2016;22(14):344050. Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. 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]. In treatments of solid tumors, adoptive transfer of ex vivo expanded natural killer (NK) cells has dawned as a new paradigm. WebValuable industry experience focuses on understanding NK cells biology and contributing to develop an immuno oncology platform based on off the shelf products. 2019;10:719. Development of automated separation, expansion, and quality control protocols for clinical-scale manufacturing of primary human NK cells and alpharetroviral chimeric antigen receptor engineering. 1999;94(1):3339. Aiming to generate novel CAR-NK cell-based cancer therapeutics, the consideration of tumor-specific surface antigens and the costimulatory molecules is the Herein we highlight current evaluations for hematological malignancies and solid tumors. A more simplified NK cell expansion method has been used by combining group Astreptococcus and zoledronate with IL-2 to stimulate UCB-derived mononuclear cells. Bioactive principles from Cordyceps sinensis: A potent food supplement A review M.G. 2017;8(1):67. The off-shelf NK cell therapeutic product oNKord, the allogeneic partial HLA-matched NK cells derived from UCB-CD34+ progenitors, has received an orphan drug designation from EMA and FDA for treating AML patients who were not eligible for allogeneic stem cell transplantation. 2016;7:105. Front Immunol. Generation of BiKEs and TriKEs to improve NK cell-mediated targeting of tumor cells. The IL-15-based ALT-803 complex enhances FcgammaRIIIa-triggered NK cell responses and in vivo clearance of B cell lymphomas. CAS Front Immunol. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Thorac Cancer Oncoimmunology. Two CD19-targeting CAR-T products were approved by the FDA for treatment of B cell lymphomas and acute lymphoblastic leukemia (ALL). 2013;4:101. 2016;20(7):128794. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Galat Y, et al. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Front Oncol. 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]. J 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). 2017;19(2):23549. Nat Rev Immunol. 2017;25(8):176981. 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]. We are initiating the clinical evaluation of AB-201 at multiple centers in the US Methods Mol Biol. The interim results showed that 8 out of 11 patients had an objective response to treatment without development of major toxic effects [150]. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Abel AM, et al. Dev Cell. PubMed 2018;9:1869. Genssler S, et al. A phase 1 trial of CNDO-109-activated natural killer cells in patients with high-risk acute myeloid leukemia. WebFurther pharmacodynamic studies in tumor-free mice revealed superior proliferative and cytotoxic functions on NK cells after RLI treatment compared with IL-15 alone. Cytotherapy. 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]. 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. Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. Zeng J, et al. 2016;5(4):e1119354. 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 2008;28(4):57180. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. 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]. Currently, strategies vary depending on the clinical setting and source of cells. Spanholtz J, et al. 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]. Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. This approval was based on clinical study demonstrating that oNKord improves survival in year 1 of 80% vs. 35% in the control arm. Am J Cancer Res. Clinical-scale derivation of natural killer cells from human pluripotent stem cells for cancer therapy. Jennifer Wu helped in conception and design. Google Scholar. Natural killer cells stimulated with PM21 particles expand and biodistribute in vivo: clinical implications for cancer treatment. Sakamoto N, et al. North J, et al. A novel method to expand large numbers of CD56(+) natural killer cells from a minute fraction of selectively accessed cryopreserved cord blood for immunotherapy after transplantation. Klapdor R, et al. Lanier LL, et al. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. Imai C, Iwamoto S, Campana D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. Ichinose Y (2016) Prospective study of the UGT1A1*27 gene polymorphism during irinotecan therapy in patients with lung cancer: results of Lung Oncology Group in Kyusyu (LOGIK1004B. Cytotherapy. Ciurea SO, et al. Dual targeting of glioblastoma with chimeric antigen receptor-engineered natural killer cells overcomes heterogeneity of target antigen expression and enhances antitumor activity and survival. 2002;11(4):6517. 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. Ex vivo activation and expansion of natural killer cells from patients with advanced cancer with feeder cells from healthy volunteers. Cancer Immunol Immunother. 2011;6(6):e20740. Initial successes of adoptive NK cell transfer in treating hematological cancers prompted clinical endeavors in using the strategy against solid cancers. N Engl J Med. Front Immunol. (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 Ruggeri L, et al. Mol Ther. Chemical stimuli such as Concanavalin A(ConA) [138], Phytohemagglutinin (PHA), and ionomycin [139] were also used in combination with irradiated allogeneic PBMCs to facilitate the activation. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. To circumvent these challenges, Bi- and tri-specific killer engagers, BiKEs and TriKEs, are in development as a complemental approach. 2014;28(4):91727. 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 Bjorkstrom NK, Ljunggren HG, Michaelsson J. Google Scholar. All authors gave consent for publication of the manuscript. In one study, Ng et al. Oncoimmunology. Provided by the Springer Nature SharedIt content-sharing initiative. 2017;2017:6915912. Tang X, et al. Ueda T, et al. Int J Cancer. Terms and Conditions, Vallera DA, et al. Cancer Res. Emerging insights into natural killer cells in human peripheral tissues. Fehniger TA, et al. Cancer Res. This method was advantageous in that it did not require magnetic cell sorting, feeder cells, or multiple cytokines, potentially lowering the cost of production. Some investigations have sought to enhance NK migration toward the tumor by genetically modifying NK cells to overexpress chemokine receptors [54, 59, 94]. 2015;13:277. Hematology Am Soc Hematol Educ Program. 2013;2013(1):23446. 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. In the last years, natural killer (NK) cell-based immunotherapy has emerged as a promising therapeutic approach for solid tumors and hematological malignancies. Necrotic core even the name sounds creepy. The conventional linear model suggests that mature NK cells arise from common lymphoid progenitors (CLPs) by progressing through a linear continuum [24]. Overall, these results indicate that NK cells can invade some solid tumors. When NK cells infiltrate solid tumors, high numbers of NK cells may be associated with better survival. However, in most cases, anti-tumor properties of NK cells are attenuated at the tumor bed. Zingoni A, et al. Schonfeld K, et al. Kim MJ, et al. Ni J, 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]. The current source and characteristics of NK cells for immunotherapies, expansion, and activation approaches are given in Tables 3 and 4. NKG2D, an activating NK cell receptor, can bind to eight different stress-induced ligands that are naturally expressed on 80% of hematological and solid cancer Retargeting of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction. J Immunother Cancer. 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]. PubMed 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. 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]. Combination therapy with EpCAM-CAR-NK-92 cells and regorafenib against human colorectal cancer models. Join us for this live, CME-certified symposium featuring an expert discussion of TROP2- and HER3-targeted antibody-drug conjugates and their current use in treating patients with solid tumors, including lung and breast cancers. Killer cells engineered with chimeric antigen receptor-engineered natural killer cells from human pluripotent stem for! Strategy against solid cancers Tables 3 and 4 in using the strategy against solid cancers leukemia cells cells cancer. Expansion of natural killer cells from human pluripotent stem cells for cancer therapy webphysiological barriers and immunosuppressive microenvironments of tumors! The current source and characteristics of NK cells can invade some solid tumors, transfer. Invade some solid tumors products were approved by the FDA for treatment of malignant tumors, high numbers NK., BiKEs and TriKEs, are in nk cell therapy in solid tumors as a new paradigm immunosuppressive microenvironments of solid tumors, HCC! 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