Table 6 summarizes updated clinical trials of NK cell-based therapy for all solid tumors. Tumor-primed human natural killer cells lyse NK-resistant tumor targets: evidence of a two-stage process in resting NK cell activation. The current source and characteristics of NK cells for immunotherapies, expansion, and activation approaches are given in Tables 3 and 4. NK Cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy. Imai K, et al. J Hematol Oncol. Blood. https://doi.org/10.1186/s13045-020-01014-w, DOI: https://doi.org/10.1186/s13045-020-01014-w. NK cell represents a specialized immune effector cell population equipped with fast-acting and potent anti-tumor capacity. Cancer Res. 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]. Hammer Q, et al. 2019;7(3):36375. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. 2004;24(3b):186171. 2020;122:2006. Distribution of reactivity and specificity. demonstrated that antibody-mediated blockade of CD73 significantly enhanced the anti-tumor activities of NKG2D-enginneered CAR-NK92 in vitro and in vivo, with improved tumor infiltration by CAR-NK cells in vivo [43]. 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]. 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. Ojo EO, et al. Due to relatively unsophisticated cues for activation, NK cell has gained significant attention in the field of cancer immunotherapy. 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]. The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced NK Cells of the Lung 2015;38(1):2436. Oelsner S, et al. It yielded a greater than 1000-fold expansion of NK cells after 3weeks of culture [38, 125, 126]. Terms and Conditions, 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]. 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 Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. Mehta RS, Shpall EJ, Rezvani K. Cord blood as a source of natural killer cells. WebCancer immunotherapy has achieved great success in the past few years. 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. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Human NK cell development: one road or many? Front Immunol. Despite decades of work, the ontogeny of NK cells in humans is still not fully elucidated. Ni J, et al. Dhar P, Wu JD. Recently, the differentiation method was also established in adherent monolayer cultures [108]. PubMed IL15 Trispecific Killer Engagers (TriKE) Make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced function. 2016;5(4):e1119354. 2016;1441:34761. In the last 3 decades, NK cells have been utilized to harness Cancer Immunol Res. Large-scale generation of natural killer lymphocytes for clinical application. Some investigations have sought to enhance NK migration toward the tumor by genetically modifying NK cells to overexpress chemokine receptors [54, 59, 94]. NKp44-NKp44 ligand interactions in the regulation of natural killer cells and other innate lymphoid cells in humans. Imai C, Iwamoto S, Campana D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. PubMed Beyond cytokines, other stimulants, including tumor cells, allogeneic PBMCs, antibodies, and microbiol derivatives, have been explored for enhancing ex vivo NK cell expansion. 2010;12(6):75063. Google Scholar. Studies on the in vitro activation of Leu-11+ granular lymphocytes with a natural killer-sensitive tumor cell, K562. Autologous natural killer cell therapy for human recurrent malignant glioma. For hematological cancers, CD19 remains a major target. 2014;28(4):91727. Phase 1 clinical trial using mbIL21 ex vivo-expanded donor-derived NK cells after haploidentical transplantation. But cancer cells can make themselves invisible, making it much more difficult for NK cells to find them and do their job. 2009;69(9):40107. WebAB-201 is our clinical-stage CAR-NK cell therapy candidate targeting HER2-positive solid tumors. Google Scholar. A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases. This approval was based on clinical study demonstrating that oNKord improves survival in year 1 of 80% vs. 35% in the control arm. Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity. Cancer Immunol Immunother. A phase 1 trial of CNDO-109-activated natural killer cells in patients with high-risk acute myeloid leukemia. Torelli GF, et al. 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 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 SNK02 clinical study will be a multi-center, open label, Phase 1 study of SNK02 in patients with advanced solid tumors who have failed at least one prior Front Immunol. Efficient mRNA-based genetic engineering of human NK cells with high-affinity CD16 and CCR7 augments rituximab-induced ADCC against lymphoma and targets NK cell migration toward the lymph node-associated chemokine CCL19. Miller et al. Nat Rev Clin Oncol. 2012;3:408. NK cells, which were discovered almost 50 years ago, can defend against tumors in most tissues without requiring detection of specific tumor antigens. By using this website, you agree to our Herberman RB, Nunn ME, Lavrin DH. With the understanding of how NK cells are activated, the initial NK cell-based therapy was pioneered in the clinical setting of hematopoietic stem cell transplants (HSCTs) whereby NK cells were shown to have the capacity to exert a graft versus leukemia effect. Front Oncol. Intraperitoneal delivery of human natural killer cells for treatment of ovarian cancer in a mouse xenograft model. McMichael EL, et al. 2013;73(8):2598607. 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 Similar to CAR-T cells, CAR-NK cells are genetically modified to express CARs that recognize a specific antigen uniquely expressed or overexpressed by target cells. Upon activation, NK cells release cytotoxic granules containing perforin and granzymes to directly lyse tumor cells, in a similar fashion to activated cytotoxic T cells. BMC Immunol. 2005;42(4):50110. Wang et al. 2006;107(1):15966. 2020;524(1):96102. Targeting immunosuppressive components in the TME to re-invigorate NK functions is also under investigation. Markers and function of human NK cells in normal and pathological conditions. Yang Y, et al. There are numerous ongoing clinical trials exploring the safety and efficacy of NK-based therapy in combination with other modalities. 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]. Conversely, tumorigenic cells or virally infected cells have downregulated MHC I expression but upregulated levels of ligands for NK cell activating receptors and thus trigger NK cell activation due to the lack of inhibitory signals and/or the presence of activating signals [11]. Due to their innate ability to eliminate tumor cells, NK cell-based immunotherapies against cancer have been investigated for decades. Hassan R, Ho M. Mesothelin targeted cancer immunotherapy. Granzin M, et al. Szmania S, et al. Vallera DA, et al. PubMed Central The broad spectrum of human natural killer cell diversity. CAS Sakamoto N, et al. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. 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]. Cookies policy. Bone marrow is considered to be the primary site of NK development. Dev Cell. volume14, Articlenumber:7 (2021) IL-21 has various effects on human NK cells. 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 Liu E, 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]. The BiKEs or TrikEs are composed of two or three linked single-chain antibody variable fragments of different antigen specificities [79]. Ng YY, Tay JCK, Wang S. cxcr1 expression to improve anti-cancer efficacy of intravenously injected CAR-NK cells in mice with peritoneal xenografts. Ferrara JL, et al. 1986;137(9):27359. Synergistic effects of cabozantinib and EGFR-specific CAR-NK-92 cells in renal cell carcinoma. Natural killer (NK) cells inhibit systemic metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the brain. 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. 2012;7(1):e30264. Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor. 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 Cell. 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. 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. Oncoimmunology. 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. CAS It is currently believed that the success of adoptive transfer requires the creation of a lymphopenic environment to provide a niche for donor cells to survive and proliferate. Chapter 5 Cordyceps as an Herbal Drug Bao-qin Lin and Shao-ping Li. 7 Potent Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. 2002;11(4):6517. Methods Mol Biol. Uherek C, et al. Based on the pre-clinical findings, CTV-1 lysate-primed human NK cells (CNDO-109-NK cells) derived from HLA-haploidentical donors were evaluated for safety in a phase I clinical trial (NCT01520558) in high-risk AML patients with AML after first complete remission [89]. All authors gave consent for publication of the manuscript. 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. Nat Immunol. 2017;25(8):176981. Clinical application of CAR-NK cell therapy in solid tumors. Ex vivo expansion of highly cytotoxic human NK cells by cocultivation with irradiated tumor cells for adoptive immunotherapy. 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]. NK cell-based cancer immunotherapy: from basic biology to clinical development. Wang W, et al. J Exp Med. Nat Rev Immunol. Clin Cancer Res. 2012;3:319. They patrol our bodies for abnormal cells like cancer and destroy them. 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. A model for the differentiation of human natural killer cells. Genetically engineered CAR NK cells display selective cytotoxicity against FLT3-positive B-ALL and inhibit in vivo leukemia growth. Cytotherapy. 1975; 16(2): 21629. Mol Ther. 2015;2:93. Cancer Res. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. et al. It is widely used as an agent to combat solid tumors including lung, colorectal, gastric, gynecologic, and other types of cancer. Parodi M, et al. For instance, in the use of CD19-modified K562 to propagate NK cells, the contamination was assessed by flow cytometry detection of surface expression of the NK cell endogenous molecule CD32 and the K562 transgene CD19 to distinguish NK cells from the feeder cells [140]. Sizhe Liu, Vasiliy Galat, Yekaterina Galat, Yoo Kyung Annie Lee, Derek Wainwright, and Jennifer Wu wrote and reviewed the manuscript. Transcription factors involved in the regulation of natural killer cell development and function: an update. Clin Cancer Res. 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. In most pre-clinical studies, lentiviral or retroviral-based transduction was used to achieve stable and sustained CAR expression in NK cells. WebExperienced R&D leader in pharmaceutical industry focusing on biologics and cell therapy drug discovery for immuno-oncology. 2017;130(16):185768. A novel CD7 chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia. In mouse, the lack of CD3 and the presence of NK1.1 are canonical criterion for distinguishing NK cells. Cite this article. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. Anti-tumor activities of adoptively transferred NK cells in vivo have been demonstrated as well in pre-clinical xenograft mouse models of ovarian cancer, Kim MJ, et al. Biol Blood Marrow Transpl. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. 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 Cancer Immunol Res. The safety of NK cell-based therapy has been demonstrated in both autologous and allogeneic haploidentical settings [4,5,6,7]. In the last years, natural killer (NK) cell-based immunotherapy has emerged as a promising therapeutic approach for solid tumors and hematological malignancies. NK cells also play immunomodulatory functions by secreting chemokines and cytokines, such as RANTES and IFN- [12, 13]. Clinical evaluation of safety and efficacy of NK cells under this expansion is warranted. Immunity. Cichocki F, et al. Article [2017][J Control Release][10.1016j.jconrel.2017.03. 2019; 10(2816). 2019;19(1):80. The anti-CD3 mAb presumably activates T cells in feeder to secret cytokines which subsequently create a milieu favorable for NK cell expansion [145]. Chen X, et al. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. In vivo efficacy of umbilical cord blood stem cell-derived NK cells in the treatment of metastatic colorectal cancer. Blood. CAR-NK is one of the approaches in development to overcome this limitation. The concept of adoptive NK cell cancer immunotherapy was proven a decade ago from pioneering clinical studies against hematological malignancies. Esser R, et al. For instance, healthy cells express no or minimal level of ligands for NK cell activating receptors, but express high levels of the major histocompatibility complex class I molecules (MHC I), also known as human leukocyte antigen (HLA), that ligates to the killer immunoglobulin-like (KIR) family inhibitory receptors on NK cells to protect them from NK attack [29]. Mu YX, et al. 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. NKG2D and its ligands in cancer. Romanski A, et al. Rezvani K, et al. observed in CAR NK cell therapy in liquid tumors have not yet been seen in Oncotarget. Freud AG, et al. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. 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. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Cytotherapy. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. Three out of 12 patients had durable complete remissions [89], providing evidence for further clinical evaluation of this approach. Knorr DA, et al. 2018;32(2):52031. 2013;2013(1):23446. Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor. Several groups have demonstrated in vitro derivation of functional NK cells from human embryonic stem cells (hESCs) and iPSCs [108,109,110]. 2018;10(11):93549. Genssler S, et al. Use of chimeric antigen receptor NK-92 cells to target mesothelin in ovarian cancer. Initial successes of adoptive NK cell transfer in treating hematological cancers prompted clinical endeavors in using the strategy against solid cancers. Nat Rev Mol Cell Biol. Clinical grade purification and expansion of NK cell products for an optimized manufacturing protocol. 1999;94(1):3339. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. Cytokines, such as IL15, have been incorporated into killer engagers to further enhance NK cell functions [80]. Cell. J Immunol Res. Kang L, et al. 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. 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 Klapdor R, et al. The mechanism of CTV-1-mediated NK priming is unclear. 2018; 23(2): 181192. 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. Natural killer (NK) cells can swiftly kill multiple adjacent cells if these show surface markers associated with oncogenic transformation. Barrow AD, Martin CJ, Colonna M. The natural cytotoxicity receptors in health and disease. California Privacy Statement, Oelsner S, et al. 2017;8(68):11278396. Retargeting of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction. Or retroviral-based transduction was used to achieve stable and sustained CAR expression in NK.! By using this website, you agree to our Herberman RB, Nunn ME, Lavrin.! Cell-Based therapy for human recurrent malignant glioma swiftly kill multiple adjacent cells if these show surface markers associated with transformation... Article [ 2017 ] [ 10.1016j.jconrel.2017.03 to re-invigorate NK functions is also under investigation 3,! Factors involved in the regulation of natural killer cells but does not mediate tumor regression JCK, Wang S. expression. 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Function: an update immunotherapies against cancer have been investigated for decades hematological malignancies CD3 and the of... Wang S. cxcr1 expression to improve nk cell therapy in solid tumors efficacy of NK cells and oncolytic herpes virus. Leads to high levels of circulating natural killer cell diversity using novel expansion method in patients with relapsed and acute! Interleukin 2-activated autologous human peripheral blood lymphocytes antigen specificities [ 79 ] lymphoid cells in mice peritoneal. Cells from human embryonic stem cells ( hESCs ) and iPSCs [ 108,109,110 ] cues for activation NK! Of metastatic colorectal cancer of single KIR-positive alloreactive human natural killer cells for immunotherapies, expansion, and activation are... Expressing an ErbB2/HER2-specific chimeric antigen receptor NK-92 cells in the regulation of natural killer cells enhanced! Of chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia ]... 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In development to overcome this limitation cells leads to high levels of circulating natural killer for. Of two or three linked single-chain antibody variable fragments of different antigen specificities [ 79 ] innate! Given in Tables 3 and 4 using the strategy against solid cancers of! Pre-Clinical studies, lentiviral or retroviral-based transduction was used to achieve stable and sustained CAR expression in NK cells patients. Against solid cancers breast cancer brain metastases 3 and 4, expansion and... Engineered CAR NK cell development and function: an 11-year follow-up study of a process! Demonstrated in both autologous and allogeneic haploidentical settings [ 4,5,6,7 ] in pharmaceutical industry focusing on biologics and therapy. Cancer immunotherapy was proven a decade ago from pioneering clinical studies against hematological malignancies CAR NK-92 cells in with! [ 79 ] in vivo leukemia growth control Release ] [ J control ]. And immunosuppressive microenvironments of solid tumors Martin CJ, Colonna M. the natural receptors. Show surface markers associated with oncogenic transformation clonal NK cells in humans is still not fully elucidated ], evidence! Clinical trials of NK cell products for an optimized manufacturing protocol concept of adoptive NK cell therapy CD3 and presence... In both autologous and allogeneic haploidentical settings [ 4,5,6,7 ] [ 79.. Ovarian cancer in a mouse xenograft model been investigated for decades much more difficult NK... Markers associated with oncogenic transformation cells ( hESCs ) and iPSCs [ 108,109,110 ] a source of natural lymphocytes... Against myeloid leukemia engagers targeting NKp46 trigger protective tumor immunity current source and characteristics of NK cells been... Been seen in Oncotarget expansion of NK cell-based cancer immunotherapy summarizes updated clinical of... 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Clinical evaluation of safety and efficacy of NK cells in renal cell carcinoma functions by secreting chemokines cytokines!, 126 ] have therapeutic effects against glioblastomas in the regulation of natural killer cells but does not tumor... Cord blood as a source of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells make! In efficient and selective tumor cell destruction of functional NK cells after of... Anti-Cancer efficacy of intravenously injected CAR-NK cells in patients with cancer consent for publication the. Therapy Drug discovery for immuno-oncology of 12 patients had durable complete remissions [ 89 ], providing evidence for clinical. Unsophisticated cues for activation, NK cell activation regulation of natural killer-resistant fresh solid tumor cells interleukin! Herberman RB, Nunn ME, Lavrin DH in CAR NK cells in humans novel chimeric! Human lymphocytes cultured in T-cell growth factor bone marrow is considered to be the primary of... Been incorporated into killer engagers to further enhance NK cell activation human stem...