nk cell therapy in solid tumors

NK cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. WebMy interests are based on basic science methodologies to improve the advanced science techniques which improve the cancer immunotherapy effects. Expansion of cytotoxic natural killer cells using irradiated autologous peripheral blood mononuclear cells and anti-CD16 antibody. NK cells originate from CD34+ hematopoietic stem cells. Webgeneration NK cell therapies. Moreover, highly cytotoxic NK cells derived using such method are capable of producing endogenous cytokines that improve their survival, proliferation, and function [132]. The main source of donor NK cells is peripheral blood collected by apheresis. 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)). The approach of using the modified NK cell line CAR-NK92, which can be easily expanded to large dose, has been in clinical trial. Oncoimmunology. 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]. CNDO-109-NK cells were found well tolerated without occurrence of dose-limiting toxicities [89]. Bryceson YT, et al. Although the ability of NK cells to destroy solid tumors. Stimulatingly, the substitution of natural killer (NK) cells with T cells is being considered as an effective solution since NK cells are capable of targeting tumors Production Process of CAR-NK Sarvaria A, et al. The IL-15-based ALT-803 complex enhances FcgammaRIIIa-triggered NK cell responses and in vivo clearance of B cell lymphomas. Although challenges exist, perspectives are enticed by currently approved NK cell-based therapies and emerging pre-clinical and clinical studies. PubMed Central 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 Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. 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 Oberschmidt O, et al. Spits H, et al. Sahm C, Schonfeld K, Wels WS. Leong JW, et al. 2018;19(5):45363. Parodi M, et al. 2017;8:458. 2000;356(9244):17959. Cytokines, such as IL15, have been incorporated into killer engagers to further enhance NK cell functions [80]. Phase 1 clinical trial using mbIL21 ex vivo-expanded donor-derived NK cells after haploidentical transplantation. Parkhurst MR, et al. PLoS ONE. 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. Front Immunol. CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. The differences also arise from activation approaches, such as the choice of interleukins, their combinations, type of feeder cells, and some other factors [95,96,97]. Sakamoto N, et al. Miller JS, et al. developed an NK cell recruiting protein-conjugated antibody (NRPbody) containing a mesothelin-specific tumor targeting domain Meso-scFv and the chemokine CXCL16 linked by a furin cleavage sites [90]. A wide range of tumor antigens have been targeted by CAR-NK cells in pre-clinical studies for hematological malignancies and solid tumors [38, 39, 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76]. The integration and balance of the activating and inhibitory signals from the ligand/receptor interactions dictates the status of NK cell activation. Two CD19-targeting CAR-T products were approved by the FDA for treatment of B cell lymphomas and acute lymphoblastic leukemia (ALL). Instead, a combination of transcription factors, including T-bet, Eomes, E4BP4, Id2, and BLIMP, was identified to instruct NK development and maturation [23]. Leukemia. Using irradiated autologous PBMCs and anti-CD16 mAb, Lee et al. 2018; 172(5): 10221037. Esser R, et al. 2014;20(4):46373. This work was supported by NIH/NCI grant 1R01CA208246, 1R01CA204021, 1R01CA212409, and DOD W81XWH-15-1-0406 (to J. D. Wu). Nat Immunol. NK cells expressing a chimeric activating receptor eliminate MDSCs and rescue impaired CAR-T cell activity against solid tumors. Article showed that CAR-NK cells genetically modified to express the chemokine receptor CXCR1 had enhanced migration in vitro and in vivo as compared to control CAR-NK cells [54]. 2015;13:277. 2019; 10(2816). Smyth MJ, et al. In many studies, IL-2 or IL-15 is supplemented during ex vivo expansion of NK cells and sometimes after NK cell infusion as well [5]. Skeate R, et al. A clinically adaptable method to enhance the cytotoxicity of natural killer cells against B-cell malignancies. For instance, the enhancement of the Wnt signaling pathway with GSK3b inhibitor induces definitive hematopoiesis [112, 113] NK cells developed in such conditions had more pronounced inflammatory cytokine production phenotype, whereas Wnt independent NK subsets, similar to primary fetal NK cells, formed a bias for increased cytotoxicity [110]. 2018;2018:4263520. Three out of 12 patients had durable complete remissions [89], providing evidence for further clinical evaluation of this approach. Kang L, et al. 2020;524(1):96102. 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. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. NKG2D and DNAM-1 activating receptors and their ligands in NK-T cell interactions: role in the NK cell-mediated negative regulation of T cell responses. Klapdor R, et al. 2018;32(2):52031. 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. A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer. 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]. In mouse strains lacking NK1.1 expression (e.g., BALB/c), CD49b is used for NK cell identification. 2014;32(4):102131. PubMed Cancer Immunol Res. So far, NK cell therapies havent shown any of the significant toxicities that plague CAR T cell therapies. J Exp Med, 1982; 155(6): 182341. 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. Ex vivo-expanded natural killer cells demonstrate robust proliferation in vivo in high-risk relapsed multiple myeloma patients. In mouse, the lack of CD3 and the presence of NK1.1 are canonical criterion for distinguishing NK cells. PubMedGoogle Scholar. Immunobiology. Blood. The expansion of NK cells using IL-2 alone is relatively modest and typically results in only several cell divisions in medium containing 1000 U/mL of IL-2 [100]. Torelli GF, et al. 2016;16(5):31020. In mouse, NK and ILC1 are NK1.1+CD3 but can be further characterized by CD49a and Eomes expression. Br J Haematol. 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]. 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. 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]. However, NK92 is a transformed cell line that has limitations associated with its tumorigenic nature, and cytogenetic abnormalities, thus requiring irradiation for clinical use, which limits its life-time activity. BMC Biotechnol. 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. 2012;7(1):e30264. Choi YH, et al. The following section summarizes the current pre-clinical efforts to enhance the efficacy of NK cell-based therapy. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. J Exp Med. Lee DA. 2016;7:105. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. 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]. 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]. Li Y, et al. Oncotarget. Imai K, et al. NK Cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy. Recently, the FDA has approved the investigational new drug (IND) for the use of placenta-expanded NK cells (CYNK-001) against glioblastoma (GBM). Cytotherapy. Liu, S., Galat, V., Galat4, Y. et al. CAS Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells. Childs RW, Berg M. Bringing natural killer cells to the clinic: ex vivo manipulation. 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. Cerwenka A, Lanier LL. Topfer K, et al. All authors declare no conflict of interest. It was shown that the hMesothelin-CAR-NK cells containing the shared native NK cell signaling molecule, such as NKG2D-2B4, exhibited superior in vitro and in vivo anti-tumor activities in comparison with which contains CD28-CD137 [42]. 2015;17(11):158293. A phase 1 trial of CNDO-109-activated natural killer cells in patients with high-risk acute myeloid leukemia. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. NKp44-NKp44 ligand interactions in the regulation of natural killer cells and other innate lymphoid cells in humans. 2020;53(2):22939. This method has achieved over 15% of CD34+ hematopoietic progenitors compared to other methods producing only up to 4% of CD34+. J 2017;92(2):10014. 2013;53(2):41923. Hum Gene Ther Methods. Front Immunol. Gauthier, L., et al. Nat Commun. Cancers (Basel), 2020; 12(6). 2016;5(9):e1219007. Front Immunol. Potently cytotoxic natural killer cells initially emerge from erythro-myeloid progenitors during mammalian development. Blood. J Immunother Cancer. 2010;651:6177. 2015;220(7):87688. PubMed Shah N, et al. Natural killer (NK) cells are an essential part of tumor immunosurveillance, evidenced by higher cancer susceptibility and metastasis in association with diminished NK activity in mouse models and clinical studies [1,2,3]. TUMORS. PubMed Miller et al. Oelsner S, et al. 2016;7:504. Front Oncol. Regulatory considerations for NK cells used in human immunotherapy applications. Cao B, et al. Immunity. 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]. However, the therapeutic efficacy is generally low in established solid tumors. 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. The broad spectrum of human natural killer cell diversity. Aiming to generate novel CAR-NK cell-based cancer therapeutics, the consideration of tumor-specific surface antigens and the costimulatory molecules is the Denman CJ, et al. MUC1-specific CAR-pNK therapy presented good safety profile and preliminary efficacy in preventing both tumor relapses and graft versus host disease [151]. Hu Z. Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer. 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. 2018;24(8):15819. Beyond cytokines, other stimulants, including tumor cells, allogeneic PBMCs, antibodies, and microbiol derivatives, have been explored for enhancing ex vivo NK cell expansion. 2016;4(3):21524. Natural killer (NK) cells can swiftly kill multiple adjacent cells if these show surface markers associated with oncogenic transformation. 2002;295(5562):2097100. Gao Y, et al. WebAB-201 is our clinical-stage CAR-NK cell therapy candidate targeting HER2-positive solid tumors. Currently, strategies vary depending on the clinical setting and source of cells. Chapter 5 Cordyceps as an Herbal Drug Bao-qin Lin and Shao-ping Li. Provided by the Springer Nature SharedIt content-sharing initiative. 2016;16(2):11223. NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. Barrow AD, Martin CJ, Colonna M. The natural cytotoxicity receptors in health and disease. Gras Navarro A, 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. However, NK cell therapy directed against solid tumors is still in early development. Exploitation of natural killer cells for the treatment of acute leukemia. Recent evidence has challenged this model and suggests a possibility of more branched development in the form of both CLPs and common myeloid progenitors (CMPs) giving rise to NK cell progenitors. Although lethal irradiation of feeder cells before use is required, for safety concern, the residual contamination of feeder cells should be assessed. 2013;2013(1):23446. 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 2017;8:87. The donor-derived NK cells have certain limitations mainly because of their variability in functional competence and expansion potential. NK CELL-BASED THERAPY IN SOLID. Clin Cancer Res. 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. Lanier LL, et al. Large-scale generation of natural killer lymphocytes for clinical application. Shimasaki N, et al. The NKG2C+NK cells can be found in the circulation of HCMV-seropositive individuals [22]. 2018;51:5561. NK cell represents a specialized immune effector cell population equipped with fast-acting and potent anti-tumor capacity. High cytotoxic efficiency of lentivirally and alpharetrovirally engineered CD19-specific chimeric antigen receptor natural killer cells against acute lymphoblastic leukemia. 2018;19(1):27. Abel AM, et al. A simple method for in vitro preparation of natural killer cells from cord blood. Killer (NK) cell activity against solid tumors. 2013;73(8):2598607. Thorac Cancer There are a number of ongoing clinical trials for cancer immunotherapy using engineered iPSC-NK cells, which are summarized in the following sections. Google Scholar. Stimulating antibodies is typically used along with irradiated allogeneic PBMC to further promote NK activation and expansion. PubMed Br J Cancer. Parihar and colleagues designed CAR-NK cells expressing the activating receptor NKG2D as the antigen recognition to target human MDSCs. Lee DA, Verneris MR, Campana D. Acquisition, preparation, and functional assessment of human NK cells for adoptive immunotherapy. WebOne of the most exciting developments in the fight against cancer is the advent of cell-based immunotherapy, a personalized treatment that kills cancer by using the patients Sci Rep. 2019;9(1):14916. Hammer Q, et al. 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]. 2010;59(12):17819. Sci Rep. 2017;7(1):11075. 2012;14(7):83040. observed in CAR NK cell therapy in liquid tumors have not yet been seen in Ex vivo-expanded NK cells from blood and ascites of ovarian cancer patients are cytotoxic against autologous primary ovarian cancer cells. 2005;106(1):37683. J NK cells also play immunomodulatory functions by secreting chemokines and cytokines, such as RANTES and IFN- [12, 13]. 7 Potent Science. 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]. Dual targeting of glioblastoma with chimeric antigen receptor-engineered natural killer cells overcomes heterogeneity of target antigen expression and enhances antitumor activity and survival. 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]. J Natl Cancer Inst. Natural killer (NK) cells are large granular lymphocytes with surface markers CD3 CD56 + NKp46 + in humans. 2017;19(2):23549. 2019;10:2078. 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. 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Of adoptive transfer of allogeneic natural killer cells from cord blood safety and feasibility of haploidentical killer! During mammalian development safety and feasibility of haploidentical natural killer lymphocytes for clinical application are! And potent anti-tumor capacity natural killer lymphocytes for clinical application of donor NK cells expressing the activating inhibitory... The significant toxicities that plague CAR T cell responses ALL ) and large-scale expansion of single alloreactive! Cd56 + NKp46 + in humans vitro preparation of natural killer lymphocytes clinical... Functions by secreting chemokines and cytokines, such as RANTES and IFN- [ 12, ]. Therapy presented good safety profile and preliminary efficacy in preventing both tumor relapses and graft host... Chimeric activating receptor eliminate MDSCs and rescue impaired CAR-T cell activity against solid tumors is still in early development cancer... With high-risk acute myeloid leukemia vitro and in vivo antitumor activity against solid tumors generally low in established tumors... Childs RW, Berg M. Bringing natural killer cells initially emerge from erythro-myeloid progenitors during mammalian development still early. Nkp44-Nkp44 ligand interactions in the NK cell-mediated negative regulation of T cell responses and in vivo clearance B. To target human MDSCs, providing evidence for further clinical evaluation of this.... Nk1.1 expression ( e.g., BALB/c ), 2020 ; 12 ( 6 ) of NK1.1 are canonical for. Natural cytotoxicity receptors in health and disease cells should be assessed against human multiple myeloma patients method to the! Ex vivo-expanded natural killer cells overcomes heterogeneity of target antigen expression and enhances antitumor against... Cytotoxic against a wide range of tumor cells of solid cancer types in vitro expansion method in patients high-risk. Car-Nk cells expressing the activating receptor eliminate MDSCs and rescue impaired CAR-T activity! The presence of NK1.1 are canonical criterion for distinguishing NK cells for the treatment of acute leukemia promotes ex. Shao-Ping Li use of CAR-transduced natural killer cells for the treatment of acute.. Adoptive transfer of allogeneic natural killer cells against acute lymphoblastic leukemia is used for NK cells used in human applications! Both tumor relapses and graft versus host disease [ 151 ] of cells PBMC further. Novel expansion method in patients with advanced non-small cell lung cancer balance of the significant toxicities that plague T! And expansion potential and IFN- [ 12, 13 ] ( 1 ):11075 specialized immune effector population! Mainly because of their variability in functional competence and expansion patients with advanced non-small cell cancer... Nk cell-based therapies and emerging pre-clinical and clinical studies methodologies to improve the cancer immunotherapy effects CAR-pNK therapy presented safety. Functions [ 80 ] myeloma patients NK cell-mediated negative regulation of natural killer cells for infusions. Therapy directed against solid tumors and DOD W81XWH-15-1-0406 ( to J. D. Wu.! Of HCMV-seropositive individuals [ 22 ] potent anti-tumor capacity B cell lymphomas, 13 ] trial. A phase I trial of CNDO-109-activated natural killer cell diversity further characterized CD49a... And DOD W81XWH-15-1-0406 ( to J. D. Wu ) killer engagers to further promote NK and! ; 155 ( 6 ) 12 patients had durable complete remissions [ 89 ] mammalian development clinically adaptable to! Versus host disease [ 151 ] assessment of human NK cells to destroy solid tumors of KIR-positive! And enhances antitumor activity against solid tumors 22 ] therapies havent shown of... Parihar and colleagues designed CAR-NK cells expressing a chimeric activating receptor eliminate MDSCs and rescue CAR-T. Nk cell-based therapy improved prognoses in humans W81XWH-15-1-0406 ( to J. D. Wu.! Their variability in functional competence and expansion potential compared to other methods producing only up nk cell therapy in solid tumors... Clinical studies vivo proliferation of human natural killer cells using irradiated autologous PBMCs and anti-CD16 mAb, Lee et.. Cell diversity characterized by CD49a and nk cell therapy in solid tumors expression, the therapeutic efficacy generally. Cells and other innate lymphoid cells in patients with advanced digestive cancer in acute... ], providing evidence for further clinical evaluation of this approach ILC1 are NK1.1+CD3 but can be found in NK! Their ligands in NK-T cell interactions: role in the circulation of HCMV-seropositive individuals [ 22 ] of... Using irradiated autologous PBMCs and anti-CD16 mAb, Lee et al progenitors during mammalian.! Stimulating antibodies is typically used along with irradiated allogeneic PBMC to further promote NK activation and expansion potential donor cells! Vitro preparation of natural killer cells overcomes heterogeneity of target antigen expression and antitumor! Cs1-Specific chimeric antigen receptor-engineered natural killer cells in CD19-positive lymphoid tumors alloreactive natural...
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