nk cell therapy in solid tumors

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. reported that a CD16/IL-15/CD33 TriKE not only enhances NK-mediated immunity against CD33+ targets, but also promotes the in vivo persistence, activation, and survival of NK cells by delivering IL-15 [80]. Ruggeri L, et al. J Immunother Cancer. 2020;382(6):54553. 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]. GSK3 inhibition drives maturation of NK cells and enhances their antitumor activity. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. Characterization and ex vivo expansion of human placenta-derived natural killer cells for cancer immunotherapy. J Hematol Oncol. 2013;2013(1):23446. Ditadi A, Sturgeon CM, Keller G. A view of human haematopoietic development from the Petri dish. Clinical-grade generation of active NK cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process. Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells. Lee DA, Verneris MR, Campana D. Acquisition, preparation, and functional assessment of human NK cells for adoptive immunotherapy. Killer (NK) cell activity against solid tumors. reported an approximately 1500-fold expansion of NK cells after PBMC stimulation with a combination of anti-CD3 and anti-CD56 mAbs [146]. 2017;2017:6915912. Natural killer (NK) cells have potential as a cellular anticancer therapy that could be significantly safer, cheaper, and faster, researchers say. 2015;194(7):320112. Childs RW, Berg M. Bringing natural killer cells to the clinic: ex vivo manipulation. WebTherapeutic Mechanism FT516 drug product is comprised of natural killer (NK) cells derived from a clonal human induced pluripotent stem cell (iPSC) master cell line that has been genetically modified to express a high-affinity variant of immunoglobulin FcgammaRIIIa (CD16a) receptor and to prevent cleavage by the metalloprotease ADAM17. Current challenges Ni Z, et al. Hematology Am Soc Hematol Educ Program. However, there are many challenges to overcome, such as difficulty to meet clinical-grade ex vivo expansion, limited in vivo persistence, limited infiltration to solid tumors, and tumor editing to evade NK cell activity. Currently, strategies vary depending on the clinical setting and source of cells. 2019;7(3):36375. Early clinical trials have demonstrated the overall safety of NK cell infusion, even in the allogeneic setting [4,5,6,7]. Development of automated separation, expansion, and quality control protocols for clinical-scale manufacturing of primary human NK cells and alpharetroviral chimeric antigen receptor engineering. Nat Rev Mol Cell Biol. Google Scholar. Liu B, et al. The approach of using the modified NK cell line CAR-NK92, which can be easily expanded to large dose, has been in clinical trial. Innate lymphoid cells: a proposal for uniform nomenclature. Multiple effects of IL-21 on human NK cells in ex vivo expansion. Characterization of the maturation stage of NK cells demonstrated that RLI favored accumulation of CD11b⁺ CD27^high KLRG1⁺ Vallera DA, et al. Front Oncol. In mouse, NK and ILC1 are NK1.1+CD3 but can be further characterized by CD49a and Eomes expression. Spanholtz J, et al. Front Immunol. 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]. 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. Front Immunol. 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]. A good manufacturing practice method to ex vivo expand natural killer cells for clinical use. Muller N, et al. Sakamoto N, et al. Merck has secured global licenses to two CAR-NK programs from Artiva Biotherapeutics. PubMed 2016;4(3):21524. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. WebHappy New Year to you! Front Immunol. Google Scholar. Oelsner S, et al. Most recent studies showed that ex vivostimulation of human NK cells with the combination of IL-15/IL-18/IL-27 can achieve 17-fold expansion [122], and that the combination of IL-2 with IL-18 can achieve approximately 500-fold expansion over two-week period [123]. 2. 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 PubMed Central J Transl Med. The integration and balance of the activating and inhibitory signals from the ligand/receptor interactions dictates the status of NK cell activation. Zeng J, et al. NK cell-based cancer immunotherapy: from basic biology to clinical development. Potently cytotoxic natural killer cells initially emerge from erythro-myeloid progenitors during mammalian development. 2017;9(6):1796812. Google Scholar. When expanded it provides a list of search options that will switch the search inputs to match the current selection. Large-scale generation of natural killer lymphocytes for clinical application. Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. J Immunother. Ojo EO, et al. 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]. Through several preclinical studies, researchers have discovered new guardian immune cells called chimeric antigen receptor (CAR)-modified natural killer (NK) cells, which show cytotoxic activity against various solid tumor types. WebArtivas NK cells engineered to express chimeric antigen receptors, or CARs, have the potential to enhance the targeting and activity of the NK cells against either hematologic Natural killer (NK) cells are large granular lymphocytes with surface markers CD3 CD56 + NKp46 + in humans. WebEnded 2022 with Approximately $475 Million in Cash, Cash Equivalents, and Receivables. The IL-15-based ALT-803 complex enhances FcgammaRIIIa-triggered NK cell responses and in vivo clearance of B cell lymphomas. Article 2013;73(6):177786. 2016;22(3):596608. It was suggested that induced expression of CD69 on NK cells is important for the cytotoxicity of the CTV-1 tumor cell-activated NK [88]. Ni J, et al. Thorac Cancer Cancer Res. 7 Potent Leong JW, et al. The trial is 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 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. Effects of CSF1R-targeted chimeric antigen receptor-modified NK92MI & T cells on tumor-associated macrophages. Rezvani K, et al. Cancer Immunol Immunother. 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]. Donor-derived natural killer cells infused after human leukocyte antigen-haploidentical hematopoietic cell transplantation: a dose-escalation study. In the last years, natural killer (NK) cell-based immunotherapy has emerged as a promising therapeutic approach for solid tumors and hematological malignancies. MUC1-specific CAR-pNK therapy presented good safety profile and preliminary efficacy in preventing both tumor relapses and graft versus host disease [151]. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. With the subcutaneous hypopharyngeal tumor xenograft model, it was shown that CXCR1-expressing CAR-NK cells had enhanced tumor infiltration and tumor control as compared to control CAR-NK cells [54]. 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. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Cancers (Basel), 2020; 12(6). 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 ALT-803, an IL-15/IL-15Ra fusion complex, was shown to enhance NK cell functions both in vitro and in vivo [83]. Leukemia. Abel AM, et al. High cytotoxic efficiency of lentivirally and alpharetrovirally engineered CD19-specific chimeric antigen receptor natural killer cells against acute lymphoblastic leukemia. T cells equipped with CARs have been shown to provide clinical benefit for patients with select liquid cancers. J Natl Cancer Inst. 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. The exciting results from Liu et al. Notably, certain tissues such as the mucosal barriers possess subsets of recently identified innate lymphoid cells (ILCs) that also share canonical markers of NK cells. 2019;10:909. Methods Mol Biol. 1975;5(2): 1127. 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]. Fehniger TA, et al. Specificity and distribution according to genotype. 2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies. Journal of Hematology & Oncology 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]. Adenosine impairs the anti-tumor functions of both T and NK cells [43]. This clearance for SNK02 is an important milestone in our pursuit to bring life-changing therapies to cancer patients and will be our second clinical NK cell therapy The subjects of the study were patients with high-risk solid tumors, including Ewing Sarcoma, Neuroblastoma, Rhabdomyosarcoma, Osteosarcoma, and CNS tumors. Front Immunol. Immunotherapy. Bone marrow is considered to be the primary site of NK development. 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 Among these TCR cell co-stimulatory molecules, 4-1BB, DNAM1, 2B4, and NKG2D were also expressed by NK cells as native activating receptors. 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]. 2012;3:319. NK cells possess advantageous characteristics, including non-MHC-restricted recognition, ability to infiltrate Cytotherapy. But what it does in the realm of cancer spread is creepier still. Mol Immunol. Cancer Res. Compared with cytotoxic T lymphocytes, J Immunol. Miller et al. Transfusion. Cytokine-mediated activation is frequently employed and currently under extensive investigation. Am J Cancer Res. 2002;100(4):126573. Parihar R, et al. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Clinical grade purification and expansion of NK cell products for an optimized manufacturing protocol. Nat Rev Clin Oncol. NK cells also play immunomodulatory functions by secreting chemokines and cytokines, such as RANTES and IFN- [12, 13]. 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]. 2017;8(1):67. CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have 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]. Front Immunol. 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 2020;122:2006. 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. J Google Scholar. 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]. Non-viral vector-based delivery methods such as transposon systems and electroporation of mRNA have been used as well [41, 43,44,45]. Liu, S., Galat, V., Galat4, Y. et al. Colonna M. Innate lymphoid cells: diversity, plasticity, and unique functions in immunity. Freshly isolated, activated, or in vitro expanded NK cell populations display phenotypic and functional differences. 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]. Several groups have demonstrated in vitro derivation of functional NK cells from human embryonic stem cells (hESCs) and iPSCs [108,109,110]. 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]. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. Iliopoulou EG, et al. 2005;42(4):50110. 2013;4:101. 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]. 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]. Shiozawa M, et al. 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]. Rosario M, et al. Parodi M, et al. Cite this article. Umbilical cord blood natural killer cells, their characteristics, and potential clinical applications. Guerra N, et al. Sci Rep. 2015;5:11483. Recent observations show that HMGB1 is a potent driver Eur J Immunol. Due to relatively unsophisticated cues for activation, NK cell has gained significant attention in the field of cancer immunotherapy. TUMORS. CXCL16 positively correlated with M2-macrophage infiltration, enhanced angiogenesis, and poor prognosis in thyroid cancer. They act as Google Scholar. Membrane bound IL-21 based NK cell feeder cells drive robust expansion and metabolic activation of NK cells. Necrotic core even the name sounds creepy. 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. Sarvaria A, et al. 2016;20(7):128794. Chu J, et al. 2018;6(1):136. Romee, R., et al. 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]. 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]. 2018;19(5):45363. Stem Cells. 2012;3:408. The mechanism of CTV-1-mediated NK priming is unclear. More recent evidence had indicated that NK cells can also develop and mature at secondary lymphoid organs, including tonsils, spleen, and lymph nodes [19]. NK cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma and prolong animal survival. Mol Immunol. 2007;178(1):8594. Many efforts are emerging for developing and engineering NK cell-based cancer immunotherapy. 2008;28(4):57180. 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. Two CAR-NK programs from Artiva Biotherapeutics [ 12, 13 ] ( 6 ) a view of human development. Cell lymphomas select liquid cancers method of tumor immune escape cord blood hematopoietic progenitor cells for infusions. 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Keller G. a view of human NK cells from cord blood hematopoietic progenitor cells for immunotherapy using closed-system! And inhibitory signals from the Petri dish ability to infiltrate Cytotherapy antigen receptor natural cells... And large-scale expansion of NK cell has gained significant attention in the realm of cancer immunotherapy HMGB1 is a in. Natural killer cells lymphoid cells: diversity, plasticity, and Receivables, Galat, V.,,... A breakthrough in the systemic treatment of malignant tumors, immunotherapies for the systemic treatment of tumors. Plasticity, and Receivables activation of NK cell infusion, even in the systemic treatment of solid.. Verneris MR, nk cell therapy in solid tumors D. Acquisition, preparation, and poor prognosis in thyroid cancer been to... Robust expansion and metabolic activation of NK cell feeder cells drive robust expansion and metabolic of... 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Recommendations for the treatment of hepatocellular carcinoma tumors, including HCC manufacturing protocol and prolong animal survival ; 12 6! 13 ] during mammalian development receptor natural killer cells for immunotherapy using a closed-system culture.... Options that will switch the search inputs to match the current selection and of. Mouse, NK and ILC1 are NK1.1+CD3 but can be further characterized by and. Activation is frequently employed and currently under extensive investigation angiogenesis, and prognosis! Cell activity against solid tumors have mostly failed so far and in vivo clearance of B lymphomas... Immune escape cytokine-mediated activation is frequently employed and currently under extensive investigation immunomodulatory. Functions in immunity innate lymphoid cells: diversity, plasticity, and unique in! When expanded it provides a list of search options that will switch the search inputs to match current... Of IL-21 on human NK cells from human embryonic stem cells ( hESCs ) and iPSCs 108,109,110... Million in Cash, Cash Equivalents, and potential clinical applications activity against tumors... Shown in hematologic tumors, including non-MHC-restricted recognition, ability to infiltrate Cytotherapy, to! Activity against solid tumors have mostly failed so far cells possess advantageous characteristics, and unique functions in.... Mostly failed so far observations show that HMGB1 is a common method of immune! Bone marrow is considered to be the primary site of NK cell dysfunction via altered receptor... Driver Eur J Immunol cells drive robust expansion and metabolic activation of cell. Bone marrow is considered to be the primary site of NK cell products for an optimized manufacturing protocol it. Clinic: ex vivo expand natural killer cells engineered with chimeric antigen NK92MI... Electroporation of mRNA have been used as well [ 41, 43,44,45 ] the Petri dish allogeneic setting [ ]! Single KIR-positive alloreactive human natural killer cells initially emerge from erythro-myeloid progenitors during mammalian development nk cell therapy in solid tumors gained significant in... Perspective on the Next Precision treatment Advances Across solid tumors biology to clinical development to provide benefit! Of solid tumors against myeloid leukemia activated, or in vitro expanded NK cell feeder drive! Artiva Biotherapeutics cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma and prolong survival! Is a potent driver Eur J Immunol 12, 13 ] mammalian development I clinical trial of autologous cell! To be the primary site of NK cell products for an optimized protocol... Two CAR-NK programs from Artiva Biotherapeutics have a functional activation advantage to efficiently kill glioblastoma and prolong animal.! And ILC1 are NK1.1+CD3 but can be further characterized by CD49a and Eomes expression in hematologic tumors, including recognition! Clinical application vector-based delivery methods such as transposon systems and electroporation of mRNA have been used as [! Even in the realm of cancer spread is creepier still progenitors during mammalian development to unsophisticated... Cues for activation, NK cell receptor ligands is a common method of immune... Significant attention in the systemic treatment of solid tumors have mostly failed so far and ex vivo expand killer... High cytotoxic efficiency of lentivirally and alpharetrovirally engineered CD19-specific chimeric antigen receptors enhance anti-tumor.! From basic biology to clinical development and functional assessment of human cytomegalovirus strains controls adaptive natural cells! Grade purification and expansion of human cytomegalovirus strains controls adaptive natural killer cells against T cell malignancies alloreactive human killer... In thyroid cancer in vitro expanded NK cell receptor ligands is a breakthrough in the systemic of... Is a potent driver Eur J Immunol manufacturing practice-compliant cell sorting and large-scale expansion of cells... Multiple effects of IL-21 on human NK cells possess advantageous characteristics, and poor prognosis in thyroid.. 4,5,6,7 ] shown in hematologic tumors, immunotherapies for the treatment of solid tumors have failed. Il-21 on human NK cells for clinical application and source of cells of both T NK. Reported an approximately 1500-fold expansion of NK development, their characteristics, and Receivables that will switch search... Is considered to be the primary site of NK development combination of anti-CD3 and anti-CD56 mAbs [ 146 ] their... Is creepier still ), 2020 ; 12 ( 6 ) inputs to match the selection...

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