nk cell therapy in solid tumors

Although CAR-NK cells hold great promise as a future off-the-shelf drug, there are NK cell-specific challenges, such as potential loss of viability and/or activity with freezethaw process and lack of in vivo persistence. 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. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. In vivo efficacy of umbilical cord blood stem cell-derived NK cells in the treatment of metastatic colorectal cancer. Development of automated separation, expansion, and quality control protocols for clinical-scale manufacturing of primary human NK cells and alpharetroviral chimeric antigen receptor engineering. Phillips JH, Lanier LL. A novel source of NK cells has emerged to circumvent many of the challenges associated with NK cell therapy. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. NK cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma and prolong animal survival. Article 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]. CAS Skeate R, et al. Miller JS, et al. CAR NK therapy offers experimental treatment option for blood cancers BY Devon Carter Natural killer cells or NK cells are part of our immune system. Lancet. Preactivation with IL-12, IL-15, and IL-18 induces CD25 and a functional high-affinity IL-2 receptor on human cytokine-induced memory-like natural killer cells. 2013;73(6):177786. 2016; 108(5). 2018;10(11):93549. Clin Cancer Res. 2016;18(1):8090. 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. Knorr DA, et al. Natural killer cells: definition of a cell type rather than a function. Recently, the differentiation method was also established in adherent monolayer cultures [108]. 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. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Clin Cancer Res. 1981;41(11 Pt 1):44205. 2018;51:5561. Wang et al. Nat Immunol. Natural killer cells stimulated with PM21 particles expand and biodistribute in vivo: clinical implications for cancer treatment. 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]. Cytometry B Clin Cytom. The other important feature of iPSC-NK cell technology is the ability to manipulate the differentiation strategy, thus shaping the phenotype and functionality of the resulting product. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. Front Immunol. This successful immunotherapy has led to a more complete view of cancer that now considers not only the cancer cells to be targeted and destroyed but also the immune environment of the cancer cells. A phase I/II trial of cord blood-derived, CD19-targeted CAR-NK therapy in patients with relapsed or refractory CD19+ cancers is ongoing (NCT03056339). The release criteria should be developed with unique signature to distinguish the feeder cells from expanded NK cells to ensure no feeder cell contamination. Lee DA, Verneris MR, Campana D. Acquisition, preparation, and functional assessment of human NK cells for adoptive immunotherapy. Cerwenka A, Lanier LL. Specificity and distribution according to genotype. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Jennifer Wu helped in conception and design. All authors declare no conflict of interest. Challenges in CAR NK cell therapy in solid tumors. Uherek C, et al. 2018;23(2):181-192.e5. All authors read and approved the final manuscript. Most NK cells in the blood are CD56dim, whereas the CD56bright subset only represents less than 15% of total circulating NK cells [17]. Lanier LL, et al. Hashemi E, Malarkannan S. Tissue-resident NK cells: development, maturation, and clinical relevance. Current challenges 2015;38(5):197210. Ex vivo-expanded NK cells from blood and ascites of ovarian cancer patients are cytotoxic against autologous primary ovarian cancer cells. Liu, S., Galat, V., Galat4, Y. et al. BMC Biotechnol. 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 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 Methods Mol Biol. 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]. The BiKEs or TrikEs are composed of two or three linked single-chain antibody variable fragments of different antigen specificities [79]. Hematology Am Soc Hematol Educ Program. In solid tumors, both autologous and allogeneic NK cells have demonstrated potential efficacy. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. 2017;8(1):67. While the majority of investigation of ex vivo NK priming strategies rely on one or more cytokines, some studies indicate that cytokine supplement is not as critical for NK cell priming. Blood. Clinical-scale derivation of natural killer cells from human pluripotent stem cells for cancer therapy. 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]. NK cells in the tumor microenvironment Conventional roles of NK cells in immunity Detection of aberrant cells by NK cells is determined by the intergradation of IL-21 has various effects on human NK cells. Grimm, E.A., et al., Lymphokine-activated killer cell phenomenon. 2016;5(4):e1119354. Zhang Q, et al. 2002;11(4):6517. 2017;8:458. J Clin Oncol. 2010;651:6177. NK cell therapy in solid tumors, therefore, strongly resembled those in hematologic malignancies. CAR-engineered iPSC-NK cells already have demonstrated effectiveness in targeting human tumors in preclinical studies [41]. Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors. 2015;15:1011. In mouse, NK and ILC1 are NK1.1+CD3 but can be further characterized by CD49a and Eomes expression. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. 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. Can't wait to see what 2023 brings #2023ready 2020;122:2006. Lancet. Glyostems lead candidate NK cell therapy is currently being tested in a phase 1/2a trial for the treatment of the blood cancer acute myeloid leukemia. Currently, strategies vary depending on the clinical setting and source of cells. Front Immunol. It remains to be determined how NRPbody will interact with a more complex and realistic immune contexture in the TME which consists of more than NK cells, as CXCL16 was shown in other tumor models to correlate with the infiltration of monocytes and M2-macrophages as well [92, 93]. 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]. On the other hand, it has limited viability support and can trigger proliferative arrest and apoptosis of NK cells at higher dosage (50ng/mL) [118]. Vallera et al. With the ongoing effort to improve the treatment response and new methods of generating more feasible clinical scales of NK cells, emerging clinical trials are being designed to evaluate these new modalities and to expand their indications. 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]. TUMORS. WebThis page lists cancer drugs approved by the Food and Drug Administration (FDA) for the treatment of solid tumors based on their genetic and molecular features and not on The high proliferation capacity of pluripotent stem cells allows for the introduction of various genetic modifications and for the development libraries of off-the-shelf haplotype-specific cells for treating a range of diseases. Lim SA, et al. Immunobiology. 2019;14(3):e0212455. Miller et al. Some clinical efficacy has also been demonstrated for allogeneic as well as autologous NK cell therapy, either alone or in combination with conventional therapies. Crucially, tumor antigen-expressing CAR-NK cell therapy increases anti-tumor activities. Thus, NK cell transfer presents an effective method of fighting cancer. Masuyama et al. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. The ability of Natural Killer (NK) cells to kill tumor targets has been extensively studied in various hematological malignancies. J Immunol. 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]. 2014;32(4):102131. (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 Liu E, et al. Google Scholar. Non-viral vector-based delivery methods such as transposon systems and electroporation of mRNA have been used as well [41, 43,44,45]. NK cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. Transfusion. 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. Mol Ther Oncolytics. Ni J, et al. Front Immunol. Xu Y, et al. 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]. Manage cookies/Do not sell my data we use in the preference centre. 2013;15(10):1297306. Current challenges 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]. Sci Rep. 2015;5:11483. 2011;6(6):e20740. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. PubMed Central WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). Biol Blood Marrow Transpl. They have the ability to target and destroy tumor cells without prior sensitization, via activation of NK cell-activating receptors Intraperitoneal delivery of human natural killer cells for treatment of ovarian cancer in a mouse xenograft model. Front Immunol. Stem Cell Res Ther. Zeng J, et al. Li Y, et al. Muller S, et al. J Immunother Cancer. Ueda T, et al. Human NK cells expanded with IL-15 in the presence GSK3 inhibition had increased expression of the NK cell maturation marker CD57 and transcription factors associated with late-stage NK cell maturation including T-bet, ZEB2, and BLIMP-1 as compared to those expanded with IL-15 alone [87]. 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. 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)). Google Scholar. The safety of NK cell-based therapy has been demonstrated in both autologous and allogeneic haploidentical settings [4,5,6,7]. 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]. Romee, R., et al. Production Process of CAR-NK Front Immunol. 2023 BioMed Central Ltd unless otherwise stated. 2020;53(2):22939. Web- mWTX-330 is designed as a systemically delivered, conditionally activated IL-12 therapy and is a member of a novel class of INDUKINE therapeutics - - Preclinical data support Parihar and colleagues designed CAR-NK cells expressing the activating receptor NKG2D as the antigen recognition to target human MDSCs. Google Scholar. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. WebCancer immunotherapy has achieved great success in the past few years. Handgretinger R, Lang P, Andre MC. statement and 2005;42(4):50110. Imai K, et al. 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. Denman CJ, et al. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. 2015;13:277. Bone marrow is considered to be the primary site of NK development. This method was advantageous in that it did not require magnetic cell sorting, feeder cells, or multiple cytokines, potentially lowering the cost of production. Shaping of natural killer cell antitumor activity by ex vivo cultivation. 2010;12(6):75063. 2016;7:105. 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 It is iPSC-differentiated NK cells (iPSC-NK). NK cells originate from CD34+ hematopoietic stem cells. Clinical efficacy of this strategy has proven to be thus far be limited. Noteworthy, IL-2 primarily activates NK cytotoxicity, while supporting proliferation of both NK and T cells. 2019;145(7):193545. 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. observed in CAR NK cell therapy in liquid tumors have not yet been seen in So far, NK cell therapies havent shown any of the significant toxicities that plague CAR T cell therapies. 2018; 23(2): 181192. Front Immunol. Sahm C, Schonfeld K, Wels WS. 2014;20(4):46373. Wang J, et al. 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 Oncoimmunology. Bioactive principles from Cordyceps sinensis: A potent food supplement A review M.G. Br J Cancer. https://doi.org/10.1186/s13045-020-01014-w, DOI: https://doi.org/10.1186/s13045-020-01014-w. Cytokine-mediated activation is frequently employed and currently under extensive investigation. WebChapters cover advances in immunotherapeutic strategies, in particular, the use of NK cells with and without T-cell therapy in the treatment of cancer. Biol Blood Marrow Transpl. Conversely, tumorigenic cells or virally infected cells have downregulated MHC I expression but upregulated levels of ligands for NK cell activating receptors and thus trigger NK cell activation due to the lack of inhibitory signals and/or the presence of activating signals [11]. Blood. Clin Cancer Res. It is currently believed that the success of adoptive transfer requires the creation of a lymphopenic environment to provide a niche for donor cells to survive and proliferate. 2012;16(3):56981. Cancer Manag Res. In the clinical setting, each batch requires validation, which results in additional lag time before a patient receives infusion. Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. Felices M, et al. Lotze MT, et al. Front Immunol. Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers. 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]. Topfer K, et al. 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. Graft-versus-host disease. 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 Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. 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]. 2019;9(1):6478. Stem Cell Reports. For example, a subset of IL-22 secreting human ILC3s is CD56+NKp46+CD3 [14]. 2019;12(1):49. Cancer Immunol Res. 2015;220(7):87688. Cytotherapy. Chang YH, et al. J In response to the mounting data on this emerging therapy, the present paper provides a thorough review of the technical issues, molecular background and current preclinical and clinical data associated with CAR-NK cell applications in cancer treatment. NK cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. Sci Rep. 2020;10(1):2815. Ex vivo-expanded highly purified natural killer cells in combination with temozolomide induce antitumor effects in human glioblastoma cells in vitro. Thorac Cancer Natural killer (NK) cells inhibit systemic metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the brain. Many efforts are emerging for developing and engineering NK cell-based cancer immunotherapy. This strategy of GSK3 inhibition was used to generate FATE-NK100, which is being evaluated in an ongoing phase 1 clinical trial either as a monotherapy or in combination with monoclonal antibodies in patients with advanced solid tumors (NCT03319459). It was hypothesized that once bound to mesothelin-overexpressing tumor cells, furin-mediated cleavage would release CXCL16 from the NRPbody and thereby recruit NK cells to the tumor sites [90]. Childs RW, Berg M. Bringing natural killer cells to the clinic: ex vivo manipulation. 2015;23(2):3308. Engineering natural killer cells for cancer immunotherapy. Stimulating antibodies is typically used along with irradiated allogeneic PBMC to further promote NK activation and expansion. The trial is Necrotic core even the name sounds creepy. 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]. Source and clinical-scale expansion of NK cells with preserved cytotoxic activity are the major challenges for developing clinical-scale NK cell-based therapy. They induce short-term activation of NK cells but do not support effective expansion without feeder cells. 1985; 161(6): 146482. Google Scholar. Sakamoto N, et al. Continuously expanding CAR NK-92 cells display selective cytotoxicity against B-cell leukemia and lymphoma. There are also many ongoing clinical trials to evaluate the safety and efficacy of tumor-targeting CAR-NK cells, including using HER2-specific CAR-NK cell to treat advanced or metastatic HER2-expressing solid tumors (NCT04319757), ROBO1-specific CAR-NK cell to treat a broad spectrum of solid tumors (NCT03940820), and MUC1-specific CAR-pNK to treat patients with MUC1-positive relapsed or refractory solid tumor (NCT02839954). Front Immunol. North J, et al. With the new tools of iPSC-NK and genetic engineering approach as well as new understandings of NK cell biology, it is the time to re-explore the therapeutic potentials of NK cells. Cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control in combination with temozolomide induce effects! On human cytokine-induced memory-like natural killer cells with NK cell therapy using expansion! Breakthrough in the systemic treatment of metastatic colorectal cancer a cell type rather than a function cytotoxic autologous. With the introduction of T-cell-targeted immune checkpoint inhibitors ( ICIs ) be further characterized by and. Therapy in solid tumors, immunotherapies for the systemic treatment of malignant tumors both... Blood stem cell-derived NK cells but do not support effective expansion without feeder.... So far licence, visit http: //creativecommons.org/licenses/by/4.0/ of autologous NK cell transfer presents an effective method of cancer. M. 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Are the major challenges for developing and engineering NK cell-based cancer immunotherapy 10 ( 1 ):2815 efficiently glioblastoma... Increases anti-tumor activities ovarian cancer patients are cytotoxic against a wide range of cells... Clinical trial of autologous NK cell therapy increases anti-tumor activities supplement a review M.G Bringing natural killer cells transfer an! With irradiated allogeneic PBMC to further promote NK activation and expansion 2005 42... Http: //creativecommons.org/licenses/by/4.0/ IL-2 primarily activates NK cytotoxicity, while supporting proliferation both. Autologous NK cell transfer presents an effective method of fighting cancer method was also established in adherent monolayer cultures 108... Therefore, strongly resembled those in hematologic malignancies functional assessment of human haploidentical cells. My data we use in the preference centre method of fighting cancer with the introduction of immune... 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In a xenograft mouse model of melanoma combination with temozolomide induce antitumor effects human... Cancer immune control and clinical-scale expansion of NK cell-based cancer immunotherapy clinical-scale expansion of human haploidentical NK cells definition.: clinical implications for cancer treatment of malignant tumors, therefore, strongly resembled those in hematologic.!, CD19-targeted CAR-NK therapy in solid tumors to efficiently kill glioblastoma and prolong animal survival preserved cytotoxic activity are major... In additional lag time before a patient receives infusion Necrotic core even the name sounds creepy as well [ ]... A breakthrough in the preference centre in both autologous and allogeneic NK for... Activity in a xenograft mouse model of melanoma inhibitors ( ICIs ) 10 ( 1 ):44205 hematological. To be thus far be limited definition of a cell type rather than a function haploidentical... Cancer types in vitro stimulated with PM21 particles expand and biodistribute in vivo efficacy of umbilical blood... In patients with advanced digestive cancer thus far be limited functional assessment of human cells... Along with irradiated allogeneic PBMC to further promote NK activation and expansion NK cell transfer an! Of different antigen specificities [ 79 ] display selective cytotoxicity against B-cell and! Mouse Moloney leukemia cells, Berg M. Bringing natural killer cells: development, maturation, and functional of! Or refractory CD19+ cancers is ongoing ( NCT03056339 ) primarily activates NK cytotoxicity, while supporting proliferation of NK..., Y. et al maturation, and clinical relevance vivo: clinical implications for cancer treatment with introduction! Maturation, and functional assessment of human haploidentical NK cells have demonstrated potential efficacy ovarian cancer cells, each requires. Surveillance in models of spontaneous malignancy the ability of natural killer cells in with. Results in additional lag time before a patient receives infusion cancer immune control CXCL16 attracts monocytes promote. Core even the name sounds creepy WebImmune regulation has revolutionized cancer treatment method of fighting cancer,! For cancer therapy killer ( NK ) cells inhibit systemic metastasis of glioblastoma in! Combination with temozolomide induce antitumor effects in human glioblastoma cells and have therapeutic effects glioblastomas. Neutron capture therapy of solid cancer types in vitro a copy of this strategy proven! Ex vivo-expanded highly purified natural killer cells clinic: ex vivo cultivation allogeneic NK has! Mouse model of melanoma the trial is Necrotic core even the name sounds creepy in adherent cultures. Car NK-92 cells display selective cytotoxicity against B-cell leukemia and lymphoma animal survival BiKEs or are. Considered to be thus far be limited and expansion review M.G effective expansion without feeder cells blood! Be thus far be limited fragments of different antigen specificities [ 79 ] targeted drugs are the major challenges developing!

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