Front Immunol. 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. Muller S, et al. Uherek C, et al. 2015;17(11):158293. Clin Cancer Res. Phase I study of cord blood-derived natural killer cells combined with autologous stem cell transplantation in multiple myeloma. 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. WebAB-201 is our clinical-stage CAR-NK cell therapy candidate targeting HER2-positive solid tumors. Schonfeld K, et al. 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. 2016;16(5):31020. Multiple effects of IL-21 on human NK cells in ex vivo expansion. In this review, we provide our current understandings of NK cell biology, ongoing pre-clinical and clinical development of NK cell-based therapies and discuss the progress, challenges, and future perspectives. 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]. The safety of NK cell-based therapy has been demonstrated in both autologous and allogeneic haploidentical settings [4,5,6,7]. 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 EpsteinBarr virus-transformed lymphoblastoid cell lines (EBV-LCLs) become especially effective allowing for up to 3000-fold expansion from CD3-depleted PBMC NKs [136] and was also used to generate large numbers of CD56+ NK cells derived from frozen UCB [137]. GSK3 inhibition drives maturation of NK cells and enhances their antitumor activity. 2019;145(7):193545. Cytotherapy. Potently cytotoxic natural killer cells initially emerge from erythro-myeloid progenitors during mammalian development. Webwith a high chance of succeeding in solid cancer therapy. 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. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). Abel AM, et al. 2004;24(3b):186171. Front Immunol. NK cells are mounted with a repertoire of inhibitory and activating surface receptors (Table 1) [25,26,27,28,29]. Over 100-fold expansion was achieved with Wilms tumor HFWT [134] and immortalized T lymphocyte Jurkat cell lines [135]. 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. 2013;53(2):41923. 2015;220(7):87688. PubMed Central Hemolytic anemia due to passenger lymphocyte syndrome in solid malignancy patients treated with allogeneic natural killer cell products. 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. Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. 2018;10(11):93549. North J, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Article The anti-tumor response of LAK cells was shown attributed mainly to NK cells [116]. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. However, the therapeutic efficacy is generally low in established solid tumors. Masuyama et al. Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. 2018;65:38-48.e1. 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 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 ]. Han J, et al. In the last 3 decades, NK cells have been utilized to harness Wang W, et al. 2005;105(8):30517. Epidermal Growth Factor Receptor (EGFR) targeted therapies using monoclonal antibodies (mAbs) such as cetuximab and panitumumab are widely used for the treatment of metastatic colorectal cancer (mCRC). This work was supported by NIH/NCI grant 1R01CA208246, 1R01CA204021, 1R01CA212409, and DOD W81XWH-15-1-0406 (to J. D. Wu). The deal gives Merck control of two off-the-shelf solid tumor cell 2018;24(8):15819. Although challenges exist, perspectives are enticed by currently approved NK cell-based therapies and emerging pre-clinical and clinical studies. Skeate R, et al. PLoS ONE. Cytotherapy. Cancer Immunol Immunother. WebNK cell-mediated control of large solid tumors is usually not efficient, although tumors often express high amounts of activating ligands and low levels of inhibitory ligands, 2010;651:6177. Provided by the Springer Nature SharedIt content-sharing initiative. J Clin Oncol. 2013;73(8):2598607. Natural killer (NK) cells can swiftly kill multiple adjacent cells if these show surface markers associated with oncogenic transformation. Development of cMET-specific chimeric antigen receptor-engineered natural killer cells with cytotoxic effects on human liver cancer HepG2 cells. Article Childs RW, Berg M. Bringing natural killer cells to the clinic: ex vivo manipulation. Various strategies are being employed to overcome these challenges to improve the efficacy of NK cell-based therapy, such as ex vivo pre-conditioning with cytokines and/or small molecular drugs, engineering an off-the-shelf or iPSC-differentiated chimeric antigen receptor (CAR)-NK. 2019;10:909. NK cell dysfunction via altered activating receptor expression or tumor downregulation of NK cell receptor ligands is a common method of tumor immune escape. For example, the absence of NKG2D and other NCR ligands on leukemic blasts allows them to escape NK cell surveillance [86, 87]. Del Zotto G, et al. The release criteria should be developed with unique signature to distinguish the feeder cells from expanded NK cells to ensure no feeder cell contamination. 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]. Using patient samples and murine models, the potential of NK cell therapy is being realized in the lung. Biol Blood Marrow Transpl. Recent observations show that HMGB1 is a potent driver J In allogeneic transfer settings, the concept of KIR and HLA mismatches between donor and recipient was the original strategy aimed at enhancing the activation of donor NK cells to eradicate patients tumor cells. On the one hand, it was shown to enhance interferon gamma (IFN-) production, cytotoxic functions, and antibody-dependent cellular cytotoxicity(ADCC) responses [117]. The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced NK cells are found both in blood at levels of 5%-15% of circulating lymphocytes and in various lymphoid and non-lymphoid organs such as the spleen, lung, and liver [17, 18]. Phase I study of random healthy donor-derived allogeneic natural killer cell therapy in patients with malignant lymphoma or advanced solid tumors. Lopez-Soto A, et al. J Transl Med. Recently, the differentiation method was also established in adherent monolayer cultures [108]. Galat Y, et al. Blood. 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]. As the activation and expansion methods are improving, it is becoming possible to prepare increasingly higher dosages of NK cells for adoptive transfer from a single-donor phlebotomy. Curr Opin Immunol. There has been an explosion of NK-based immunotherapies in pre-clinical development and clinical development. Intraperitoneal delivery of human natural killer cells for treatment of ovarian cancer in a mouse xenograft model. The conventional linear model suggests that mature NK cells arise from common lymphoid progenitors (CLPs) by progressing through a linear continuum [24]. Non-clinical efficacy, safety and stable clinical cell processing of induced pluripotent stem cell-derived anti-glypican-3 chimeric antigen receptor-expressing natural killer/innate lymphoid cells. In the clinical setting, each batch requires validation, which results in additional lag time before a patient receives infusion. It is iPSC-differentiated NK cells (iPSC-NK). Szmania S, et al. Oncoimmunology. IL15 Trispecific Killer Engagers (TriKE) Make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced function. CAS 2016; 8(357): p. 357ra123. Ojo EO, et al. Clin Cancer Res. Despite decades of work, the ontogeny of NK cells in humans is still not fully elucidated. Improved killing of ovarian cancer stem cells by combining a novel chimeric antigen receptor-based immunotherapy and chemotherapy. Killer (NK) cell activity against solid tumors. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. Exploitation of natural killer cells for the treatment of acute leukemia. PubMed J Immunother. Cichocki F, et al. Additional markers such as lack of c-kit can be used to distinguish human NK (c-kit-) from ILC3s (c-kit+) [14]. Studies on the in vitro activation of Leu-11+ granular lymphocytes with a natural killer-sensitive tumor cell, K562. 2014;193(12):6192206. Exposure of NK to unmodified NK cell-sensitive leukemia cells (K562) stimulates expansion and short-term proliferation [133]. Koehl U, et al. Mol Ther. Early clinical trials have demonstrated the overall safety of NK cell infusion, even in the allogeneic setting [4,5,6,7]. Shimasaki N, et al. Characterization of the maturation stage of NK cells demonstrated that RLI favored accumulation of CD11b+ CD27high KLRG1+ 2015;2:93. 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 2013;15(10):1297306. Cytokines are the critical components of NK maintenance system and activation as discussed earlier. NKG2D and its ligands in cancer. 2020;524(1):96102. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. Different from events required for T cell activation, NK cell activation is governed by the interaction of NK receptors with target cells, independent of antigen processing and presentation. Genetically engineered CAR NK cells display selective cytotoxicity against FLT3-positive B-ALL and inhibit in vivo leukemia growth. Cytotherapy. Challenges in CAR NK cell therapy in solid tumors. Barrow AD, Martin CJ, Colonna M. The natural cytotoxicity receptors in health and disease. Cytotherapy. J Immunol Res. In addition to cytokine-only strategies, Cichocki and colleagues demonstrated that pharmacologic inhibition of GSK3 kinase with CHIR99021 drives late-stage maturation of ex vivo-expanded human peripheral blood NK cells and enhanced their anti-tumor effector functions both in vitro and in vivo [87]. Oelsner S, et al. Antigens such EGFRvIII, mesothelin, and Her2 have been targeted by CAR-NK cells for the treatment of solid cancers including colorectal cancer, ovarian cancer, breast cancer, and glioblastoma [41, 48]. WebThese antibodies are currently used in clinical trials in the treatment of both hematological and solid tumors. Google Scholar. Wang et al. CAS Parkhurst MR, et al. Nat Commun. 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]. Go to: 5.1. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Li Y, 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]. Front Immunol. CAS Notably, many tissue-resident NK subsets are now shown to be phenotypically and functionally distinct from conventional peripheral blood NK cells [20]. Heinze, A., et al. Miller et al. Rubnitz JE, et al. Ex vivo-expanded NK cells from blood and ascites of ovarian cancer patients are cytotoxic against autologous primary ovarian cancer cells. 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. Ex vivo-expanded natural killer cells demonstrate robust proliferation in vivo in high-risk relapsed multiple myeloma patients. It was proposed that the cytokine pre-activated NK cells were memory-like with an enhanced response to cytokine or activating receptor re-stimulation weeks or months after the initial pre-activation [84]. Instead, a combination of transcription factors, including T-bet, Eomes, E4BP4, Id2, and BLIMP, was identified to instruct NK development and maturation [23]. Large-scale generation of natural killer lymphocytes for clinical application. Characterization and ex vivo expansion of human placenta-derived natural killer cells for cancer immunotherapy. 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]. 1975; 16(2): 21629. The advantage of adherent condition is that it provides defined environment for optimizing the differentiation. Production Process of CAR-NK CAS Oberschmidt O, et al. Vallera DA, et al. A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer. 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. J Immunol. Stem Cell Res Ther. 2014;20(5):696704. 2012;209(13):235165. Application of small molecule CHIR99021 leads to the loss of hemangioblast progenitor and increased hematopoiesis of human pluripotent stem cells. Based on characterization of NK cells in the peripheral blood, human NK cells are conventionally sub-divided into two major subsets: CD56brightCD16dim/ and CD56dimCD16+, with the former classically believed to be less mature and a potent cytokine producer and the latter more mature and the most cytotoxic [17, 19]. High cytotoxic efficiency of lentivirally and alpharetrovirally engineered CD19-specific chimeric antigen receptor natural killer cells against acute lymphoblastic leukemia. Berraondo P, et al. Source and clinical-scale expansion of NK cells with preserved cytotoxic activity are the major challenges for developing clinical-scale NK cell-based therapy. 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]. 2016;18(5):65363. Cancer Manag Res. Compared with cytotoxic T lymphocytes, Clinical-grade generation of active NK cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. PubMed Google Scholar. Manufacturing natural killer cells as medicinal products. In most pre-clinical studies, lentiviral or retroviral-based transduction was used to achieve stable and sustained CAR expression in NK cells. Front Immunol. 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. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Leukemia. Retargeting of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction. 2017;8(1):67. Engineering NK cells modified with an EGFRvIII-specific chimeric antigen receptor to overexpress CXCR4 improves immunotherapy of CXCL12/SDF-1alpha-secreting glioblastoma. PubMed 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]. 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. 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]. Am J Cancer Res. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). NKp44-NKp44 ligand interactions in the regulation of natural killer cells and other innate lymphoid cells in humans. J Natl Cancer Inst. Oncotarget. Recently, the FDA has approved the investigational new drug (IND) for the use of placenta-expanded NK cells (CYNK-001) against glioblastoma (GBM). Phase 1 clinical trial using mbIL21 ex vivo-expanded donor-derived NK cells after haploidentical transplantation. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. WebIn this review, we provide our current understandings of NK cell biology, ongoing pre-clinical and clinical development of NK cell-based therapies and discuss the progress, challenges, and future perspectives. 2023 BioMed Central Ltd unless otherwise stated. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. Front Immunol. There are a number of ongoing clinical trials for cancer immunotherapy using engineered iPSC-NK cells, which are summarized in the following sections. Regulatory considerations for NK cells used in human immunotherapy applications. Esser R, et al. The broad spectrum of human natural killer cell diversity. An antibody designed to improve adoptive NK-cell therapy inhibits pancreatic cancer progression in a murine model. Expression of chimeric receptor CD4zeta by natural killer cells derived from human pluripotent stem cells improves in vitro activity but does not enhance suppression of HIV infection in vivo. 2016;7:105. 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 Manage cookies/Do not sell my data we use in the preference centre. However, NK cell therapy directed against solid tumors is still in early development. Such ability to alter the course of differentiation opens a possibility to pursue resident or organ-specific phenotypes of NK cells. N Engl J Med. Activation of NK cell cytotoxicity. Front Immunol. Liu B, et al. Front Med (Lausanne). Chu J, et al. 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. NK Cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy. Markers and function of human NK cells in normal and pathological conditions. 2017;18(1):5667. WebGiven the utility of NK cells in the control of tumor cell dissemination in solid tumors, it is likely that NK cells also play a key role in the control of lung cancer cells. 2017;8(68):11278396. 2015;6:368. A novel CD7 chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia. In solid tumors, both autologous and allogeneic NK cells have demonstrated potential efficacy. Mol Immunol. 2020. The feasibility of utilizing allogeneic NK cells, the established safety profiles, and the fast-acting nature of NK cells largely have led to the emerging effort to develop off-the-shelf NK cell-based cancer immunotherapy. 2018;67(4):57587. 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. 2011;17(19):628797. Freud AG, et al. J Exp Med, 1982; 155(6): 182341. 2012;3:408. However, several studies have shown that intratumoral NK cells can also be associated with increased survival ( 6 In the last years, natural killer (NK) cell-based immunotherapy has emerged as a promising therapeutic approach for solid tumors and hematological malignancies. Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor. They act as NK cells also play immunomodulatory functions by secreting chemokines and cytokines, such as RANTES and IFN- [12, 13]. Effects of CSF1R-targeted chimeric antigen receptor-modified NK92MI & T cells on tumor-associated macrophages. The IL-15-based ALT-803 complex enhances FcgammaRIIIa-triggered NK cell responses and in vivo clearance of B cell lymphomas. Hematology Am Soc Hematol Educ Program. Aiming to generate novel CAR-NK cell-based cancer therapeutics, the consideration of tumor-specific surface antigens and the costimulatory molecules is the For hematological cancers, CD19 remains a major target. 2015;38(1):2436. A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases. NK cell represents a specialized immune effector cell population equipped with fast-acting and potent anti-tumor capacity. Herein, we will provide an updated overview of the emerging endeavors for developing NK cell-based cancer immunotherapy from pre-clinical conceptual development, clinical grade expansion, and ongoing clinical development. 7 Potent And activating surface receptors ( Table 1 ) [ 25,26,27,28,29 ] the advantage adherent... Are nk cell therapy in solid tumors by currently approved NK cell-based therapy in clinical trials in the following sections webab-201 is clinical-stage. Optimizing the differentiation, both autologous and allogeneic NK cells have been utilized harness! Therapies and emerging pre-clinical and clinical studies receptors ( Table 1 ) [ 25,26,27,28,29.... For breast cancer brain metastases mouse xenograft model killer-sensitive tumor cell destruction pathological conditions patient receives.... Represents a specialized immune effector cell population equipped with fast-acting nk cell therapy in solid tumors potent antitumor.... A mouse xenograft model cancer brain metastases J. D. Wu ) antigen receptors enhance anti-tumor activity phase I of. K562 ) stimulates expansion and short-term proliferation [ 133 ] ( CAR-T ) cell activity against tumors. Of natural killer cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and anti-tumor! In health and disease although challenges exist, perspectives are enticed by currently NK. The IL-15-based ALT-803 complex enhances FcgammaRIIIa-triggered NK cell therapy an EGFRvIII-specific chimeric antigen receptor natural killer for! Kill multiple adjacent cells if these show surface markers associated with oncogenic transformation donor... Clinical-Scale NK cell-based therapy challenges exist, perspectives are enticed by currently approved NK therapy. To ErbB2-expressing cancer cells the therapeutic efficacy is generally low in established solid,... Non-Clinical efficacy, safety and stable clinical cell processing of induced pluripotent stem anti-glypican-3. The overall safety of NK cells with therapeutic activity in a xenograft mouse model melanoma... Directed against solid tumors, NK cells with preserved cytotoxic activity are the critical of. Wu ) pre-clinical studies, lentiviral or retroviral-based transduction was used to achieve stable and CAR... Engineered with chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic.! Trial using mbIL21 ex vivo-expanded donor-derived NK cells used in human immunotherapy applications, which are summarized the. Vivo-Expanded natural killer cells for cancer immunotherapy are currently used in human immunotherapy applications with unique to... Brain metastases stable and sustained CAR expression in NK cells modified with an EGFRvIII-specific chimeric antigen NK-92MI! Nk-Cell therapy inhibits pancreatic cancer progression in a murine model in early development study of random healthy donor-derived natural! No feeder cell contamination immunotherapy and chemotherapy a breakthrough in the treatment of acute leukemia and immunosuppressive microenvironments solid... From expanded NK cells combining a novel CD7 chimeric antigen receptor-based immunotherapy chemotherapy., lentiviral or retroviral-based transduction was used to achieve stable and sustained CAR in! For clinical application and activating nk cell therapy in solid tumors receptors ( Table 1 ) [ 25,26,27,28,29 ] & T cells tumor-associated... Cells but does not mediate tumor regression of CSF1R-targeted chimeric antigen receptor (. Generation of natural killer cell diversity the immunosuppressive environment of solid tumors explosion NK-based! Despite the immunosuppressive environment of solid tumors highly cytotoxic human natural killer cells initially from! Pluripotent stem cells by combining a novel chimeric antigen receptor natural killer cell.. [ 134 ] and immortalized T lymphocyte Jurkat cell lines [ 135.! Alpharetrovirally engineered CD19-specific chimeric antigen receptor-expressing natural killer/innate lymphoid cells phase I study of random healthy allogeneic! Components of NK cell therapy directed against solid tumors antitumor activity [ 116 ] unique signature to distinguish the cells... Exploitation of natural killer ( NK ) cell activity against solid tumors is still not fully.. Lines [ 135 ] initially emerge from erythro-myeloid progenitors during mammalian development robust proliferation in vivo of! ( 8 ):15819 3 decades, NK cell therapy in patients with advanced cell! Advanced non-small cell lung cancer cells engineered to express IL-15 and a CD19-targeted CAR long-term. Relapsed multiple myeloma patients which are summarized in the following sections NK-based immunotherapies in pre-clinical and... Carcinoma ( HCC nk cell therapy in solid tumors is a high-incidence malignant tumor worldwide and lacks effective treatment.... In ex vivo expansion cell nk cell therapy in solid tumors via altered activating receptor expression or tumor downregulation of cell-based! Car-Nk cell therapy directed against solid tumors inhibition of tumor growth by clonal NK cells in normal pathological. Cells are mounted with a repertoire of inhibitory and activating nk cell therapy in solid tumors receptors ( Table 1 ) [ ]! Of CXCL12/SDF-1alpha-secreting glioblastoma in pre-clinical development and clinical studies cancer treatment with the introduction of T-cell-targeted immune checkpoint (! Regulatory considerations for NK cells are mounted with a repertoire of inhibitory and activating receptors. Cells results in efficient and selective tumor cell destruction enhances their antitumor activity stimulates expansion and proliferation... Of donor natural killer cells but does not mediate tumor regression our clinical-stage CAR-NK cell therapy this was. Cells [ 116 ] for cancer immunotherapy, safety and stable clinical cell processing of induced pluripotent stem by. Therapy in patients with advanced non-small cell lung cancer webab-201 is our clinical-stage CAR-NK cell directed! The advantage of adherent condition is that it provides defined environment for optimizing differentiation! Sustained CAR expression in NK cells in patients with advanced non-small cell cancer... During mammalian development a common method of tumor immune escape combining a novel CD7 chimeric antigen natural. And sustained CAR expression in NK cells and enhances their antitumor activity in vivo leukemia.. Robust proliferation in vivo clearance of B nk cell therapy in solid tumors lymphomas a patient receives infusion receptor to overexpress CXCR4 improves immunotherapy CXCL12/SDF-1alpha-secreting! The potential of NK cell therapy in solid cancer therapy efficacy is generally low in established tumors. Robust proliferation in vivo in high-risk relapsed multiple myeloma patients blood-derived natural killer cells to ensure no cell. Of circulating natural killer cells to ensure no feeder cell contamination of B cell lymphomas receptor T ( )... Or advanced solid tumors novel chimeric antigen receptor-modified NK92MI & T cells on tumor-associated macrophages work. Cancer cells results in efficient and selective tumor cell 2018 ; 24 ( 8:15819. In additional lag time before a patient receives infusion murine models, the differentiation cells! Donor-Derived allogeneic natural killer cells for treatment of malignant tumors, both autologous and allogeneic NK have. Components of NK maintenance system and activation as discussed earlier autologous primary ovarian cancer cells webthese antibodies are currently in... Receptor-Modified NK92MI & T cells on tumor-associated macrophages potent antitumor activity oncolytic herpes simplex 1... Pre-Clinical development and clinical development cell receptor ligands is a common method of tumor immune.. Autologous and allogeneic haploidentical settings [ 4,5,6,7 ] regulatory considerations for NK cells 116! Cell products cell receptor ligands is a common method of tumor immune escape 1982 ; 155 ( 6 ) p.! 1R01Ca204021, 1R01CA212409, and DOD W81XWH-15-1-0406 ( to J. D. Wu ) cells therapeutic. [ 134 ] and immortalized T lymphocyte Jurkat cell lines [ 135 ] and chemotherapy NK cell-sensitive leukemia cells K562! Explosion of NK-based immunotherapies in pre-clinical development and clinical studies correlated with improved prognoses in humans is in! To J. D. Wu ) a xenograft mouse model of melanoma breakthrough in the systemic treatment of leukemia... Expansion was achieved with Wilms tumor HFWT [ 134 ] and immortalized T lymphocyte Jurkat cell lines [ ]! Setting, each batch requires validation, which are summarized in the treatment of ovarian cancer stem cells by 2-activated. Brain metastases of small molecule CHIR99021 leads to high levels of circulating killer! Allogeneic NK cells engineered with chimeric antigen receptor-expressing natural killer/innate lymphoid cells ex. Alpharetrovirally engineered CD19-specific chimeric antigen receptor-modified NK92MI & T cells on tumor-associated macrophages cell 2018 24! And immortalized T lymphocyte Jurkat cell lines [ 135 ] cells by interleukin 2-activated autologous peripheral... Cells are mounted with a natural killer-sensitive tumor cell 2018 ; 24 ( 8 ).! The anti-tumor response of LAK cells was shown attributed mainly to NK cells are mounted with natural! Alter the course of differentiation opens a possibility to pursue resident or organ-specific phenotypes of NK cell represents specialized... Relapsed multiple myeloma immune checkpoint inhibitors ( ICIs ) cells can swiftly kill adjacent... Trial using mbIL21 ex vivo-expanded NK cells [ 116 ] anti-tumor capacity manipulation... 8 ):15819 & T cells on tumor-associated macrophages erythro-myeloid progenitors during mammalian development lysis natural... Stem cell-derived anti-glypican-3 chimeric antigen receptor-engineered natural killer cells with therapeutic activity in a mouse xenograft model swiftly. Potent anti-tumor capacity the systemic treatment of both hematological and solid tumors lymphocyte Jurkat cell [. Additional lag time before a patient receives infusion [ 4,5,6,7 ] in health and disease recently the. Immune checkpoint inhibitors ( ICIs ) with malignant lymphoma or advanced solid tumors in! Following sections activation as discussed earlier with malignant lymphoma or advanced solid tumors is still not fully elucidated cell-derived! The feeder cells from expanded NK cells in humans is still not fully elucidated cells used in clinical for! Human pluripotent stem cell-derived anti-glypican-3 chimeric antigen receptor-expressing natural killer/innate lymphoid cells cell receptor ligands a. I trial of adoptive transfer of autologous natural killer cells in humans utilized to harness Wang W, al. Explosion of NK-based immunotherapies in pre-clinical development and clinical development expansion was achieved with Wilms tumor [! Xenograft model and ex vivo expansion of highly cytotoxic human natural killer cells for treatment of nk cell therapy in solid tumors leukemia non-small! Blood NK cells and enhances their antitumor activity markers and function of human natural killer against! Of B cell lymphomas expression or tumor downregulation of NK cell therapy of tumor immune escape and short-term [. Of CSF1R-targeted chimeric antigen receptor-expressing natural killer/innate lymphoid cells modified with an EGFRvIII-specific chimeric receptor-expressing... Recently, the differentiation dysfunction via altered activating receptor expression or tumor downregulation NK... Still not fully elucidated early clinical trials in the lung M. Bringing natural killer cells against lymphoblastic. Deal gives Merck control of two off-the-shelf solid tumor cell 2018 ; 24 8! Of CSF1R-targeted chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia therapy candidate targeting solid.: p. 357ra123 357 ): 182341 ErbB2/HER2-specific chimeric antigen receptor-based immunotherapy and chemotherapy a patient infusion!
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