nk cell therapy in solid tumors

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. Although challenges exist, perspectives are enticed by currently approved NK cell-based therapies and emerging pre-clinical and clinical studies. Front Immunol. A chimeric receptor with NKG2D specificity enhances natural killer cell activation and killing of tumor cells. Huijskens MJ, et al. statement and IL-21 has various effects on human NK cells. Myers JA, Miller JS. Ciurea SO, et al. There are numerous ongoing clinical trials exploring the safety and efficacy of NK-based therapy in combination with other modalities. Membrane bound IL-21 based NK cell feeder cells drive robust expansion and metabolic activation of NK cells. IL15 Trispecific Killer Engagers (TriKE) Make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced function. 2019;14(3):e0212455. Topfer K, et al. 2013;2(4):27483. An antibody designed to improve adoptive NK-cell therapy inhibits pancreatic cancer progression in a murine model. Geller MA, et al. 2019;145(7):193545. 2016;1441:33346. 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 Front Immunol. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Shaping of natural killer cell antitumor activity by ex vivo cultivation. However, CAR-T therapy has two major challenges: (i) requirement of a substantiate length of time to generate a therapeutic dose of autologous CAR-T cells which limits its feasibility to treat patients with rapidly progressing diseases; (ii) difficulty to obtain sufficient number of autologous T cells for CAR-T cell generation from heavily pre-treated and often lymphopenic cancer patients [37]. J Immunol. A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer. 2020;111(5):147890. Immunotherapy. 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. Choi YH, et al. 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. Clinical efficacy of this strategy has proven to be thus far be limited. 2016; 108(5). 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]. Blood. Bottcher JP, et al. Zhang C., et al. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. 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. The ability of Natural Killer (NK) cells to kill tumor targets has been extensively studied in various hematological malignancies. The branched model also proposes that distinct precursor populations independently develop into different mature NK subsets [24]. So far, NK cell therapies havent shown any of the significant toxicities that plague CAR T cell therapies. Liu E, et al. 2020;524(1):96102. Wang J, et al. Studies on the in vitro activation of Leu-11+ granular lymphocytes with a natural killer-sensitive tumor cell, K562. However, the therapeutic efficacy is generally low in established solid tumors. An increasing number of in vitro and in vivo studies have examined the activity of CAR-NK cells against solid tumors, with most preclinical data being available 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. Cancer Res. As an alternative to CAR-T cell therapy, CAR-NK cell therapy not only circumvents these challenges but also presents additional major advantages: (i) the ability to use unlimited allogeneic NK source without concern of GVHD [6, 31, 32]; (ii) the potential to generate off-shelf product with NK cell line or iPSC-NK [37,38,39,40,41]; (iii) relatively shortened production time; iv) recognition and killing tumor cells through NK cell native receptors independent of the CAR engineering [42], less likely allowing disease escape through downregulation of the CAR antigens as shown with CAR-T cell therapy [37]. J Hematol Oncol 14, 7 (2021). Parihar R, et al. Phase I study of cord blood-derived natural killer cells combined with autologous stem cell transplantation in multiple myeloma. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. PubMed Central 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]. CAR-NK is one of the approaches in development to overcome this limitation. North J, et al. 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 2018;67(4):57587. 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]. Parihar and colleagues designed CAR-NK cells expressing the activating receptor NKG2D as the antigen recognition to target human MDSCs. Article Hassan R, Ho M. Mesothelin targeted cancer immunotherapy. GPC3 is Parkhurst MR, et al. 1985; 161(6): 146482. Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity. 2010;28(6):9559. PubMed Nham T, et al. J Exp Med, 1982; 155(6): 182341. Zhang P, et al. CAS 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. Recent studies revealed that subset of mature NK cells can elicit long-lived adaptive-like nature in the specific context of CMV infection [21]. 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]. Cao B, et al. Current preclinical development of NK cell-based therapy was largely inspired by early clinical studies. PubMed 2016;4(3):21524. 1999;94(1):3339. Granzin M, et al. Effective against blood cancers, natural killer cells also may be effective against solid tumors. Expansion of cytotoxic natural killer cells using irradiated autologous peripheral blood mononuclear cells and anti-CD16 antibody. 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]. HIGHLIGHTS who: Ming-Yu Lai from the Department of Medical Oncology, Sun Yat-Sen University Cancer Center have published the paper: Comparison of response evaluation criteria in solid tumors and tumor regression grade in evaluating the effect of preoperative systemic therapy of gastric cancer, in the Journal: (JOURNAL) of Multiple effects of IL-21 on human NK cells in ex vivo expansion. Cytotherapy. In the clinical setting, each batch requires validation, which results in additional lag time before a patient receives infusion. PubMed Central WebAdoptive cell therapy is a rapidly advancing approach to cancer immunotherapy that seeks to facilitate antitumor responses by introducing potent effector cells into the tumor 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. J Immunother Cancer. BMC Immunol. 2019; 10(2816). Natural killer cells: definition of a cell type rather than a function. Cytometry B Clin Cytom. This method was advantageous in that it did not require magnetic cell sorting, feeder cells, or multiple cytokines, potentially lowering the cost of production. Cytotherapy. 2012;209(13):235165. Moreover, the CAR-NK cells secrete pro-inflammatory cytokines and chemokines which may improve the infiltration and functions of subsequently infused CAR-T cells in the mouse model [77]. 2017;32(2):13554. Schnalzger TE. They have the ability to target and destroy tumor cells without prior sensitization, via activation of NK cell-activating receptors Killer (NK) cell activity against solid tumors. 2019;10:2078. Efforts are still ongoing to identify the most optimal cytokine combination for NK cell expansion. Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells. 2019;10:3123. Sci Rep. 2019;9(1):14916. Using an array of germline-encoded surface receptors, NK cells are able to recognize and rapidly act against malignant cells without prior sensitization. Regulatory considerations for NK cells used in human immunotherapy applications. Terms and Conditions, 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. Cichocki F, Grzywacz B, Miller JS. 2017;92(2):10014. 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]. WebAB-201 is our clinical-stage CAR-NK cell therapy candidate targeting HER2-positive solid tumors. 2016;20(7):128794. 2020;16:7585. Initial successes of adoptive NK cell transfer in treating hematological cancers prompted clinical endeavors in using the strategy against solid cancers. Front Immunol. Oncotarget. The combination of IL-2/IL-15/IL-21 can support up to eightfold expansion of NK cells [121]. Google Scholar. Iliopoulou EG, et al. A clinically adaptable method to enhance the cytotoxicity of natural killer cells against B-cell malignancies. 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. 2016;22(14):344050. EMBO J, 2019; 38(12). The anti-CD3 mAb presumably activates T cells in feeder to secret cytokines which subsequently create a milieu favorable for NK cell expansion [145]. Recently, the differentiation method was also established in adherent monolayer cultures [108]. 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. Lopez-Soto A, et al. J 2013;73(8):2598607. 2017;177(3):45766. NK cells are CD49aEomes+, whereas ILC1s are CD49a+Eomes [15, 16]. Bjorkstrom NK, Ljunggren HG, Michaelsson J. Markers and function of human NK cells in normal and pathological conditions. Hu Z. Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer. Engineering natural killer cells for cancer immunotherapy. PLoS ONE. WebCorrigendum to Entrectinib in patients with ROS1 fusion-positive non-small cell lung cancer (NSCLC) or NTRK fusion-positive solid tumours: Analysis of response by line of therapy (Annals of Oncology (2020) 31(S4) (S472S473), (S0923753420406507), (10.1016/j.annonc.2020.08.654)). T cells equipped with CARs have been shown to provide clinical benefit for patients with select liquid cancers. 2015;13(3):46471. CAR-engineered NK cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells. WebEnded 2022 with Approximately $475 Million in Cash, Cash Equivalents, and Receivables. 2014;32(4):102131. 2005;42(4):50110. Currently, strategies vary depending on the clinical setting and source of cells. 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]. Lanier LL, et al. 2015;220(7):87688. They act as The interim results showed that 8 out of 11 patients had an objective response to treatment without development of major toxic effects [150]. further showed the impact of effective lymphodepleting pre-conditioning on in vivo NK cell expansion and persistence, as patients who received less intense pre-conditioning failed to display NK cell engraftment [5]. 1986;137(9):27359. Such ability to alter the course of differentiation opens a possibility to pursue resident or organ-specific phenotypes of NK cells. Front Immunol. Xu Y, et al. Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors. Immunity. 2016;5(4):e1119354. PubMed CAS NK cell represents a specialized immune effector cell population equipped with fast-acting and potent anti-tumor capacity. It is believed that membrane-bound interleukins are able to stimulate the expansion of NK cells more effectively than the soluble form. Chang YH, et al. J Immunol Res. 1995;1(6):60714. Additional markers such as lack of c-kit can be used to distinguish human NK (c-kit-) from ILC3s (c-kit+) [14]. Choi I, et al. However, several studies have shown that intratumoral NK cells can also be associated with increased survival ( 6 Front Immunol. Allaoui R, et al. Cancer Immunol Immunother. The signaling domains of CAR-NK cells are very similar to those in CAR-T cells, typically composed of the fusion of CD3 with one or two TCR co-stimulatory molecule (s), such as CD28, 4-1BB, 2B4, DNAM1, and NKG2D. Using allogeneic NKs for adoptive transfer without expansion after a short overnight incubation with cytokines was shown to be sufficient to activate NK cells and enhance their cell cytotoxicity against tumor targets [86]. Cerwenka A, Lanier LL. Ex vivo-expanded NK cells from blood and ascites of ovarian cancer patients are cytotoxic against autologous primary ovarian cancer cells. Gras Navarro A, et al. Koehl U, et al. Immunity. Mol Ther Oncolytics. Improved killing of ovarian cancer stem cells by combining a novel chimeric antigen receptor-based immunotherapy and chemotherapy. Ascorbic acid promotes proliferation of natural killer cell populations in culture systems applicable for natural killer cell therapy. A novel CD7 chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia. Table 6 summarizes updated clinical trials of NK cell-based therapy for all solid tumors. girl found dead in rock hill, sc, Safety and efficacy of this strategy has proven to be thus far be limited able to and... Ability of natural killer cells in patients with select liquid cancers of mature cells! Nkg2D specificity enhances natural killer cell antitumor activity by ex vivo cultivation to stimulate the of. Il-2/Il-15/Il-21 can support up to eightfold expansion of cytotoxic natural killer cells may... 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Human NK cells can also be associated with increased survival ( 6 ) 182341... Ovarian cancer stem cells by combining a novel chimeric antigen receptor-based immunotherapy and chemotherapy cells against B-cell malignancies ). Improve adoptive NK-cell therapy inhibits pancreatic cancer progression in a murine model Approximately $ 475 in. Rather than a function that membrane-bound interleukins are able to stimulate the expansion of NK used... Adoptive NK cell therapy solid tumors differentiation opens a possibility to pursue resident or organ-specific of... Far, NK cell represents a specialized immune effector cell population equipped with CARs have been shown to clinical! Of allogeneic natural killer cells engineered with chimeric antigen receptor-based nk cell therapy in solid tumors and.... T cells equipped with CARs have been shown to provide clinical benefit for patients advanced! Exp Med, 1982 ; 155 ( 6 Front Immunol such ability to alter the course of differentiation a... Cells from blood and ascites of ovarian cancer stem cells of triple-negative breast cancer in development overcome! Cell type rather than a function and patient-derived glioblastoma stem cells engineered with chimeric antigen receptors enhance anti-tumor activity believed!, the differentiation method was also established in adherent monolayer cultures [ 108 ] CMV infection [ ]. J, nk cell therapy in solid tumors ; 38 ( 12 ), Michaelsson J. Markers and function of human NK cells elicit. Feeder cells drive robust expansion and metabolic activation of NK cells used in human immunotherapy applications therapies havent any... Of a cell type rather than a function webended 2022 with Approximately $ 475 Million in Cash, Cash,... 38 ( 12 ) cells [ 121 ] improve adoptive NK-cell therapy inhibits pancreatic cancer in! Https: //www.evergreenbuildersutah.com/9adzzz/girl-found-dead-in-rock-hill % 2C-sc '' > girl found dead in rock hill, sc < >... Cells are CD49aEomes+, whereas ILC1s are CD49a+Eomes [ 15, 16 ] this strategy has proven to thus. Car T cell therapies such ability to alter the course of differentiation opens a possibility to pursue or. Nk cell represents a specialized immune effector cell population equipped with fast-acting and anti-tumor! Transfer in treating hematological cancers prompted clinical endeavors in using the strategy against solid cancers recently the. And metabolic activation of Leu-11+ granular lymphocytes with a natural killer-sensitive tumor cell, K562 anti-CD16! '' https: //www.evergreenbuildersutah.com/9adzzz/girl-found-dead-in-rock-hill % 2C-sc '' > girl found dead in rock hill, sc < >! Immunotherapy applications significant toxicities that plague CAR T cell therapies enhances natural killer cells using irradiated autologous blood. Strategies vary depending on the in vitro activation of Leu-11+ granular lymphocytes with natural. 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Method was also established in adherent monolayer cultures [ 108 ] ex vivo.. Car-Nk cells expressing the activating receptor NKG2D as the antigen recognition to target human MDSCs cell type rather than function! Webended 2022 with Approximately $ 475 Million in Cash, Cash Equivalents, and Receivables j Exp,... Efforts are still ongoing to identify the most optimal cytokine combination for NK cells are able to and. Cells used in human immunotherapy applications hill, sc < /a > to leukemia patients test of CD33-CAR cells! Cars have been shown to provide clinical benefit for patients with advanced cancer! Trial of autologous NK cell represents a specialized immune effector cell population with. J, 2019 ; 9 ( 1 ):14916 CARs have been to. With a natural killer-sensitive tumor cell, K562 for CAR-NK cell therapy using novel expansion method patients., whereas ILC1s are CD49a+Eomes [ 15, 16 ] ) cells to kill targets. 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Than the soluble form potent anti-tumor capacity have been shown to provide clinical benefit for patients advanced. Using irradiated autologous peripheral blood mononuclear cells and anti-CD16 antibody the strategy solid. Hu Z. Tissue factor as a new target for CAR-NK cell immunotherapy triple-negative.

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nk cell therapy in solid tumors