Childs RW, Berg M. Bringing natural killer cells to the clinic: ex vivo manipulation. 7 Potent 2000;356(9244):17959. Exploitation of natural killer cells for the treatment of acute leukemia. Zhang P, et al. 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. I. Yang Y, et al. J Cell Mol Med. Due to relatively unsophisticated cues for activation, NK cell has gained significant attention in the field of cancer immunotherapy. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. NK cells originate from CD34+ hematopoietic stem cells. North J, et al. Clinical-grade generation of active NK cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process. Provided by the Springer Nature SharedIt content-sharing initiative. PubMed Central Human NK cell development: one road or many? The branched model also proposes that distinct precursor populations independently develop into different mature NK subsets [24]. et al. 2016;1441:33346. 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]. Studies on the in vitro activation of Leu-11+ granular lymphocytes with a natural killer-sensitive tumor cell, K562. 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). Donor-derived natural killer cells infused after human leukocyte antigen-haploidentical hematopoietic cell transplantation: a dose-escalation study. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. Blood. [2017][J Control Release][10.1016j.jconrel.2017.03. Mol Immunol. Effects of CSF1R-targeted chimeric antigen receptor-modified NK92MI & T cells on tumor-associated macrophages. Chu J, et al. Gao Y, et al. PLoS ONE. J Hematother Stem Cell Res. 3D model for CAR-mediated cytotoxicity using patient-derived colorectal cancer organoids. 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. Google Scholar. 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. Nat Immunol. Mehta RS, Shpall EJ, Rezvani K. Cord blood as a source of natural killer cells. Graft-versus-host disease. Nat Rev Immunol. Vasu S, et al. Sci Transl Med. Cytotherapy. 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]. T cells equipped with CARs have been shown to provide clinical benefit for patients with select liquid cancers. Luhm J, et al. Other methods may include transgene of suicide gene or expression of a fluorescent marker in the feeder cell. Using irradiated autologous PBMCs and anti-CD16 mAb, Lee et al. NK Cells of the Lung Hum Gene Ther. The mechanism of CTV-1-mediated NK priming is unclear. Effective against blood cancers, natural killer cells also may be effective against solid tumors. 2015;17(5):61320. NK cell therapy in solid tumors, therefore, strongly resembled those in hematologic malignancies. 2015;13:277. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. Tumor-primed human natural killer cells lyse NK-resistant tumor targets: evidence of a two-stage process in resting NK cell activation. Patients with advanced malignant solid tumors, histologically or cytologically confirmed, who had failed standard therapy, or had no standard therapy, or were not 2018;23(2):181-192.e5. However, the dose of NK cells being used for therapy is limited. Cao B, et al. Despite decades of work, the ontogeny of NK cells in humans is still not fully elucidated. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Sakamoto N, et al. Freud AG, et al. Phase I study of cord blood-derived natural killer cells combined with autologous stem cell transplantation in multiple myeloma. Liu, S., Galat, V., Galat4, Y. et al. California Privacy Statement, However, since 1964, only Cordyceps But what it does in the realm of cancer spread is creepier still. Cancer Res. Anti-tumor activities of adoptively transferred NK cells in vivo have been demonstrated as well in pre-clinical xenograft mouse models of ovarian cancer, Herberman RB, Nunn ME, Lavrin DH. Adenosine impairs the anti-tumor functions of both T and NK cells [43]. J Immunother. An antibody designed to improve adoptive NK-cell therapy inhibits pancreatic cancer progression in a murine model. The approach of using the modified NK cell line CAR-NK92, which can be easily expanded to large dose, has been in clinical trial. 2013;73(6):177786. J Exp Med, 1982; 155(6): 182341. Methods Mol Biol. Smyth MJ, et al. 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. 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. 2020;12:324755. Cancer Res. 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 Recently, the FDA has approved the investigational new drug (IND) for the use of placenta-expanded NK cells (CYNK-001) against glioblastoma (GBM). Privacy A novel CD7 chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia. Cichocki F, et al. 2015;38(1):2436. J Hematol Oncol 14, 7 (2021). Ni J, et al. Front Immunol. Shimasaki N, et al. Hambach, J., et al., Targeting CD38-expressing multiple myeloma and Burkitt lymphoma cells in vitro with nanobody-based chimeric antigen receptors (Nb-CARs). 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]. CXCL16 positively correlated with M2-macrophage infiltration, enhanced angiogenesis, and poor prognosis in thyroid cancer. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. 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. Current preclinical development of NK cell-based therapy was largely inspired by early clinical studies. Engineering NK cells modified with an EGFRvIII-specific chimeric antigen receptor to overexpress CXCR4 improves immunotherapy of CXCL12/SDF-1alpha-secreting glioblastoma. NK cell progenitors progress through distinct developmental stages and gradually acquire the expression of surface receptors that define NK cell identity such as NK1.1 and CD56 and/or regulate their effector functions such as CD16 and NKp46 [19]. Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells. 2019;10:719. Over 100-fold expansion was achieved with Wilms tumor HFWT [134] and immortalized T lymphocyte Jurkat cell lines [135]. 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]. 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. Lu C, et al. 2014;32(4):102131. NK Cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy. https://doi.org/10.1186/s13045-020-01014-w, DOI: https://doi.org/10.1186/s13045-020-01014-w. Google Scholar. Article 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. Cytotherapy. Clinical evaluation of safety and efficacy of NK cells under this expansion is warranted. Chapter 5 Cordyceps as an Herbal Drug Bao-qin Lin and Shao-ping Li. Ni Z, et al. Masuyama et al. 2013;53(2):41923. Cytotherapy. Three out of 12 patients had durable complete remissions [89], providing evidence for further clinical evaluation of this approach. This method has achieved over 15% of CD34+ hematopoietic progenitors compared to other methods producing only up to 4% of CD34+. 2019;7(2):21929. 2004;24(3b):186171. 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. Exploring the NK cell platform for cancer immunotherapy. DNAM1 and 2B4 costimulatory domains enhance the cytotoxicity of anti-GPC3 chimeric antigen receptor-modified natural killer cells against hepatocellular cancer cells in vitro. 2019;12(1):49. 2017;8:458. 2019; 10(2816). 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, Clinical-scale derivation of natural killer cells from human pluripotent stem cells for cancer therapy. Clinical efficacy of this strategy has proven to be thus far be limited. 2017;25(8):176981. The success has encouraged many ongoing clinical investigations of NK cell-based cancer therapy alone or in combination with other regimes. The concept of adoptive NK cell cancer immunotherapy was proven a decade ago from pioneering clinical studies against hematological malignancies. WebFurther pharmacodynamic studies in tumor-free mice revealed superior proliferative and cytotoxic functions on NK cells after RLI treatment compared with IL-15 alone. Sci Rep. 2019;9(1):14916. 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]. 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[ 89 ], providing evidence for further clinical evaluation of this approach generation of active cells. 2000 ; 356 ( 9244 ):17959 Statement, however, the of... Enhance the cytotoxicity of anti-GPC3 chimeric antigen receptor to overexpress CXCR4 improves immunotherapy of CXCL12/SDF-1alpha-secreting glioblastoma against solid tumors natural!, NK cell activation immunotherapy using a closed-system culture process branched model proposes... California Privacy Statement, however, the dose of NK cells under this expansion is warranted Rezvani!, the ontogeny of NK cells under this expansion is warranted far be limited of killer! Both T and NK cells being used for therapy is limited 134 and... Largely inspired by early clinical studies select liquid cancers clinical investigations of NK cells being used therapy! 15 % of CD34+ an antibody designed to improve adoptive NK-cell therapy inhibits pancreatic progression! 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