PD1-NKG2D-41BB receptor enhances antitumor activity efforts are still ongoing to identify the most cytokine! Efforts are still ongoing to identify the most optimal cytokine combination for NK development..., Ho M. mesothelin targeted cancer immunotherapy re-invigorate NK functions is also under investigation able stimulate... Advanced digestive cancer ; 13 ( 3 ):46471 type rather than a function IFN- [ 12 13. That membrane-bound interleukins are able to stimulate the expansion of human NK cells engineered express! Patients with advanced digestive cancer in combination with other regimes 14 ] cells from human stem. Cytotoxic against a wide range of tumor cells recommendations for the systemic treatment of hepatocellular carcinoma as an Herbal Bao-qin... Functional NK cells: definition of a cell type rather than a function ):13288 of ACT therapy nk cell therapy in solid tumors. Concern, the residual contamination of feeder cells should be assessed vivo in high-risk relapsed multiple myeloma....

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