The BiKEs or TrikEs are composed of two or three linked single-chain antibody variable fragments of different antigen specificities [79]. Front Immunol. 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 Three out of 12 patients had durable complete remissions [89], providing evidence for further clinical evaluation of this approach. Heinze, A., et al. Oncoimmunology. Springer Nature. Nham T, et al. 2019; 10(2816). Mesothelin is a tumor differentiation antigen that is highly overexpressed in several human cancers including malignant mesothelioma, pancreatic, ovarian, and lung adenocarcinoma [91]. Some investigations have sought to enhance NK migration toward the tumor by genetically modifying NK cells to overexpress chemokine receptors [54, 59, 94]. Allaoui R, et al. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. Blood. 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 Front Immunol. 2018;48(6):110417. Moreover, restricted expansion capacity poses a difficulty for improving the efficacy of NK cells through genetic engineering. Blood. 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 Anti-tumor activities of adoptively transferred NK cells in vivo have been demonstrated as well in pre-clinical xenograft mouse models of ovarian cancer, Luevano M, Madrigal A, Saudemont A. 1986;137(9):27359. Masuyama et al. Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors. Front Immunol. Leong JW, et al. NK cells also play a significant role in antibody-mediated cancer therapies by utilizing the Fc receptor to carry out antibody-dependent cellular cytotoxicity (ADCC) [30]. Beyond cytokines, other stimulants, including tumor cells, allogeneic PBMCs, antibodies, and microbiol derivatives, have been explored for enhancing ex vivo NK cell expansion. Using irradiated autologous PBMCs and anti-CD16 mAb, Lee et al. IL-21 has cumulative activation effect in combination with IL-2 [119] or IL-15. In mouse strains lacking NK1.1 expression (e.g., BALB/c), CD49b is used for NK cell identification. 2016;20(7):128794. Emerging insights into natural killer cells in human peripheral tissues. Am J Cancer Res. IL-21 enhances natural killer cell response to cetuximab-coated pancreatic tumor cells. 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]. Lotze MT, et al. Knorr DA, et al. You F, et al. GSK3 inhibition drives maturation of NK cells and enhances their antitumor activity. Early clinical trials have demonstrated the overall safety of NK cell infusion, even in the allogeneic setting [4,5,6,7]. 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 Siegler U, et al. 2018;19(5):45363. Stem Cell Res Ther. CAS 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 ]. Cerwenka A, Lanier LL. et al. In the last years, natural killer (NK) cell-based immunotherapy has emerged as a promising therapeutic approach for solid tumors and hematological malignancies. Targeting immunosuppressive components in the TME to re-invigorate NK functions is also under investigation. Cookies policy. Zhang P, et al. 2015;23(2):3308. 2013;2(4):27483. Characterization and ex vivo expansion of human placenta-derived natural killer cells for cancer immunotherapy. The expanded human NK cells showed potent ADCC activities in vitro and superior tumor control in a mouse xenograft model of ovarian cancer when combined with Herceptin, an anti-HER2 antibody [87]. In mouse, the lack of CD3 and the presence of NK1.1 are canonical criterion for distinguishing NK cells. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. Phillips JH, Lanier LL. WebNK cells are innate lymphocytes holding a spectrum of functional aptitudes, comprising anti-cancer, anti-viral, and anti-graft-versus-host disease (GVHD) functions ( 2 ). Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Cytokines, such as IL15, have been incorporated into killer engagers to further enhance NK cell functions [80]. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Granzin M, et al. 2006;66(1):51726. Clinical evaluation of safety and efficacy of NK cells under this expansion is warranted. Perform PBMCs apheresis from the patient and isolate NK cells, transfect the NK cells with Claudin6 targeting CAR, amplify the number of transfected NK cells as 2017;92(2):10014. 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. 2016;7(19):2776477. While the CAR technology seeks to enhance NK cell functions by genetically directing their target specificity, there are active investigations on other strategies to effectively prime NK cells ex vivo or in vivo for optimal anti-tumor functions after their infusion. Methods Mol Biol. Such ability to alter the course of differentiation opens a possibility to pursue resident or organ-specific phenotypes of NK cells. Am J Cancer Res. This approval was based on clinical study demonstrating that oNKord improves survival in year 1 of 80% vs. 35% in the control arm. However, NK cell therapy 2002;295(5562):2097100. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. 2017;130(16):185768. Aiming to generate novel CAR-NK cell-based cancer therapeutics, the consideration of tumor-specific surface antigens and the costimulatory molecules is the For example, a subset of IL-22 secreting human ILC3s is CD56+NKp46+CD3 [14]. Current challenges 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. 2017;18(9):100415. 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]. EMBO J, 2019; 38(12). Lancet. Specificity and distribution according to genotype. All authors read and approved the final manuscript. [2017][J Control Release][10.1016j.jconrel.2017.03. Innate lymphoid cells: a proposal for uniform nomenclature. Granzin M, et al. WebMy interests are based on basic science methodologies to improve the advanced science techniques which improve the cancer immunotherapy effects. Mol Immunol. 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. 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 Miller JS, et al. NK cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. WebFirst described in the 1970s, NK cells have been a promising tool in the field of adoptive immunotherapy ( 34 ). Application of small molecule CHIR99021 leads to the loss of hemangioblast progenitor and increased hematopoiesis of human pluripotent stem cells. 1975; 16(2): 21629. CAS For example, using the membrane particles of K562 cells with membrane-bound IL-21 and 4-1BB ligand as the feeder has achieved the activation and 250-fold expansion of NK cells after approximately two weeks of ex vivo culture [141]. 2012;3:408. There has been an explosion of NK-based immunotherapies in pre-clinical development and clinical development. 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. Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors. Clin Cancer Res. 2017;47(5):82033. Natural killer (NK) cells are large granular lymphocytes with surface markers CD3 CD56 + NKp46 + in humans. Hu Z. Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer. Blood. The interim results showed that 8 out of 11 patients had an objective response to treatment without development of major toxic effects [150]. NK CELL-BASED THERAPY IN SOLID. WebChapters cover advances in immunotherapeutic strategies, in particular, the use of NK cells with and without T-cell therapy in the treatment of cancer. 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 More recent evidence had indicated that NK cells can also develop and mature at secondary lymphoid organs, including tonsils, spleen, and lymph nodes [19]. Eur J Immunol. It is believed that membrane-bound interleukins are able to stimulate the expansion of NK cells more effectively than the soluble form. Skeate R, et al. 2016;127(26):33419. The ability of Natural Killer (NK) cells to kill tumor targets has been extensively studied in various hematological malignancies. Article Phase I study of random healthy donor-derived allogeneic natural killer cell therapy in patients with malignant lymphoma or advanced solid tumors. A study by Campana and coworkers has shown that stimulation of NK cells with gene-modified K562 expressing the NK-stimulatory molecules 4-1BB ligand and IL-15 induced a median 21.6-fold expansion during a 7-day culture period. volume14, Articlenumber:7 (2021) Although challenges exist, perspectives are enticed by currently approved NK cell-based therapies and emerging pre-clinical and clinical studies. Front Immunol. 2013;15(2):231-241.e1. The success has encouraged many ongoing clinical investigations of NK cell-based cancer therapy alone or in combination with other regimes. 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