Upon ligation, these receptors transmit either inhibitory or activating signals to control NK activation. PLoS ONE. Bottcher JP, et al. 2015;23(2):3308. Over 100-fold expansion was achieved with Wilms tumor HFWT [134] and immortalized T lymphocyte Jurkat cell lines [135]. Thus, feeder-free approaches are an alternative or a more desirable method to avoid safety concerns associated with the clinical application of cancer cell-derived feeder cells. Blood. Three out of 12 patients had durable complete remissions [89], providing evidence for further clinical evaluation of this approach. 2015;2:93. 2018; 23(2): 181192. 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. With the ongoing effort to improve the treatment response and new methods of generating more feasible clinical scales of NK cells, emerging clinical trials are being designed to evaluate these new modalities and to expand their indications. reported an approximately 1500-fold expansion of NK cells after PBMC stimulation with a combination of anti-CD3 and anti-CD56 mAbs [146]. Recent studies revealed that subset of mature NK cells can elicit long-lived adaptive-like nature in the specific context of CMV infection [21]. GPC3 is 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]. 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. 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. PubMed Methods Mol Biol. They have been recognized as a subset of innate lymphoid cells (ILCs) that lack antigen receptors with recombination activating gene (RAG)-dependent rearrangement [ 1, 2 ]. MUC1-specific CAR-pNK therapy presented good safety profile and preliminary efficacy in preventing both tumor relapses and graft versus host disease [151]. Masuyama et al. Notably, certain tissues such as the mucosal barriers possess subsets of recently identified innate lymphoid cells (ILCs) that also share canonical markers of NK cells. Purinergic targeting enhances immunotherapy of CD73(+) solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells. Clin Cancer Res. Front Immunol. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Colonna M. Innate lymphoid cells: diversity, plasticity, and unique functions in immunity. Chang YH, et al. 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. WebChapters cover advances in immunotherapeutic strategies, in particular, the use of NK cells with and without T-cell therapy in the treatment of cancer. Esser R, et al. 2013;13(2):1459. 2018;8(6):10839. NK cells are a key member of the innate immune system, and while they have some similarities to cytotoxic T lymphocytes (CTLs) in term of killing features, they have an extra intrinsic capability to detect and kill transformed/mutant cells independent of specific antigen recognition processes indicating MHC-unrestricted cytotoxicity done with Cell Stem Cell. Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor. NK cells engineered to express a GD2 -specific antigen receptor display built-in ADCC-like activity against tumour cells of neuroectodermal origin. CXCL16 positively correlated with M2-macrophage infiltration, enhanced angiogenesis, and poor prognosis in thyroid cancer. Parodi M, 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). Due to relatively unsophisticated cues for activation, NK cell has gained significant attention in the field of cancer immunotherapy. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. The IL-15-based ALT-803 complex enhances FcgammaRIIIa-triggered NK cell responses and in vivo clearance of B cell lymphomas. 2004;24(3b):186171. WebCancer immunotherapy has achieved great success in the past few years. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. Parihar and colleagues designed CAR-NK cells expressing the activating receptor NKG2D as the antigen recognition to target human MDSCs. J Natl Cancer Inst. Phase I study of cord blood-derived natural killer cells combined with autologous stem cell transplantation in multiple myeloma. WebHappy New Year to you! Zhang P, et al. 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]. PubMed Central 2019; 10(2816). A new drug application (IND) is expected to be filed by Cytovia by June 2022, requesting the clearance of the GPC3 CAR NK-cell therapy for clinical testing. Ng YY, Tay JCK, Wang S. cxcr1 expression to improve anti-cancer efficacy of intravenously injected CAR-NK cells in mice with peritoneal xenografts. This approval was based on clinical study demonstrating that oNKord improves survival in year 1 of 80% vs. 35% in the control arm. INTRODUCTION Cordyceps is the composite of a genus of fungus that grows on the larva of insects. 2014;32(4):102131. Hambach, J., et al., Targeting CD38-expressing multiple myeloma and Burkitt lymphoma cells in vitro with nanobody-based chimeric antigen receptors (Nb-CARs). Ciurea SO, et al. Front Immunol. 2013;15(2):231-241.e1. ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma. 2016; 108(5). Methods Mol Biol. 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 A novel source of NK cells has emerged to circumvent many of the challenges associated with NK cell therapy. Immunobiology. Br J Haematol. 2019;10:2078. Cytokines, such as IL15, have been incorporated into killer engagers to further enhance NK cell functions [80]. Front Immunol. With the ongoing effort to improve the treatment response and new methods of generating more feasible clinical scales of NK cells, emerging clinical trials are being designed to evaluate these new modalities and to expand their indications. Lancet. The broad spectrum of human natural killer cell diversity. Immunity. Springer Nature. 2016;127(26):33419. 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. J Immunol. The antigen recognition domain usually consists of a single-chain fragment (scFV) molecule derived from a monoclonal antibody, and nanobody-based constructs have been used in limited studies to date [72]. Manufacturing natural killer cells as medicinal products. 2018;23(2):181-192.e5. 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. 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. Natural killer cells stimulated with PM21 particles expand and biodistribute in vivo: clinical implications for cancer treatment. The BiKEs or TrikEs are composed of two or three linked single-chain antibody variable fragments of different antigen specificities [79]. Blood. Sci Transl Med. 2015;38(5):197210. The safety of NK cell-based therapy has been demonstrated in both autologous and allogeneic haploidentical settings [4,5,6,7]. Li Y, et al. With the new era of cancer immunotherapy, the use of Chimeric Antigen Receptor (CAR) T-cells has been applied with other possible approaches like NK (natural Patients with advanced malignant solid tumors, histologically or cytologically confirmed, who had failed standard therapy, or had no standard therapy, or were not NK cells in the tumor microenvironment Conventional roles of NK cells in immunity Detection of aberrant cells by NK cells is determined by the intergradation of In 2005, it was reported that haploidentical allogeneic NK cells Two CD19-targeting CAR-T products were approved by the FDA for treatment of B cell lymphomas and acute lymphoblastic leukemia (ALL). Many efforts are emerging for developing and engineering NK cell-based cancer immunotherapy. 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 Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases. Hassan R, Ho M. Mesothelin targeted cancer immunotherapy. 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 vivo efficacy of umbilical cord blood stem cell-derived NK cells in the treatment of metastatic colorectal cancer. 2007;178(1):8594. This property, which is unique among immune cells, and their capacity to enhance antibody and T cell responses support a role for NK cells as anticancer agents. 2017;2017:6915912. 2019;10:909. Jennifer Wu supervised the study. Klapdor R, et al. CAS 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]. Pharmacologically upregulated carcinoembryonic antigen-expression enhances the cytolytic activity of genetically-modified chimeric antigen receptor NK-92MI against colorectal cancer cells. 2016;16(5):31020. Exposure of NK to unmodified NK cell-sensitive leukemia cells (K562) stimulates expansion and short-term proliferation [133]. Cytokine-mediated activation is frequently employed and currently under extensive investigation. Nat Immunol. Cytotherapy. 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]. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies. Cell Stem Cell. Guerra N, et al. Smyth MJ, et al. Am J Cancer Res. J Transl Med. Cytokines are the critical components of NK maintenance system and activation as discussed earlier. Thorac Cancer Xu Y, et al. To circumvent these challenges, Bi- and tri-specific killer engagers, BiKEs and TriKEs, are in development as a complemental approach. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. Mol Ther. 2016;7:13050. Freshly isolated, activated, or in vitro expanded NK cell populations display phenotypic and functional differences. For hematological cancers, CD19 remains a major target. 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. Immunity. Sizhe Liu, Vasiliy Galat, Yekaterina Galat, Yoo Kyung Annie Lee, Derek Wainwright, and Jennifer Wu wrote and reviewed the manuscript. 2017;177(3):45766. Engineering NK cells modified with an EGFRvIII-specific chimeric antigen receptor to overexpress CXCR4 improves immunotherapy of CXCL12/SDF-1alpha-secreting glioblastoma. PubMed Central (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 Engineering natural killer cells for cancer immunotherapy. Additional markers such as lack of c-kit can be used to distinguish human NK (c-kit-) from ILC3s (c-kit+) [14]. IL-21 has various effects on human NK cells. Wang J, et al. Furthermore, IL-2, streptococcus A group, and zoledronate have all been approved for human use. The interim results showed that 8 out of 11 patients had an objective response to treatment without development of major toxic effects [150]. 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 Sahm C, Schonfeld K, Wels WS. Google Scholar. Cytotherapy. Galat Y, et al. This TriKE design (GTB-3550) is currently in clinical trial for treating high-risk hematological malignancies (NCT03214666). Manage cookies/Do not sell my data we use in the preference centre. 2013;4:101. T cells equipped with CARs have been shown to provide clinical benefit for patients with select liquid cancers. Schnalzger TE. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. 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]. Cichocki F, et al. Exploring the NK cell platform for cancer immunotherapy. Regulatory considerations for NK cells used in human immunotherapy applications. CAS Knorr DA, et al. Cerwenka A, Lanier LL. Google Scholar. 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]. IL-2 was used to induce lymphokine-activated killer (LAK) cells, a heterogeneous population of cells consisting primarily of NK, NKT, and T cell for autologous killer cell-based cancer therapy decades ago [115]. Front Immunol. Autologous peripheral blood stem cell transplantation and adoptive immunotherapy with activated natural killer cells in the immediate posttransplant period. Tanaka Y, et al. Romanski A, et al. McMichael EL, et al. In the last 3 decades, NK cells have been utilized to harness Clin Cancer Res. Improved killing of ovarian cancer stem cells by combining a novel chimeric antigen receptor-based immunotherapy and chemotherapy. J Hematol Oncol. The anti-CD3 mAb presumably activates T cells in feeder to secret cytokines which subsequently create a milieu favorable for NK cell expansion [145]. 2019;14(3):e0212455. Lee J, et al. 2018;19(5):45363. 2008;28(4):57180. 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). Front Immunol. J Exp Med. Clinical-scale derivation of natural killer cells from human pluripotent stem cells for cancer therapy. Oncoimmunology. Siegler U, et al. Vasu S, et al. The natural cytotoxic receptor NKp46 is also often used to identify mouse and human NK cells in combination with the absence of CD3 expression. 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To circumvent these challenges, Bi- and tri-specific killer engagers, BiKEs and TrikEs, are in as. Nct03214666 ) study of a genus of fungus that grows on the Precision... Ng YY, Tay JCK, Wang S. cxcr1 expression to improve anti-cancer efficacy intravenously... In humans of fungus that grows on the larva of insects been approved human. Treating high-risk hematological malignancies ( NCT03214666 ) stimulates expansion and short-term proliferation [ 133 ] human... Trikes, are in development as a complemental approach three out of 12 patients had durable remissions. Wang S. cxcr1 expression to improve anti-cancer efficacy of intravenously injected CAR-NK cells in mice with xenografts!
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