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Verma, Divya, Mukesh Verma, and Rangnath Mishra. "Stem Cell Therapy and Innate Lymphoid Cells." Stem Cells International 2022 (August 2, 2022): 1–12. http://dx.doi.org/10.1155/2022/3530520.
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Innate lymphoid cells have the capability to communicate with other immune cell types to coordinate the immune system functioning during homeostasis and inflammation. However, these cells behave differently at the functional level, unlike T cells, these cells do not need antigen receptors for activation because they are activated by the interaction of their receptor ligation. In hematopoietic stem cell transplantation (HSCT), T cells and NK cells have been extensively studied but very few studies are available on ILCs. In this review, an attempt has been made to provide current information related to NK and ILCs cell-based stem cell therapies and role of the stem cells in the regulation of ILCs as well. Also, the latest information on the differentiation of NK cells and ILCs from CD34+ hematopoietic stem cells is covered in the article.
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Wang, Hua, Bi-bo Fu, Robert Peter Gale, and Yang Liang. "NK-/T-cell lymphomas." Leukemia 35, no. 9 (June 11, 2021): 2460–68. http://dx.doi.org/10.1038/s41375-021-01313-2.
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AbstractNatural killer/T-cell lymphoma (NKTL) is a sub-type of Epstein–Barr virus (EBV)-related non-Hodgkin lymphomas common in Asia and Latin America but rare elsewhere. Its pathogenesis is complex and incompletely understood. Lymphoma cells are transformed from NK- or T-cells, sometimes both. EBV-infection and subsequent genetic alterations in infected cells are central to NKTL development. Hemophagocytic syndrome is a common complication. Accurate staging is important to predict outcomes but there is controversy which system is best. More than two-thirds of NKTL lympohmas are localized at diagnosis, are frequently treated with radiation therapy only and have 5-year survival of about 70 percent. Persons with advanced NKTLs receive radiation therapy synchronously or metachronously with diverse multi-drug chemotherapy typically including l-asparginase with 5-year survival of about 40 percent. Some persons with widespread NKTL receive chemotherapy only. There are few data on safety and efficacy of high-dose therapy and a haematopoietic cell autotransplant. Immune therapies, histone deacetylase (HDAC)-inhibitors and other drugs are in early clinical trials. There are few randomized controlled clinical trials in NKTLs and no therapy strategy is clearly best; more effective therapy(ies) are needed. Some consensus recommendations are not convincingly evidence-based. Mechanisms of multi-drug resistance are considered. We discuss these issues including recent advances in our understanding of and therapy of NKTLs.
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Lachota, Mieszko, Marianna Vincenti, Magdalena Winiarska, Kjetil Boye, Radosław Zagożdżon, and Karl-Johan Malmberg. "Prospects for NK Cell Therapy of Sarcoma." Cancers 12, no. 12 (December 11, 2020): 3719. http://dx.doi.org/10.3390/cancers12123719.
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Natural killer (NK) cells are innate lymphoid cells with potent antitumor activity. One of the most NK cell cytotoxicity-sensitive tumor types is sarcoma, an aggressive mesenchyme-derived neoplasm. While a combination of radical surgery and radio- and chemotherapy can successfully control local disease, patients with advanced sarcomas remain refractory to current treatment regimens, calling for novel therapeutic strategies. There is accumulating evidence for NK cell-mediated immunosurveillance of sarcoma cells during all stages of the disease, highlighting the potential of using NK cells as a therapeutic tool. However, sarcomas display multiple immunoevasion mechanisms that can suppress NK cell function leading to an uncontrolled tumor outgrowth. Here, we review the current evidence for NK cells’ role in immune surveillance of sarcoma during disease initiation, promotion, progression, and metastasis, as well as the molecular mechanisms behind sarcoma-mediated NK cell suppression. Further, we apply this basic understanding of NK–sarcoma crosstalk in order to identify and summarize the most promising candidates for NK cell-based sarcoma immunotherapy.
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Xiao, Jiani, Tianxiang Zhang, Fei Gao, Zhengwei Zhou, Guang Shu, Yizhou Zou, and Gang Yin. "Natural Killer Cells: A Promising Kit in the Adoptive Cell Therapy Toolbox." Cancers 14, no. 22 (November 17, 2022): 5657. http://dx.doi.org/10.3390/cancers14225657.
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As an important component of the innate immune system, natural killer (NK) cells have gained increasing attention in adoptive cell therapy for their safety and efficacious tumor-killing effect. Unlike T cells which rely on the interaction between TCRs and specific peptide-MHC complexes, NK cells are more prone to be served as “off-the-shelf” cell therapy products due to their rapid recognition and killing of tumor cells without MHC restriction. In recent years, constantly emerging sources of therapeutic NK cells have provided flexible options for cancer immunotherapy. Advanced genetic engineering techniques, especially chimeric antigen receptor (CAR) modification, have yielded exciting effectiveness in enhancing NK cell specificity and cytotoxicity, improving in vivo persistence, and overcoming immunosuppressive factors derived from tumors. In this review, we highlight current advances in NK-based adoptive cell therapy, including alternative sources of NK cells for adoptive infusion, various CAR modifications that confer different targeting specificity to NK cells, multiple genetic engineering strategies to enhance NK cell function, as well as the latest clinical research on adoptive NK cell therapy.
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Hurton, Lenka, R. Iram Siddik, Harjeet Singh, Simon Olivares, Brian Rabinovich, William Hildebrand, Dean Lee, et al. "Identifying NK-Cell Donors for Cell Therapy Based on Functional Phenotype." Blood 110, no. 11 (November 16, 2007): 3271. http://dx.doi.org/10.1182/blood.v110.11.3271.3271.
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Abstract Donor natural killer (NK) cells after haploidentical hematopoietic stem-cell transplantation (HSCT) and infusion of haploidentical NK-cells have demonstrated a therapeutic effect. NK alloreactivity resulting from appropriate Killer cell Ig-like receptor (KIR)-ligand disparity in human-leukocyte-antigen (HLA)-haplotype mismatched HSCT has resulted in improved engraftment and decreased incidence of leukemia relapse. Yet, not all patient-donor pairs benefit for an allogeneic NK-cell effect. To identify NK-cell donors with a suitable KIR-ligand mismatch, we have developed a functional assay to measure NK-cell killing through KIR-ligand interactions. NK-cell lysis of target cells is blocked by inhibitory KIR that recognize classical HLA class I allotypes and HLA mismatches of an altered allelic repertoire, as in haploidentical HSCT, leading to KIR-ligand mismatch and alloreactive NK cell-mediated target killing (Figure 1A). A cytotoxicity assay was developed based on the NK-cell target HLAnull 721.221 cells, and a panel of targets with enforced expression of HLA genes recognized by KIR. After the killing assay was optimized for high throughput and sensitivity, we used the panel of targets to determine whether bulk populations of donor NK cells could be predicted to kill based on KIR and HLA typing. The results demonstrate patterns of target-cell lysis for the KIR repertoires corresponding, for some donors, with predicted donor-versus-recipient NK-cell alloreactivity (Figure 1B). A relative inhibition of HLA+ target-cell lysis of >30% was associated with binding of KIR to introduced HLA class I molecules. The benefit of this assay to transplant physicians is a tool to actually measure phenotype (lysis), rather than relying on predictive models based on genotype. This assay will be combined with typing data to help identify donors with NK-cell killing function for recipients of haploidentical HSCT and infusion of haploidentical NK cells. Figure 1. (A) Schematic of alloreactivity generated between NK cells that are KIR-ligand mismatched with targets. (B) Observed lysis of 721.221 cells, with enforced expression of HLA class I, by KIR-typed donar(box). Figure 1. (A) Schematic of alloreactivity generated between NK cells that are KIR-ligand mismatched with targets. (B) Observed lysis of 721.221 cells, with enforced expression of HLA class I, by KIR-typed donar(box).
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Parameswaran, Reshmi, David N. Wald, Marcos De Lima, Dean A. Lee, and Stephen Moreton. "Novel Approach for NK Cell Therapy for Cancer." Blood 124, no. 21 (December 6, 2014): 3836. http://dx.doi.org/10.1182/blood.v124.21.3836.3836.
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Abstract Novel therapeutic approaches are urgently needed for many malignancies such as Acute Myeloid Leukemia (AML). We have developed a new therapeutic strategy based upon NK cell immunotherapy that exhibits high clinical potential based upon cell and animal studies. While the harnessing of NK cells for cellular therapy against malignancies has been a topic of interest for several decades, our approach overcomes a major hurdle of insufficient NK cell cytotoxic activity. We have identified that targeting the kinase GSK3 through pharmacologic and genetic approaches leads to the hyperactivation of human blood derived NK cells and a significant improvement in efficacy as compared to traditionally used activated NK cells or chemotherapy in our mouse AML model systems. Importantly this GSK3 inhibition can be achieved through a short ex-vivo incubation of NK cells with a GSK3 inhibitor paving the way for a rapid implementation into a clinical trial. Utilizing both in vitro studies with AML cell lines (ex. OCI-AML3 and HL-60)) and primary human AML cells we observe approximately a 50% increase in efficacy with GSK3 inhibited NK cells as compared to untreated NK cells. Further, we demonstrate significant efficacy of GSK3 inhibited NK cells in a mouse model of circulating human AML. After 4 weekly injections of human NK cells, there is a 50% greater reduction in human AML cells present in the mouse bone marrow with GSK3 inhibited NK cells as compared to vehicle treated NK cells. Besides efficacy studies, our work has led a model of how GSK3-inhibition enhances NK cell activity as depicted in figure 1. GSK3 inhibition leads to a dramatic increase in adhesion of NK cells to target cells as demonstrated by a flow cytometric adhesion assay (49% vs 83% after 20 min incubation) as well as live cell imaging. Consistent with the increased adhesion, GSK3 inhibited NK cells as well as target cells (after co-incubation) exhibit increased expression of essential NK cell-target adhesion molecules including L-selectin (on NK cells) and ICAM (on target cells). The induction of ICAM on target cells is due to a marked induction in TNFa production from the NK cells upon incubation with target cells (>7 fold increase in TNFa production). TNFa neutralization impairs the NK activity of the GSK3 inhibited NK cells (~30%) but not vehicle treated cells. Finally, GSK3 inhibition also leads to changes in the NK cells that enhance activity such as increased expression of granzyme and perforin and secretion of IFNg. Overall, our work has a revealed a novel strategy for NK cell therapy that holds high clinical potential. Figure 1. Model of how GSK3 inhibition leads to hyperactive NK cells. GSK3I - GSK3 inhibitor Figure 1. Model of how GSK3 inhibition leads to hyperactive NK cells. GSK3I - GSK3 inhibitor Disclosures No relevant conflicts of interest to declare.
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Liberatore, Concetta, Marusca Capanni, Nicola Albi, Isabella Volpi, Elena Urbani, Loredana Ruggeri, Amedea Mencarelli, Francesco Grignani, and Andrea Velardi. "Natural Killer Cell–mediated Lysis of Autologous Cells Modified by Gene Therapy." Journal of Experimental Medicine 189, no. 12 (June 21, 1999): 1855–62. http://dx.doi.org/10.1084/jem.189.12.1855.
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This study investigated the role of natural killer (NK) cells as effectors of an immune response against autologous cells modified by gene therapy. T lymphocytes were transduced with LXSN, a retroviral vector adopted for human gene therapy that carries the selectable marker gene neo, and the autologous NK response was evaluated. We found that (i) infection with LXSN makes cells susceptible to autologous NK cell–mediated lysis; (ii) expression of the neo gene is responsible for conferring susceptibility to lysis; (iii) lysis of neo-expressing cells is clonally distributed and mediated only by NK clones that exhibit human histocompatibility leukocyte antigen (HLA)-Bw4 specificity and bear KIR3DL1, a Bw4-specific NK inhibitory receptor; and (iv) the targets are cells from HLA-Bw4+ individuals. Finally, neo peptides anchoring to the Bw4 allele HLA-B27 interfered with KIR3DL1-mediated recognition of HLA-B27, i.e., they triggered NK lysis. Moreover, neo gene mutations preventing translation of two of the four potentially nonprotective peptides reduced KIR3DL1+ NK clone–mediated autologous lysis. Thus, individuals expressing Bw4 alleles possess an NK repertoire with the potential to eliminate autologous cells modified by gene therapy. By demonstrating that NK cells can selectively detect the expression of heterologous genes, these observations provide a general model of the NK cell–mediated control of viral infections.
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Valamehr, Bahram. "Advancing iPSC-derived NK cell therapy." Cell and Gene Therapy Insights 5, no. 12 (December 18, 2019): 1655–61. http://dx.doi.org/10.18609/cgti.2019.173.
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Mehta, Rohtesh S., Brion Randolph, May Daher, and Katayoun Rezvani. "NK cell therapy for hematologic malignancies." International Journal of Hematology 107, no. 3 (January 27, 2018): 262–70. http://dx.doi.org/10.1007/s12185-018-2407-5.
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Chu, Yaya, Margaret Lamb, Mitchell S. Cairo, and Dean A. Lee. "The Future of Natural Killer Cell Immunotherapy for B Cell Non-Hodgkin Lymphoma (B Cell NHL)." Current Treatment Options in Oncology 23, no. 3 (March 2022): 381–403. http://dx.doi.org/10.1007/s11864-021-00932-2.
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Opinion statementNatural killer (NK) cells have played a critical—if largely unrecognized or ignored—role in the treatment of B cell non-Hodgkin lymphoma (NHL) since the introduction of CD20-directed immunotherapy with rituximab as a cornerstone of therapy over 25 years ago. Engagement with NK cells leading to lysis of NHL targets through antibody-dependent cellular cytotoxicity (ADCC) is a critical component of rituximab’s mechanism of action. Despite this important role, the only aspect of B cell NHL therapy that has been adopted as standard therapy that even indirectly augments or restores NK cell function is the introduction of obinutuzumab, a CD20 antibody with enhanced ability to engage with NK cells. However, over the last 5 years, adoptive immunotherapy with effector lymphocytes of B cell NHL has experienced tremendous growth, with five different CAR T cell products now licensed by the FDA, four of which target CD19 and have approved indications for some subtype of B cell NHL—axicabtagene ciloleucel, brexucabtagene autoleucel, lisocabtagene maraleucel, and tisagenlecleucel. These T cell-based immunotherapies essentially mimic the recognition, activation pathway, and cytotoxic machinery of a CD19 antibody engaging NK cells and lymphoma targets. Despite their efficacy, these T cell-based immunotherapies have been difficult to implement because they require 4–6 weeks of manufacture, are costly, and have significant toxicities. This renewed interest in the potential of cellular immunity—and the manufacturing, supply chain, and administration logistics that have been addressed with these new agents—have ignited a new wave of enthusiasm for NK cell-directed therapies in NHL. With high safety profiles and proven anti-lymphoma efficacy, one or more new NK cell-directed modalities are certain to be introduced into the standard toolbox of NHL therapy within the next few years, be it function-enhancing cytokine muteins, multi-domain NK cell engagers, or adoptive therapy with expanded or genetically modified NK cells.
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Silang, Jiangcun, Zhenxian Cai, Ge Liu, and Baopeng Zhang. "Cell Surface Engineering to Improve Migration of Natural Killer Cells Toward Bladder Cancer." Journal of Biomaterials and Tissue Engineering 12, no. 11 (November 1, 2022): 2246–53. http://dx.doi.org/10.1166/jbt.2022.3180.
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Natural killer (NK) cells therapy for bladder cancer has shown a promise in clinical studies. However, insufficient of NK cells to the bladder cancer represents an important reason for the poor clinic trials against bladder cancer. How to improve the homing of infused NK cells is an important challenge. It is well known that chemokine receptor 3 which induces NK cells migration toward bladder cancer, expressed on NK cells. We hypothesized that CXCR3-modified NK cells could improving anti-tumor effect by enhancing homing of infused NK cells to the bladder cancer area. In this study, to provide a good mean to improve the homing of NK cells, we studied a surface modification method to incorporate CXCR3 on the surface of NK cells. In the results, this modification method shows a good biocompatibility for NK cells, and the results show that the migration of NK cells toward and against bladder cancer was enhanced. These preclinical findings suggest that CXCR3 modified NK cells may be a promising therapy for targeting bladder cancer and other tumors.
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Lance, Jennie Rachel, Max Yano, Xiaokui Mo, Dean Anthony Lee, Natarajan Muthusamy, and John C. Byrd. "IL-21-Expanded NK Cells As Autologous Cell Therapy for CLL." Blood 134, Supplement_1 (November 13, 2019): 4303. http://dx.doi.org/10.1182/blood-2019-131034.
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Introduction: While treatments for CLL have improved in recent years, CLL remains incurable for most patients who often rely on long-term suppressive medications. These can present complications associated with undesirable side effects and the risk of relapse. NK cell therapy holds great promise due to NK cells' powerful innate anti-tumor effects, with the potential to induce deep remission or even cure. However, previous efforts have been constrained by low cell numbers and limited cytotoxicity against CLL cells. Stimulating NK cells ex vivo with K562-based feeder cells expressing membrane-bound IL-21 (mbIL-21) induces high levels of expansion and activation, with potent cytotoxicity against various tumor cells (Denman et al. PLoS ONE 2012). We have recently demonstrated that allogeneic NKs from normal donors, expanded using mbIL-21, are potently cytotoxic to CLL cells (Yano et al. iwCLL 2019).Here, we test this technique with autologous NK cells. Autologous therapy will allow the benefits of administering activated NK cells without the risks of immunosuppression required for allogeneic treatment. Methods: We isolated NK cells from CLL patient blood and expanded them for 21 days using IL-21 expressing feeder cells and IL-2 (Denman et al. PLoS ONE 2012). We then characterized the cytotoxic capacity of the CLL-derived expanded NKs (CLL-XNKs) using calcein release assays. We measured both direct cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) against OSU-CLL and Mec1 CLL cell lines, allogeneic primary CLL cells, and autologous CLL cells. We compared CLL-XNK cells to unstimulated NK cells from normal donors and to normal donor-derived expanded NKs (ND-XNKs), produced using the same protocol. Results: During mbIL-21 NK stimulation, CLL-derived NK cells underwent an average of 5,900-fold expansion and maintained exponential growth throughout the 21-day expansion. This growth is similar to normal donor-derived NK cells (doubling time 1.6 days for CLL-derived vs. 1.5 days for donor-derived, p = 0.26, n=5). Cytotoxicity data comparing CLL-XNK cells versus ND-XNKs and unstimulated donor-derived NK cells is included in Table 1. We tested a range of effector:target ratios and found a dose response pattern of increasing cytotoxicity from 0.3125:1 to 10:1 ratios. Interestingly, while ADCC with either antibody was superior to direct cytotoxicity, obinutuzumab was not superior to rituximab for stimulating CLL-XNK cytotoxicity, differing from our experiences with ND-XNKs (Yano et al. iwCLL 2019). First, we demonstrate that CLL-XNK cells show potent cytotoxicity against both OSU-CLL and Mec1 CLL cell lines, via both direct cytotoxicity and ADCC (Table 1). These results show CLL-XNK cells to be similar or greater in potency in comparison to both ND-XNKs and normal unstimulated NKs. CLL-XNK cells also show cytotoxicity against allogeneic primary CLL cells, with greater cytotoxic activity than unstimulated, normal donor-derived NK cells (Table 1). Interestingly, while ADCC with obinutuzumab was similar between CLL-XNKs and ND-XNKs (p=.44), direct cytotoxicity and rituximab-induced cytotoxicity were both higher with CLL-XNKs than ND-XNKs (p=.0001 and .041) (Table 1). These results contrast with previous reports that LAKs derived from CLL patients have decreased potency (Foa et al. and Santiago-Schwarz et al. Blood 1990). Finally, CLL-XNKs showed potent cytotoxicity against autologous CLL cells using both direct cytotoxicity and ADCC (Table 1). Conclusion: We have successfully expanded NK cells from CLL patients and demonstrated their cytotoxicity against CLL cell lines, unmatched CLL cells, and autologous CLL cells. These patient-derived cells are superior to normal unstimulated NKs and are similar or even better than expanded donor NK cells. Ongoing studies will explore in vivo function of these NK cells, combination with CLL-targeted treatments, and further functional measures. IL-21-expanded NK cells represent a promising new therapy for CLL in both allogeneic and autologous settings. (*MY and JRL contributed equally to this work. MY is a recipient of a Pelotonia Graduate Fellowship and JRL is a recipient of a Hendrix Summer Scholars Fellowship. This work was supported by NIH R35 CA197734.) Disclosures Lee: Kiadis Pharma: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Muthusamy:Ohio State University: Patents & Royalties: OSU-2S. Byrd:Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Acerta: Research Funding; Genentech: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding.
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Velasquez, Mireya Paulina, Arpad Szoor, Challice L. Bonifant, Abishek Vaidya, Lorenzo Brunetti, Michael C. Gundry, Robin Parihar, Margaret Goodell, and Stephen Gottschalk. "Two-Pronged Cell Therapy for B-Cell Malignancies: Engineering NK Cells to Target CD22 and Redirect Bystander T Cells to CD19." Blood 128, no. 22 (December 2, 2016): 4560. http://dx.doi.org/10.1182/blood.v128.22.4560.4560.
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Abstract Background: T-cell therapy with CD19-CAR T cells has been very successful for the treatment of B-cell derived malignancies in humans. However, cytokine release syndrome, neurotoxicity, and development of CD19- escape variants have emerged as potential limitations. Developing CAR NK-cell based therapies might overcome some of these side effects since NK cells do not rapidly expand or persist long-term after adoptive transfer. However, CAR NK-cell therapies are less effective than CAR T-cell therapies in preclinical models. To overcome these limitations we have devised a strategy to genetically modify NK cells with CD22-CARs and CD19/CD3-bispecific T-cell engager (CD19-ENG) molecules. These NK cells should not only kill CD22+ B cells directly, but also redirect bystander T cells to malignant CD19+ B cells, enhancing antitumor effects and preventing immune escape. Methods: NK cells were generated using K562s expressing 41BBL and membrane bound IL15, and genetically modified with a retroviral vector encoding a CD22-CAR with a 41BB.ζ endodomain and/or a retroviral vector encoding CD19-ENG and mOrange separated by an IRES. To mimic immune escape, CD19 or CD22 knockout (ko) Ph+ leukemia cells (BV173) were generated by CRISPR/cas9. The effector function of genetically modified NK cells was evaluated using standard immunological assays. Results: After transduction 70-80% of NK cells expressed CD22-CARs, and ~50% expressed CD22-CARs and CD19-ENGs as judged by FACS analysis. We performed coculture and cytotoxicity assays using non-transduced (NT), CD22-CAR, CD19-ENG, and CD22-CAR/CD19-ENG NK cells as effectors and BV173 (CD19+/CD22+), BV173.koCD19, BV173.koCD22, Daudi (CD19+/CD22+), and KG1a (CD19-,CD22-) as targets. Cocultures were preformed +/- T cells and after 24 hours IFNγ and IL2 was determined by ELISA. In the absence of T cells, CD22-CAR and CD22-CAR/CD19-ENG NK cells only recognized CD22+ targets as judged by IFNγ production. Moreover, CD22-CAR/CD19-ENG and CD19-ENG NK cells efficiently redirected T cells to secrete IFNγ in the presence of CD19+/CD22- targets. No NK-cell population produced IL2, however CD22-CAR/CD19-ENG and CD19-ENG NK cells induced IL2 production of T cells in the presence of CD19+ targets. No significant cytokine production was observed in the absence of antigen (media, KG1a). Specificity of generated NK cells was confirmed in cytotoxicity assays. In vivo studies to confirm our in vitro findings are in progress. Conclusions: We have generated for the first time NK cells that kill B-cell malignancies through a CAR (CD22) and simultaneously redirect bystander T cells to a 2nd B-cell antigen (CD19) to enhance antitumor effects and prevent immune escape. Genetic modification of NK cells to enhance their antitumor activity and redirect bystander T cells may present a promising addition to current cell therapies for B-cell malignancies. Disclosures No relevant conflicts of interest to declare.
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Oh, Sooyeon, Joo-Ho Lee, KyuBum Kwack, and Sang-Woon Choi. "Natural Killer Cell Therapy: A New Treatment Paradigm for Solid Tumors." Cancers 11, no. 10 (October 11, 2019): 1534. http://dx.doi.org/10.3390/cancers11101534.
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In treatments of solid tumors, adoptive transfer of ex vivo expanded natural killer (NK) cells has dawned as a new paradigm. Compared with cytotoxic T lymphocytes, NK cells take a unique position targeting tumor cells that evade the host immune surveillance by down-regulating self-antigen presentation. Recent findings highlighted that NK cells can even target cancer stem cells. The efficacy of allogeneic NK cells has been widely investigated in the treatment of hematologic malignancies. In solid tumors, both autologous and allogeneic NK cells have demonstrated potential efficacy. In allogeneic NK cell therapy, the mismatch between the killer cell immunoglobulin-like receptor (KIR) and human leukocyte antigen (HLA) can be harnessed to increase the antitumor activity. However, the allogeneic NK cells cause more adverse events and can be rejected by the host immune system after repeated injections. In this regard, the autologous NK cell therapy is safer. This article reviews the published results of clinical trials and discusses strategies to enhance the efficacy of the NK cell therapy. The difference in immunophenotype of the ex vivo expanded NK cells resulted from different culture methods may affect the final efficacy. Furthermore, currently available standard anticancer therapy, molecularly targeted agents, and checkpoint inhibitors may directly or indirectly enhance the efficacy of NK cell therapy. A recent study discovered that NK cell specific genetic defects are closely associated with the tumor immune microenvironment that determines clinical outcomes. This finding warrants future investigations to find the implication of NK cell specific genetic defects in cancer development and treatment, and NK cell deficiency syndrome should be revisited to enhance our understanding. Overall, it is clear that NK cell therapy is safe and promises a new paradigm for the treatment of solid tumors.
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Stoltzman, Carrie, Devikha Chandrasekaran, Erika von Euw, Cyd McKay, Christina Root, and Colleen Delaney. "Abstract 2 Development of CAR-NK Cell Therapy for Hematologic Malignancies." Stem Cells Translational Medicine 11, Supplement_1 (September 1, 2022): S4. http://dx.doi.org/10.1093/stcltm/szac057.002.
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Abstract Introduction Natural killer (NK) cells can kill tumor cells without priming or prior activation through their complement of activating and inhibitory surface molecules. Chimeric antigen receptor (CAR) expression by engineered NK cells can improve both specificity and potency of the NK cells’ anti-tumor efficacy. CAR-NK cell therapy may be a safer, more clinically accessible, and cost effective allogeneic cellular therapy in comparison to autologous CAR-T cell therapy, as NK cells do not cause graft versus host disease (GvHD) or cytokine release syndrome (CRS). Objective We aimed to develop an allogeneic, cryopreserved, off-the-shelf CAR-NK cell product for the treatment of hematologic malignancies. Methods Our CD56+ NK cells are generated from cord blood-derived CD34+ cells, which undergo expansion and priming on a proprietary Notch ligand cell culture platform followed by a second culture phase of NK cell differentiation. These cells were transduced using a viral vector to express a CAR specific for an antigen expressed on the cell surface of acute lymphoblastic leukemia (ALL) cells. The CAR-NK cells were assessed for CAR expression, NK cell phenotype, and in vitro cytotoxicity both pre- and post-cryopreservation. An ALL xenograft mouse model was treated using repeat doses of cryopreserved CAR-NK cell product, with readouts of body weight, tumor growth, and survival. Results The transduced CAR-NK cell product displayed viability and phenotyping comparable to the untransduced control NK cell product but possessed significantly enhanced cytotoxicity against ALL target cells in vitro. Following cryopreservation and thaw, the CAR-NK cell product retained CAR expression and maintained enhanced anti-tumor function in vitro. Cryopreserved CAR-NK cell product was safely given in up to 8 repeat doses to ALL xenograft mice and significantly inhibited tumor growth as well as increased survival compared with control NK cell product. Discussion We have demonstrated in this proof-of-concept study that our cord blood CD34+ cell-derived CAR-NK cell product can maintain CAR expression, with specific and enhanced potency both in vitro and in vivo, following cryopreservation and thaw. Additional preclinical studies are planned to develop CAR-NK off-the-shelf cell therapy for AML and other hematologic malignancies.
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Lopez, Rebecca, Andreas Lundqvist, Stephanie Sellers, Maria Berg, Muthalagu Ramanathan, Sumithira Vasu, Aleah Smith, Cynthia E. Dunbar, and Richard W. Childs. "A Rhesus Macaque Model to Optimize Adoptive NK Cell Therapy." Blood 112, no. 11 (November 16, 2008): 3905. http://dx.doi.org/10.1182/blood.v112.11.3905.3905.
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Abstract NK cell based immunotherapy represents a promising treatment approach for patients with cancer. Although preliminary clinical trials in humans suggest NK cell infusions can mediate anti-tumor effects, animal models are needed to provide insight into methods to enhance both the function and in vivo longevity of adoptively infused NK cells. Research conducted in our laboratory has shown that ex vivo expanded human NK cells are highly activated, up-regulating NKG2D, Granzyme B, TRAIL and Fas-ligand expression making them much more cytotoxic to tumor cells compared to freshly isolated NK cells. However, important questions remain regarding whether in vitro expansion alters the capacity of these cells to replicate, and traffic to tissues in vivo following their adoptive infusion into recipients. Differences in the genotype and phenotype of mouse NK cells compared to human NK cells limit the value of murine animal models to address these questions. In contrast to mice, Rhesus macaques have orthologues to most of the human MHC class I and II genes and possess NK cells expressing KIRs that are phenotypically and functionally similar to human NK cells, thus providing an excellent model system for evaluating questions related to adoptive NK cell therapy. We developed an in vitro method to expand macaque NK cells to characterize their in vivo longevity and tissue trafficking following adoptive infusion. Macaque NK cells were enriched from peripheral blood mononuclear cells by depleting CD3+ cells using immunomagnetic beads and were then expanded in vitro with autologous plasma and a human EBV-LCL feeder cell line using culture conditions identical to those used to expand NK cells from humans. NK cell cultures expanded 50- to 100-fold over 7 to 20 days, were greater than 99% CD3 negative, and had a similar phenotype to human NK cells including a large proportion of CD16/CD56 double positive cells, and ubiquitous expression of NKG2D, KIR2D, LFA-1, granzyme B, and CXCR3. In contrast to mice but analogous to human NK cells, macaque expanded NK cells upregulated surface expression of TRAIL and were highly cytotoxic to K562 cells and other human tumor lines (Figure). CFSE labelling of expanded NK cells did not alter their phenotype or tumor cytotoxic function. Data characterizing the longevity, proliferative capacity, and tissue trafficking patterns in the blood, bone marrow and lymph node of in vitro expanded and adoptively infused CFSE labeled NK cells (up to 1 × 108 NK Cells/kg i.v.) in macaque recipients will be presented from this analysis. Figure Figure
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Alderson, Kory L., and Paul M. Sondel. "Clinical Cancer Therapy by NK Cells via Antibody-Dependent Cell-Mediated Cytotoxicity." Journal of Biomedicine and Biotechnology 2011 (2011): 1–7. http://dx.doi.org/10.1155/2011/379123.
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Natural killer (NK) cells are powerful effector cells that can be directed to eliminate tumor cells through tumor-targeted monoclonal antibodies (mAbs). Some tumor-targeted mAbs have been successfully applied in the clinic and are included in the standard of care for certain malignancies. Strategies to augment the antitumor response by NK cells have led to an increased understanding of how to improve their effector responses. Next-generation reagents, such as molecularly modified mAbs and mAb-cytokine fusion proteins (immunocytokines, ICs) designed to augment NK-mediated killing, are showing promise in preclinical and some clinical settings. Continued research into the antitumor effects induced by NK cells and tumor-targeted mAbs suggests that additional intrinsic and extrinsic factors may influence the antitumor response. Therefore more research is needed that focuses on evaluating which NK cell and tumor criteria are best predictive of a clinical response and which combination immunotherapy regimens to pursue for distinct clinical settings.
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King, Cecile. "CAR NK Cell Therapy for T Follicular Helper Cells." Cell Reports Medicine 1, no. 1 (April 2020): 100009. http://dx.doi.org/10.1016/j.xcrm.2020.100009.
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Zambello, Renato, Gregorio Barilà, Sabrina Manni, Francesco Piazza, and Gianpietro Semenzato. "NK cells and CD38: Implication for (Immuno)Therapy in Plasma Cell Dyscrasias." Cells 9, no. 3 (March 21, 2020): 768. http://dx.doi.org/10.3390/cells9030768.
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Immunotherapy represents a promising new avenue for the treatment of multiple myeloma (MM) patients, particularly with the availability of Monoclonal Antibodies (mAbs) as anti-CD38 Daratumumab and Isatuximab and anti-SLAM-F7 Elotuzumab. Although a clear NK activation has been demonstrated for Elotuzumab, the effect of anti-CD38 mAbs on NK system is controversial. As a matter of fact, an initial reduction of NK cells number characterizes Daratumumab therapy, limiting the potential role of this subset on myeloma immunotherapy. In this paper we discuss the role of NK cells along with anti-CD38 therapy and their implication in plasma cell dyscrasias, showing that mechanisms triggered by anti-CD38 mAbs ultimately lead to the activation of the immune system against myeloma cell growth.
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Alvarez, Maite, and William Murphy. "Combination of IL-2 and anti-TGF-β increases natural killer cell reconstitution after hematopoietic stem cell transplantation (169.7)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 169.7. http://dx.doi.org/10.4049/jimmunol.186.supp.169.7.
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Abstract Despite the efficacy of hematopoietic stem cell transplantation (HSCT) as a cancer therapy, cancer relapse remains a significant complication. Natural killer (NK) cells are the first lymphoid population to recover after HSCT and can kill transformed or virally-infected cells without prior sensitization. Therefore, accelerating NK cell reconstitution may improve HSCT therapy. We utilized the combination of administering the stimulatory cytokine, IL-2 concurrently with the blockade of the immunosuppressive cytokine, transforming growth factor-beta (TGF-β) as a possible therapy to accelerate NK cell reconstitution after syngeneic HSCT. Resting C57BL/6 mice were treated with daily doses of IL-2 (2x105 IU) and anti-TGF-β (120ug, clone 1D11) every other day for one week. Although combinatorial therapy did not significantly expand NK cell numbers in comparison with IL-2 monotherapy, NK cytotoxicity, as measured by the ability to lyse Yac-1 tumor cells, was significantly greater. However in a HSCT model, combinatorial therapy administered in C57BL/6 mice starting at day 11 post-HSCT did significantly increase both the percentage of activated NK cells and NK tumor lytic ability compared with IL-2 alone. Additionally, mice showed no outward evidence of toxicity during administration of therapy. Together, these results suggest that this combination regimen improves reconstitution of NK cells after HSCT which may lead to better anti-viral and anti-tumor responses.
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Du, Nawen, Feifei Guo, Yufeng Wang, and Jiuwei Cui. "NK Cell Therapy: A Rising Star in Cancer Treatment." Cancers 13, no. 16 (August 17, 2021): 4129. http://dx.doi.org/10.3390/cancers13164129.
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Immunotherapy has become a robust and routine treatment strategy for patients with cancer; however, there are efficacy and safety issues that should be resolved. Natural killer (NK) cells are important innate immune cells that have attracted increasing attention owing to their major histocompatibility complex-independent immunosurveillance ability. These cells provide the first-line defense against carcinogenesis and are closely related to cancer development. However, NK cells are functionally suppressed owing to multiple immunosuppressive factors in the tumor microenvironment; thus, releasing the suppressed state of NK cells is an emergent project and a promising solution for immunotherapy. As a result, many clinical trials of NK cell therapy alone or in combination with other agents are currently underway. This review describes the current status of NK cell therapy for cancer treatment based on the effector function and releasing the inhibited state of NK cells in the cancer microenvironment.
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Yang, Yuanzheng, Nancy Gordon, Eugenie S. Kleinerman, and Gangxiong Huang. "Promoting NK cell trafficking to improve therapeutic effect of NK cell therapy on osteosarcoma." Journal for ImmunoTherapy of Cancer 3, Suppl 2 (2015): P24. http://dx.doi.org/10.1186/2051-1426-3-s2-p24.
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Shih, Alvin. "Realizing the potential of NK cell therapy." Immuno Oncology Insights 03, no. 01 (January 26, 2022): 1–5. http://dx.doi.org/10.18609/ioi.2022.001.
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Miller, J. S. "NK cell therapy in cancer and transplantation." ISBT Science Series 7, no. 1 (June 13, 2012): 157–59. http://dx.doi.org/10.1111/j.1751-2824.2012.01570.x.
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Suzuki, Ritsuro. "NK/T Cell Lymphoma: Updates in Therapy." Current Hematologic Malignancy Reports 13, no. 1 (January 24, 2018): 7–12. http://dx.doi.org/10.1007/s11899-018-0430-5.
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Abakushina, Elena V., Liubov I. Popova, Andrey A. Zamyatnin, Jens Werner, Nikolay V. Mikhailovsky, and Alexandr V. Bazhin. "The Advantages and Challenges of Anticancer Dendritic Cell Vaccines and NK Cells in Adoptive Cell Immunotherapy." Vaccines 9, no. 11 (November 19, 2021): 1363. http://dx.doi.org/10.3390/vaccines9111363.
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In the last decade, an impressive advance was achieved in adoptive cell therapy (ACT), which has improved therapeutic potential and significant value in promising cancer treatment for patients. The ACT is based on the cell transfer of dendritic cells (DCs) and/or immune effector cells. DCs are often used as vaccine carriers or antigen-presenting cells (APCs) to prime naive T cells ex vivo or in vivo. Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells are used as major tool effector cells for ACT. Despite the fact that NK cell immunotherapy is highly effective and promising against many cancer types, there are still some limitations, including insignificant infiltration, adverse conditions of the microenvironment, the immunosuppressive cellular populations, and the low cytotoxic activity in solid tumors. To overcome these difficulties, novel methods of NK cell isolation, expansion, and stimulation of cytotoxic activity should be designed. In this review, we discuss the basic characteristics of DC vaccines and NK cells as potential adoptive cell preparations in cancer therapy.
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Sordo-Bahamonde, Christian, Massimo Vitale, Seila Lorenzo-Herrero, Alejandro López-Soto, and Segundo Gonzalez. "Mechanisms of Resistance to NK Cell Immunotherapy." Cancers 12, no. 4 (April 7, 2020): 893. http://dx.doi.org/10.3390/cancers12040893.
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Immunotherapy has recently been a major breakthrough in cancer treatment. Natural killer (NK) cells are suitable targets for immunotherapy owing to their potent cytotoxic activity that may target cancer cells in a major histocompatibility complex (MHC) and antigen-unrestricted manner. Current therapies targeting NK cells include monoclonal antibodies that promote NK cell antibody-dependent cell-mediated cytotoxicity (ADCC), hematopoietic stem cell transplantation (HSCT), the adoptive transfer of NK cells, the redirection of NK cells using chimeric antigen receptor (CAR)-NK cells and the use of cytokines and immunostimulatory drugs to boost the anti-tumor activity of NK cells. Despite some encouraging clinical results, patients receiving these therapies frequently develop resistance, and a myriad of mechanisms of resistance affecting both the immune system and cancer cells have been reported. A first contributing factor that modulates the efficacy of the NK cell therapy is the genetic profile of the individual, which regulates all aspects of NK cell biology. Additionally, the resistance of cancer cells to apoptosis and the immunoediting of cancer cells, a process that decreases their immunogenicity and promotes immunosuppression, are major determinants of the resistance to NK cell therapy. Consequently, the efficacy of NK cell anti-tumor therapy is specific to each patient and disease. The elucidation of such immunosubversive mechanisms is crucial to developing new procedures and therapeutic strategies to fully harness the anti-tumor potential of NK cells.
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Yano, Max, Jennie Rachel Lance, Xiaokui Mo, Dean Anthony Lee, Natarajan Muthusamy, and John C. Byrd. "IL-21-Expanded Natural Killer Cells As Autologous Cell Therapy for CLL." Blood 134, Supplement_1 (November 13, 2019): 4302. http://dx.doi.org/10.1182/blood-2019-127620.
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Introduction: While treatments for CLL have improved in recent years, CLL remains incurable for most patients who often rely on long-term suppressive medications. These can present complications associated with undesirable side effects and the risk of relapse. NK cell therapy holds great promise due to NK cells' powerful innate anti-tumor effects, with the potential to induce deep remission or even cure. However, previous efforts have been constrained by low cell numbers and limited cytotoxicity against CLL cells. Stimulating NK cells ex vivo with K562-based feeder cells expressing membrane-bound IL-21 (mbIL-21) induces high levels of expansion and activation, with potent cytotoxicity against various tumor cells (Denman et al. PLoS ONE 2012). We have recently demonstrated that allogeneic NKs from normal donors, expanded using mbIL-21, are potently cytotoxic to CLL cells (Yano et al. iwCLL 2019). Here, we test this technique with autologous NK cells. Autologous therapy will allow the benefits of administering activated NK cells without the risks of immunosuppression required for allogeneic treatment. Methods: We isolated NK cells from CLL patient blood and expanded them for 21 days using IL-21 expressing feeder cells and IL-2 (Denman et al. PLoS ONE 2012). We then characterized the cytotoxic capacity of the CLL-derived expanded NKs (CLL-XNKs) using calcein release assays. We measured both direct cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) against OSU-CLL and Mec1 CLL cell lines, allogeneic primary CLL cells, and autologous CLL cells. We compared CLL-XNK cells to unstimulated NK cells from normal donors and to normal donor-derived expanded NKs (ND-XNKs), produced using the same protocol. Results: During mbIL-21 NK stimulation, CLL-derived NK cells underwent an average of 5,900-fold expansion and maintained exponential growth throughout the 21-day expansion. This growth is similar to normal donor-derived NK cells (doubling time 1.6 days for CLL-derived vs. 1.5 days for donor-derived, p = 0.26, n=5). Cytotoxicity data comparing CLL-XNK cells versus ND-XNKs and unstimulated donor-derived NK cells is included in Table 1. We tested a range of effector:target ratios and found a dose response pattern of increasing cytotoxicity from 0.3125:1 to 10:1 ratios. Interestingly, while ADCC with either antibody was superior to direct cytotoxicity, obinutuzumab was not superior to rituximab for stimulating CLL-XNK cytotoxicity, differing from our experiences with ND-XNKs (Yano et al. iwCLL 2019). First, we demonstrate that CLL-XNK cells show potent cytotoxicity against both OSU-CLL and Mec1 CLL cell lines, via both direct cytotoxicity and ADCC (Table 1). These results show CLL-XNK cells to be similar or greater in potency in comparison to both ND-XNKs and normal unstimulated NKs. CLL-XNK cells also show cytotoxicity against allogeneic primary CLL cells, with greater cytotoxic activity than unstimulated, normal donor-derived NK cells (Table 1). Interestingly, while ADCC with obinutuzumab was similar between CLL-XNKs and ND-XNKs (p=.44), direct cytotoxicity and rituximab-induced cytotoxicity were both higher with CLL-XNKs than ND-XNKs (p=.0001 and .041) (Table 1). These results contrast with previous reports that LAKs derived from CLL patients have decreased potency (Foa et al. and Santiago-Schwarz et al. Blood 1990). Finally, CLL-XNKs showed potent cytotoxicity against autologous CLL cells using both direct cytotoxicity and ADCC (Table 1). Conclusion: We have successfully expanded NK cells from CLL patients and demonstrated their cytotoxicity against CLL cell lines, unmatched CLL cells, and autologous CLL cells. These patient-derived cells are superior to normal unstimulated NKs and are similar or even better than expanded donor NK cells. Ongoing studies will explore in vivo function of these NK cells, combination with CLL-targeted treatments, and further functional measures. IL-21-expanded NK cells represent a promising new therapy for CLL in both allogeneic and autologous settings. (*MY and JRL contributed equally to this work. MY is a recipient of a Pelotonia Graduate Fellowship and JRL is a recipient of a Hendrix Summer Scholars Fellowship. This work was supported by NIH R35 CA197734.) Disclosures Lee: Kiadis Pharma: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Muthusamy:Ohio State University: Patents & Royalties: OSU-2S. Byrd:Novartis: Other: Travel Expenses, Speakers Bureau; BeiGene: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Acerta: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau.
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Greer, John P. "Therapy of Peripheral T/NK Neoplasms." Hematology 2006, no. 1 (January 1, 2006): 331–37. http://dx.doi.org/10.1182/asheducation-2006.1.331.
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AbstractThe mature T/natural killer (NK) lymphoma/leukemias represent 5–15% of all non-Hodgkin lymphoma. These diseases have a geographic variation, with more nodal disease in North America and Europe, including peripheral T cell lymphomas, unspecified, anaplastic large cell lymphoma, and angioimmunoblastic T cell lymphoma; and more extranodal disease in Asia due to Epstein-Barr virus–related nasal NK/T lymphoma and human T-cell leukemia virus (HTLV)-1–associated adult T cell leukemia/lymphoma. The prognosis in most peripheral T/NK neoplasms is poor, with 5-year survival less than 30%. Progress has been slow due to the rarity of the diseases, geographic variation, relative chemoresistance, and lack of randomized trials. There is no consensus about optimal therapy in T/NK neoplasms, and recommendations are based on anecdotal reports, small series, and phase II trials. In this review, topics include the question of CHOP as standard therapy, prognostic factors, disease-adapted therapy, novel approaches, monoclonal antibody therapy, and stem cell transplantation.
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Barrow, Alexander, and Marco Colonna. "Exploiting NK Cell Surveillance Pathways for Cancer Therapy." Cancers 11, no. 1 (January 8, 2019): 55. http://dx.doi.org/10.3390/cancers11010055.
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Natural killer (NK) cells can evoke potent anti-tumour activity. This function is largely mediated through a battery of specialised cell-surface receptors which probe the tissue microenvironment for changes in surface and secretory phenotypes that may alert to the presence of infection or malignancy. These receptors have the potential to arouse the robust cytotoxic and cytokine-secreting functions of NK cells and so must be tightly regulated to prevent autoimmunity. However, such functions also hold great promise for clinical intervention. In this review, we highlight some of the latest breakthroughs in fundamental NK cell receptor biology that have illuminated our understanding of the molecular strategies NK cells employ to perceive malignant cells from normal healthy cells. Moreover, we highlight how these sophisticated tumour recognition strategies are being harnessed for cancer immunotherapies in the clinic.
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Yang, Chaopin, Yue Li, Yaozhang Yang, and Zhiyi Chen. "Overview of Strategies to Improve Therapy against Tumors Using Natural Killer Cell." Journal of Immunology Research 2020 (January 21, 2020): 1–16. http://dx.doi.org/10.1155/2020/8459496.
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NK cells are lymphocytes with antitumor properties and can directly lyse tumor cells in a non-MHC-restricted manner. However, the tumor microenvironment affects the immune function of NK cells, which leads to immune evasion. This may be related to the pathogenesis of some diseases. Therefore, great efforts have been made to improve the immunotherapy effect of natural killer cells. NK cells from different sources can meet different clinical needs, in order to minimize the inhibition of NK cells and maximize the response potential of NK cells, for example, modification of NK cells can increase the number of NK cells in tumor target area, change the direction of NK cells, and improve their targeting ability to malignant cells. Checkpoint blocking is also a promising strategy for NK cells to kill tumor cells. Combination therapy is another strategy for improving antitumor ability, especially in combination with oncolytic viruses and nanomaterials. In this paper, the mechanisms affecting the activity of NK cells were reviewed, and the therapeutic potential of different basic NK cell strategies in tumor therapy was focused on. The main strategies for improving the immune function of NK cells were described, and some new strategies were proposed.
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Wolf, Natalie K., Chris Nicolai, Susanna Dang, Gail Synder, Cristina Blaj, Sarah McWhirter, Lora Picton, K. Christopher Garcia, and David H. Raulet. "Combination therapy to enhance NK cell anti-tumor responses." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 88.10. http://dx.doi.org/10.4049/jimmunol.204.supp.88.10.
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Abstract Current cancer immunotherapies are targeted at mobilizing CD8 T cells, although numerous tumors have few or no antigens for CD8 T cells, or have lost MHC I, thereby evading CD8 T cells. There is therefore a need for improved therapies that mobilize other immune cells, such as NK cells, to the tumor microenvironment. A recent therapy candidate, cyclic dinucleotide (CDN), activates the cGAS-STING pathway of the innate immune system. Intratumoral CDN injections induce type I IFNs and other mediators that amplify the CD8 T cell response and induce regressions of primary tumors. MHC I-deficient tumors are not susceptible to CD8 T cell-mediated rejection, but data from our lab demonstrates that STING activation still leads to long-term tumor regressions, mediated by NK cells and in some cases CD4 T cells, in 30–100% of animals in 5/6 transplant models tested. In order to improve upon CDN monotherapy, we are testing combinations of CDN therapy with other therapies to target and activate NK cells in the tumor microenvironment and prevent or delay the onset of desensitization. Our results show that engineered IL-2 family cytokines synergize with CDN therapy to mobilize anti-tumor responses by NK cells and in some cases CD4 T cells. These anti-tumor responses are due to increased recruitment of NK cells to the tumor and sustained activation of these recruited NK cells. Our combination therapy regimen shows enhanced systemic effects, both in vivo in abscopal tumor models, and ex vivo by cytolysis of target cells mediated by splenocytes. Overall, our work demonstrates the impact of a novel combination therapy in mobilizing powerful NK cell-mediated anti-tumor activity, providing evidence for the potential of NK cell-targeted immunotherapeutics for cancer.
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Liu, Sizhe, Payal Dhar, and Jennifer D. Wu. "NK Cell Plasticity in Cancer." Journal of Clinical Medicine 8, no. 9 (September 19, 2019): 1492. http://dx.doi.org/10.3390/jcm8091492.
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Natural killer (NK) cells are critical immune components in controlling tumor growth and dissemination. Given their innate capacity to eliminate tumor cells without prior sensitization, NK-based therapies for cancer are actively pursued pre-clinically and clinically. However, recent data suggest that tumors could induce functional alterations in NK cells, polarizing them to tumor-promoting phenotypes. The potential functional plasticity of NK cells in the context of tumors could lead to undesirable outcomes of NK-cell based therapies. In this review, we will summarize to-date evidence of tumor-associated NK cell plasticity and provide our insights for future investigations and therapy development.
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Naranjo-Gomez, Mar, Marine Cahen, Jennifer Lambour, Myriam Boyer-Clavel, and Mireia Pelegrin. "Immunomodulatory Role of NK Cells during Antiviral Antibody Therapy." Vaccines 9, no. 2 (February 8, 2021): 137. http://dx.doi.org/10.3390/vaccines9020137.
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Monoclonal antibodies (mAbs) are now considered as a therapeutic approach to prevent and treat severe viral infections. Using a mouse retroviral model, we showed that mAbs induce protective immunity (vaccinal effects). Here, we investigated the role of natural killer (NK) cells on this effect. NK cells are effector cells that are crucial to control viral propagation upon mAb treatment. However, their immunomodulatory activity during antiviral mAb immunotherapies has been little studied. Our data reveal that the mAb treatment of infected mice preserves the functional activation of NK cells. Importantly, functional NK cells play an essential role in preventing immune dysfunction and inducing antiviral protective immunity upon mAb therapy. Thus, NK cell depletion in mAb-treated, viral-infected mice leads to the upregulation of molecules involved in immunosuppressive pathways (i.e., PD-1, PD-L1 and CD39) on dendritic cells and T cells. NK cell depletion also abrogates the vaccinal effects induced by mAb therapy. Our data also reveal a role for IFNγ-producing NK cells in the enhancement of the B-cell responses through the potentiation of the B-cell helper properties of neutrophils. These findings suggest that preserved NK cell functions and counts might be required for achieving mAb-induced protective immunity. They open new prospects for improving antiviral immunotherapies.
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Klingemann, Hans-Georg, Carrie Grodman, Andreas K. Klein, Kellie Sprague, Kenneth B. Miller, Tarun Kewalramani, Raymond L. Comenzo, et al. "Allogeneic NK Cell Therapy After Autologous Stem Cell Transplant: Results of a Phase I Study." Blood 116, no. 21 (November 19, 2010): 4299. http://dx.doi.org/10.1182/blood.v116.21.4299.4299.
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Abstract Abstract 4299 Previous reports have shown that infusion of NK cells from a MHC mismatched donor can mediate an anti-leukemic effect in the recipient of an allogeneic hematopoietic stem cell transplant (HSCT). In this phase I study, we infused increasing numbers of allogeneic NK-cell enriched mononuclear cells (NK-MNC) from a MHC haplo-mismatched relative into patients who had recently undergone autologous stem cell transplant. We sought to determine whether infusion of mismatched, allogeneic NK-MNC cells was safe without concern for GvHD or graft rejection, and also whether cell collection, processing and patient treatment could feasibly be performed at different cities across the US. MNC were obtained by apheresis from healthy haploidentical relatives by one steady-state leukapheresis of 2–4 hours on day 1, and were sent by air courier to the PACT* cell processing facility (University of Minnesota) where immunomagnetic depletion of CD3 cells (Miltenyi CliniMACS) was performed. The CD3-depleted cells were then cultured in X-VIVO 15, without gentamicin and phenol red (Cambrex BioScience, Walkersville, Maryland), supplemented with 1000 U/mL IL-2 (Chiron Corporation, Emeryville, CA) and 10% human heat-inactivated AB serum (Valley Biomedical Products and Services, Inc., Winchester, VA) in VueLife™Teflon® (FEP) bags (American Fluoroseal Corporation, Gaithersburg, MD). The resulting NK-MNC products were then returned by air courier at approximately body temperature to Boston for infusion on day 3. Twelve patients (age range: 27–63) within 49–191 days (median 106 days) after autologous HSCT were treated at four different dose levels of NK-MNC: 105, 106, 107 and 2×107 NK-MNC/kg. No logistical transport issues between Boston and the processing facility in Minnesota occurred. Release criteria (< 5 × 105 CD3+ cells/kg, > 20% CD3-/CD56+ cells, viability >70%, Gram stain – no organisms) were met in all but one case. Side effects after infusion occurred only at the higher dose level of NK-MNC infusion: rigors (n=2) and muscle aches (n=1), responsive to meperidine. None of the patients required discontinuation of NK-MNC infusion. No GvHD or marrow suppression occurred. Chimerism analysis (STR-PCR) from leukocytes on peripheral blood samples collected 24 hours after the NK-MSC infusion failed to detect donor-derived NK-MNC in the recipients (sensitivity: 3 %). Given these results, we conclude that long-distance transport of manipulated NK-MNC products between treatment and processing centers is feasible and reliable, clearly supporting the premise of PACT, and that CD3-depleted allogeneic NK-MNC from a MHC-mismatched relative can be safely administered to recipients of a recent autologous HSCT. This project has been funded in part by the National Heart, Lung, and Blood Institute, National Institutes of Health, under the University of Minnesota Contract [] N01-HB-37164 and HHSN268201000008C *PACT: Production Assistance for Cellular Therapies Disclosures: No relevant conflicts of interest to declare.
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Molgora, Martina, Victor S. Cortez, and Marco Colonna. "Killing the Invaders: NK Cell Impact in Tumors and Anti-Tumor Therapy." Cancers 13, no. 4 (February 3, 2021): 595. http://dx.doi.org/10.3390/cancers13040595.
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Natural Killer cells belong to group 1 innate lymphoid cells, which also includes ILC1s. NK/ILC1s are highly heterogeneous cell types showing distinct phenotypes across tissues and conditions. NK cells have long been described as innate lymphocytes able to directly and rapidly kill tumor cells without antigen-restriction. Different mechanisms were shown to modulate NK cell activation and tumor resistance, mainly based on cytokine stimulation and receptor–ligand interactions, and several strategies have been developed to target NK cells in tumor immunotherapy to promote NK cell function and overcome tumor evasion. The characterization of ILC1 distinct phenotype and function and the specific role in tumors still needs further investigation and will be essential to better understand the impact of innate lymphoid cells in tumors. Here, we review key aspects of NK cell biology that are relevant in tumor immune surveillance, emphasizing the most recent findings in the field. We describe the novel therapeutical strategies that have been developed in tumor immunotherapy targeting NK cells, and we summarize some recent findings related to NK cell/ILC1 transition in tumor models.
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Bi, Jiacheng, Chen Huang, Xiaomeng Jin, Chaoyue Zheng, Yingying Huang, Xiaohu Zheng, Zhigang Tian, and Haoyu Sun. "TIPE2deletion improves the therapeutic potential of adoptively transferred NK cells." Journal for ImmunoTherapy of Cancer 11, no. 2 (February 2023): e006002. http://dx.doi.org/10.1136/jitc-2022-006002.
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BackgroundTo enhance the efficacy of adoptive NK cell therapy against solid tumors, NK cells must be modified to resist exhaustion in the tumor microenvironment (TME). However, the molecular checkpoint underlying NK cell exhaustion in the TME remains elusive.MethodsWe analyzed the correlation betweenTIPE2expression and NK cell functional exhaustion in the TME both in humans and mice by single-cell transcriptomic analysis and by using gene reporter mice. We investigated the effects ofTIPE2deletion on adoptively transferred NK cell therapy against cancers by using NK cells from NK-specificTipe2-deficient mice or peripheral blood-derived or induced pluripotent stem cell (iPSC)-derived human NK cells withTIPE2deletion by CRISPR/Cas9. We also investigated the potential synergy of double deletion ofTIPE2and another checkpoint molecule,CISH.ResultsBy single-cell transcriptomic analysis and by using gene reporter mice, we found thatTIPE2expression correlated with NK cell exhaustion in the TME both in humans and mice and that theTIPE2highNK cell subset correlated with poorer survival of tumor patients.TIPE2deletion promoted the antitumor activity of adoptively transferred mouse NK cells and adoptively transferred human NK cells, either derived from peripheral blood or differentiated from iPSCs.TIPE2deletion rendered NK cells with elevated capacities for tumor infiltration and effector functions.TIPE2deletion also synergized withCISHdeletion to further improve antitumor activity in vivo.ConclusionsThis study highlighted TIPE2 targeting as a promising approach for enhancing adoptive NK cell therapy against solid tumors.
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Hoogstad-van Evert, Janneke, Romy Paap, Annemiek Nap, and Renate van der Molen. "The Promises of Natural Killer Cell Therapy in Endometriosis." International Journal of Molecular Sciences 23, no. 10 (May 16, 2022): 5539. http://dx.doi.org/10.3390/ijms23105539.
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Endometriosis is a gynaecological disease defined by the growth of endometrium-like tissue outside the uterus. The disease is present in approximately 5–10% of women of reproductive age and causes pelvic pain and infertility. The pathophysiology is not completely understood, but retrograde menstruation and deficiency in natural killer (NK) cells that clear endometriotic cells in the peritoneal cavity play an important role. Nowadays, hormonal therapy and surgery to remove endometriosis lesions are used as treatment. However, these therapies do not work for all patients, and hormonal therapy prevents patients from getting pregnant. Therefore, new treatment strategies should be developed. Since the cytotoxicity of NK cells is decreased in endometriosis, we performed a literature search into the possibility of NK cell therapy. Available treatment options include the inhibition of receptor–ligand interaction for KIR2DL1, NKG2A, LILRB1/2, and PD-1/PD-L1; inhibition of TGF-β; stimulation of NK cells with IL-2; and mycobacterial treatment with BCG. In preclinical work, these therapies show promising results but unfortunately have side effects, which have not specifically been studied in endometriosis patients. Before NK cell treatment can be used in the clinic, more research is needed.
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Kim, Dong Hwan, Suzanne Kamel-Reid, Hong Chang, Robert Sutherland, Chul Won Jung, Hyeoung Joon Kim, Je-Jung Lee, and Jeffrey H. Lipton. "Natural Killer (NK) or NK/T Cell Lineage Large Granular Lymphocytosis Associated with Dasatinib Therapy for Philadelphia Chromosome Positive Leukemia." Blood 112, no. 11 (November 16, 2008): 933. http://dx.doi.org/10.1182/blood.v112.11.933.933.
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Abstract Dasatinib, a dual tyrosine kinase inhibitor, is known to modulate or suppress T-cell activation and proliferation. We report a series of patients of chronic peripheral lymphocytosis development, identified as natural killer (NK) cells or NK/T-cells based on their large granular lymphocyte (LGL) morphologies and CD16+CD56+CD3− or CD3+ immunophenotypic profiles during dasatinib therapy. All cases that developed LGL lymphocytosis achieved optimal molecular response (8/8 in LGL+ patients vs 3/10 in LGL− patients, p=0.002). A 51Cr release assay demonstrated that NK cell cytotoxicity has been enhanced in a case of LGL lymphocytosis compared to normal healthy donors (Figure 1), and that NK cell cytotoxicity in dasatinib-responders was superior to that in non-responders (Figure 2). In summary, the present study suggests that NK or NK/T cell lineage LGL lymphocytosis develops associated with dasatinib therapy and that LGL might have a therapeutic effect on Ph+ leukemic cells. Figure 1. Cytotoxicity of NK cells isolated from the patients developing large granular lymphocytosis following dasatinib therapy as assessed by 51Cr release assays using target cells as K562 (A) and T2 cell line (B) as target cells. Figure 1. Cytotoxicity of NK cells isolated from the patients developing large granular lymphocytosis following dasatinib therapy as assessed by 51Cr release assays using target cells as K562 (A) and T2 cell line (B) as target cells. Figure 2. The result of 51Cr release assays comparing cytotoxicity of NK cells isolated from patients responding to dasatinib therapy (responder) and not responding (non-responder) following dasatinib therapy using K562 cell line as target cells. Figure 2. The result of 51Cr release assays comparing cytotoxicity of NK cells isolated from patients responding to dasatinib therapy (responder) and not responding (non-responder) following dasatinib therapy using K562 cell line as target cells.
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Berrien-Elliott, Melissa M., Michelle Becker-Hapak, Amanda F. Cashen, Miriam Jacobs, Pamela Wong, Mark Foster, Ethan McClain, et al. "Systemic IL-15 promotes allogeneic cell rejection in patients treated with natural killer cell adoptive therapy." Blood 139, no. 8 (February 24, 2022): 1177–83. http://dx.doi.org/10.1182/blood.2021011532.
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Abstract Natural killer (NK) cells are a promising alternative to T cells for cancer immunotherapy. Adoptive therapies with allogeneic, cytokine-activated NK cells are being investigated in clinical trials. However, the optimal cytokine support after adoptive transfer to promote NK cell expansion, and persistence remains unclear. Correlative studies from 2 independent clinical trial cohorts treated with major histocompatibility complex-haploidentical NK cell therapy for relapsed/refractory acute myeloid leukemia revealed that cytokine support by systemic interleukin-15 (IL-15; N-803) resulted in reduced clinical activity, compared with IL-2. We hypothesized that the mechanism responsible was IL-15/N-803 promoting recipient CD8 T-cell activation that in turn accelerated donor NK cell rejection. This idea was supported by increased proliferating CD8+ T-cell numbers in patients treated with IL-15/N-803, compared with IL-2. Moreover, mixed lymphocyte reactions showed that IL-15/N-803 enhanced responder CD8 T-cell activation and proliferation, compared with IL-2 alone. Additionally, IL-15/N-803 accelerated the ability of responding T cells to kill stimulator-derived memory-like NK cells, demonstrating that additional IL-15 can hasten donor NK cell elimination. Thus, systemic IL-15 used to support allogeneic cell therapy may paradoxically limit their therapeutic window of opportunity and clinical activity. This study indicates that stimulating patient CD8 T-cell allo-rejection responses may critically limit allogeneic cellular therapy supported with IL-15. This trial was registered at www.clinicaltrials.gov as #NCT03050216 and #NCT01898793.
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Liu, Xiao-ran, Bin Shao, Hui-ping Li, Yan-lian Yang, Hope S. Rugo, Wei-yao Kong, Guo-hong Song, et al. "Combined peripheral natural killer (NK) cell and circulating tumor cell (CTC) enumeration to enhance prognostic efficiency in patients (pts) with triple-negative breast cancer (TNBC)." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 1105. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.1105.
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1105 Background: CTCs have emerged as an independent prognostic factor for metastatic breast cancer. However, the prognostic value of baseline CTCs regarding PFS in TNBC is still controversial, especially beyond first-line. We evaluated a novel combined NK cell/CTC detection system for enumeration to better understand the impact of cell count on prognosis in TNBC. Methods: 83 consecutive patients with metastatic TNBC were enrolled and received a new line of therapy (median=2, range: 1~5). Baseline circulating CTCs and NK cells were isolated and enumerated simultaneously prior to starting a new line of therapy using our previously published method targeting EpCAM (Bai et al. J Mater Chem B, 2014) and flow cytometry (antibodies against CD3-, CD45+, CD56+) respectively. The NK cell level was expressed as the proportion of total lymphocytes (%). Patients with normal to high NK cell proportion (≥ 9.15%) and > 2 CTC/2 ml were defined as NK resistant CTC, the rest were defined as non-NK resistant CTC. Results: 33 out of 83 TNBCs had first-line of therapy. Pts with ≤ 2 CTC/2 ml had a significantly longer median PFS than those with > 2 CTC/2 ml ( P = 0.028). The differences in median PFS were not significant ( P=0.110) for the entire group of pts with TNBC receiving different lines of therapy. Pts with non-NK resistant CTCs had a significantly longer median PFS than those with NK resistant CTCs ( P= 0.025), regardless of line of therapy. Conclusions: Including peripheral NK cell level into consideration can improve CTC prognostic efficiency in predicting PFS for TNBCs receiving different line of therapy. Further analysis of the unique biological features of NK-resistant CTCs and associated clinical consequence holds promise in guiding clinical practice. [Table: see text]
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van Vliet, Amanda A., Anna-Maria Georgoudaki, Monica Raimo, Tanja D. de Gruijl, and Jan Spanholtz. "Adoptive NK Cell Therapy: A Promising Treatment Prospect for Metastatic Melanoma." Cancers 13, no. 18 (September 21, 2021): 4722. http://dx.doi.org/10.3390/cancers13184722.
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Adoptive cell therapy (ACT) represents a promising alternative approach for patients with treatment-resistant metastatic melanoma. Lately, tumor infiltrating lymphocyte (TIL) therapy and chimeric antigen receptor (CAR)-T cell therapy have shown improved clinical outcome, compared to conventional chemotherapy or immunotherapy. Nevertheless, they are limited by immune escape of the tumor, cytokine release syndrome, and manufacturing challenges of autologous therapies. Conversely, the clinical use of Natural Killer (NK) cells has demonstrated a favorable clinical safety profile with minimal toxicities, providing an encouraging treatment alternative. Unlike T cells, NK cells are activated, amongst other mechanisms, by the downregulation of HLA class I molecules, thereby overcoming the hurdle of tumor immune escape. However, impairment of NK cell function has been observed in melanoma patients, resulting in deteriorated natural defense. To overcome this limitation, “activated” autologous or allogeneic NK cells have been infused into melanoma patients in early clinical trials, showing encouraging clinical benefit. Furthermore, as several NK cell-based therapeutics are being developed for different cancers, an emerging variety of approaches to increase migration and infiltration of adoptively transferred NK cells towards solid tumors is under preclinical investigation. These developments point to adoptive NK cell therapy as a highly promising treatment for metastatic melanoma in the future.
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Alvarez, Maite, Antonio Pierini, Jeanette Baker, and Robert Negrin. "NK cell reconstitution is improved during allogeneic hematopoietic stem cell transplantation by infusion of NK cell-committed progenitor cells (HEM5P.233)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 120.13. http://dx.doi.org/10.4049/jimmunol.194.supp.120.13.
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Abstract Failure of hematopoietic stem cell transplantation (HSCT) has been associated with the immunodeficiency that follows shortly after therapy, which renders patients susceptible to opportunistic infections and cancer relapse. Thus, strategies that induce more robust immune recovery are needed which may improve outcomes. Natural killer (NK) cells have been utilized to improve HSCT given their importance in eliminating infected and transformed cells. We explored whether the infusion of recently described NK cell-committed progenitor (NKP:CD3-CD19-Ly6D-NK1.1-CD27+CD244+cKit+CD127+CD135-CD122+/-) subsets along with unfractioned bone marrow cells (uBMC) accelerated NK cell reconstitution following allogeneic HSCT (alloHSCT). Administration of donor-type NKP (H2b) along with uBMC in alloHSCT settings resulted in increased number and percentages of donor-type precursor NK cells (CD3-CD122+NKG2D+NK1.1-DX5-) compared to recipients that received uBMC alone or in combination with common lymphoid progenitors (CLP:CD135+CD122-) at day 14 post-HSCT. By day 21, NK cell numbers were significantly higher and displayed a more mature phenotype (CD3-CD122+NKG2D+NK1.1+DX5+) with co-expression of CD27 and CD11b. These data demonstrate faster NK cell development when NKP are given after alloHSCT. More importantly, infusion of NKP during alloHSCT to accelerate NK cell reconstitution could result in stronger anti-tumor responses while reducing graft vs. host disease making alloHSCT more effective.
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Wong, Hing C., Michael J. Dee, Niraj Shrestha, Pallavi Chaturvedi, Giles M. Leclerc, Xiaoyun Zhu, Bai Liu, et al. "A feeder cell-free activation and expansion strategy to generate memory-like NK cells sufficient for off-the-shelf multi-dose adoptive cell therapy." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 116.16. http://dx.doi.org/10.4049/jimmunol.208.supp.116.16.
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Abstract Adoptive cell therapy (ACT) using NK cells is a promising armament in the fight against cancer. Cytokine induced memory like (CIML) NK cells have been shown in clinical studies to have potent antitumor activity with superior in vivo persistence. Currently, the expansion of NK cells for clinical development is mainly based on feeder cells, which imposes significant regulatory hurdles and increases the costs for manufacturing. We have developed fusion proteins, HCW9201 and HCW9206 comprising of IL-15/IL-18/IL-12 and IL15/IL-7/IL-21, respectively, capable of priming memory-like differentiation and expanding CIML NK cell products without using feeder cells. This “Kick and Expand” strategy allows greater than 100x expansion of CIML NK cells from donor PBMCs in as little as 14 days without the use of exogenous feeder cells. Continued expansion can yield sufficient CIML NK cells for cryopreservation and multiple ACT infusions. The NK cells generated have bona fide memory-like properties: enhanced antitumor activity across multiple cancer cell lines, higher metabolic capacity, stable epigenetic demethylation of the IFN-γ promoter and increased persistence in NSG mice, when compared to conventional NK cells. In conclusion, this “Kick and Expand” process supports generation of abundant CIML NK cells for multiple ACT infusions and provides simpler, more regulatory friendly, off-the-shelf platform for generating NK cell products, including those with chimeric antigen receptor (CAR) constructs.
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Fujisaki, Hiroyuki, Harumi Kakuda, Chihaya Imai, and Dario Campana. "Sustained Expansion of Human Natural Killer Cells for Leukemia Therapy." Blood 108, no. 11 (November 16, 2006): 3719. http://dx.doi.org/10.1182/blood.v108.11.3719.3719.
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Natural killer (NK) cells are a promising tool for cell therapy of hematologic malignancies. They have potential for enhancing graft-versus-leukemia responses in recipients of hematopoietic stem cell transplant, and can also be used in a non-transplant setting, where haploidentical donor NK cells have been shown to expand in vivo. NK cells represent a small subset of peripheral blood cells. Hence, it can be problematic to obtain them in quantities sufficient to exert significant anti-leukemic activity in patients. We sought to identify culture conditions that would stimulate vigorous, sustained and specific expansion of CD56+ CD3− NK cells. NK cell proliferation was stimulated by contact with the K562 leukemia cell line transfected with two NK stimulatory molecules: membrane-bound interleukin 15 and 4-1BB ligand. Exposure of peripheral blood cells from 23 donors to irradiated K562-mb15-41BBL cells in the presence of 10 IU/mL interleukin-2 resulted in a median expansion of CD56+ CD3− cells of 22-fold (range, 9- to 87-fold) after only 7 days of culture; expansion of CD3+ T cells was negligible. After 14 days of culture, K562-mb15-41BBL cells were completely lysed by the NK cells and no further expansion occurred. However, further NK cell expansion could be achieved by addition of fresh K562-mb15-41BBL cells to the cultures. Using this method, NK cell expansions ranged from 2,000- to 98,000-fold (n = 4) after 65 days of culture. We noted that NK cells eventually became unresponsive to stimulation and underwent senescence after 2–5 months of culture. To determine whether NK cell senescence could be overcome by enforced expression of human telomerase reverse transcriptase (hTERT), we stimulated NK cells for 1 week with K562-mb15-41BBL cells and then transfected them using an MSCV retroviral vector and the hTERT gene (gift of Dr. J. Dome, St. Jude). hTERT expression and telomerase activity was demonstrated by reverse transcriptase-polymerase chain reaction and telomerase repeat amplification protocol assay. The cultures were then stimulated with periodic pulses of K562-mb15-41BBL cells. In 2 donors, enforced expression of hTERT overcame senescence: NK cells transfected with an empty vector died after 85 and 170 days of culture, whereas hTERT-NK cells continue to grow after more than 350 days of culture, while retaining a normal karyotype. hTERT-NK cells maintained their cytotoxicity against the NK-sensitive leukemic cell lines K562, KG1, U937, HL60 and Jurkat. They could be also be genetically modified to express anti-CD19 chimeric signaling receptors, thus becoming cytotoxic against NK-resistant CD19+ B-lineage acute lymphoblastic leukemia cells. Cytotoxicity against CD19+ targets was similar to that of NK cells transfected with the signaling receptor after only one week of culture. In conclusion, coculture of human peripheral blood mononuclear cells with pulses of irradiated K562-mb15-41BBL cells allows the generation of a large numbers of NK cells which have powerful anti-leukemic capacity and can be redirected to lyse NK-resistant target cells. Although senescence eventually ensues, this can be overcome by hTERT expression. The culture system described here has now been adapted to large scale expansion for clinical use.
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Meiliana, Anna, Nurrani Mustika Dewi, and Andi Wijaya. "Prospect of Natural Killer Cells in Cancer Imunotherapy." Indonesian Biomedical Journal 10, no. 3 (December 28, 2018): 192–202. http://dx.doi.org/10.18585/inabj.v10i3.532.
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BACKGROUND: Current understanding in molecular character of natural killer (NK) cell, its function and mechanisms, send people the ideas to develop a NK-cell-based immunotherapeutic strategies against human cancer.CONTENT: Before being regards as a cell-based cellular therapy, NK cell have to be clinical proven. Early studies with NK cells infusions for acute myeloid leukemia and lung cancer showed a promising result. NK cells need simplified methods for enriching and expanding, in addition to its transfection with chimeric antigen receptors (CARs). NK-92 arise as an assuring effector cells to augment monoclonal and bispecific antibody therapy. Thus, NK cells show a potential opportunity for cell engineering, outstep the era of T cells.SUMMARY: It is believed that NK cells bring a bright hope for future cancer immunotherapies, either alone or in combination as a harmonious therapy.KEYWORDS: NK-cells, NK-92 cells, immunotherapy, CAR
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Franks, S. Elizabeth, Benjamin Wolfson, and James W. Hodge. "Natural Born Killers: NK Cells in Cancer Therapy." Cancers 12, no. 8 (July 31, 2020): 2131. http://dx.doi.org/10.3390/cancers12082131.
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Cellular therapy has emerged as an attractive option for the treatment of cancer, and adoptive transfer of chimeric antigen receptor (CAR) expressing T cells has gained FDA approval in hematologic malignancy. However, limited efficacy was observed using CAR-T therapy in solid tumors. Natural killer (NK) cells are crucial for tumor surveillance and exhibit potent killing capacity of aberrant cells in an antigen-independent manner. Adoptive transfer of unmodified allogeneic or autologous NK cells has shown limited clinical benefit due to factors including low cell number, low cytotoxicity and failure to migrate to tumor sites. To address these problems, immortalized and autologous NK cells have been genetically engineered to express high affinity receptors (CD16), CARs directed against surface proteins (PD-L1, CD19, Her2, etc.) and endogenous cytokines (IL-2 and IL-15) that are crucial for NK cell survival and cytotoxicity, with positive outcomes reported by several groups both preclinically and clinically. With a multitude of NK cell-based therapies currently in clinic trials, it is likely they will play a crucial role in next-generation cell therapy-based treatment. In this review, we will highlight the recent advances and limitations of allogeneic, autologous and genetically enhanced NK cells used in adoptive cell therapy.
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Froelich, Warren. "CAR NK Cell Therapy Directed Against Pancreatic Cancer." Oncology Times 43, no. 11 (June 5, 2021): 46. http://dx.doi.org/10.1097/01.cot.0000754736.41993.ee.
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Ruggeri, Loredana, Marusca Capanni, Massimo F. Martelli, and Andrea Velardi. "Cellular therapy: exploiting NK cell alloreactivity in transplantation." Current Opinion in Hematology 8, no. 6 (November 2001): 355–59. http://dx.doi.org/10.1097/00062752-200111000-00007.
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Sender, Leonard. "Driving NK cell therapy manufacture to commercial scale." Cell and Gene Therapy Insights 6, no. 7 (September 22, 2020): 1179–82. http://dx.doi.org/10.18609/cgti.2020.129.
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