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Joseph, Murphy. "Natural Killer Cells: Future Role for Cancer Immunotherapy." International Journal of Pharmaceutical and Bio-Medical Science 02, no. 06 (2022): 116–17. https://doi.org/10.5281/zenodo.6619677.
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Natural killer (NK) cells are cytotoxic lymphocytes of the innate immune system that are capable of killing virally infected and physiologically stressed cells, like tumor cells. In addition to their ability to directly kill cancer cells, NK cells are capable of enhancing both antibody and T-cell responses. Moreover, <em>ex vivo</em> activation, expansion, and genetic modification of NK cells can greatly enhance their anti-tumor activity and equip them to overcome resistance. As a result of these observations, NK cells are currently the focus of intense investigation with the potential to become a key therapeutic modality in the next wave of cancer treatments.
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Zhao, Yu, and Xiaorong Zhou. "Engineering chimeric antigen receptor-natural killer cells for cancer immunotherapy." Immunotherapy 12, no. 9 (2020): 653–64. http://dx.doi.org/10.2217/imt-2019-0139.
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Adoptive cell transfer has attracted considerable attention as a treatment for cancer. The success of chimeric antigen receptor (CAR)-engineered T (CAR-T) cells for the treatment of haematologic tumors has demonstrated the potential of CAR. In this review, we describe the current CAR-engineered natural killer (CAR-NK) cell construction strategies, including the design principles and structural characteristics of the extracellular, transmembrane and intracellular regions of the CAR structure. In addition, we review different cellular carriers used to develop CAR-NK cells, highlighting existing problems and challenges. We further discuss possible ways to optimize CAR from the perspective of the tumor microenvironment to harness the strength of CAR-NK cells and provided rationales to combine CAR-NK cells with other treatment regimens to enhance antitumor effects.
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Wu, Ming-Ru, Tong Zhang, and Charles Sentman. "NKp30-based chimeric antigen receptors promote T-cell effector functions and anti-tumor efficacy (53.11)." Journal of Immunology 188, no. 1_Supplement (2012): 53.11. http://dx.doi.org/10.4049/jimmunol.188.supp.53.11.
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Abstract NKp30 is a natural cytotoxicity receptor (NCR) that is expressed on natural killer (NK) cells and recognizes B7-H6, which is expressed on several types of tumors but few normal cells. To target effector T cells against B7-H6-positive tumors, we have developed several chimeric antigen receptors (CAR) based on NKp30, which contain the CD28, Dap10, CD27, and/or CD3ζ signaling domains with the transmembrane domains from CD3ζ, CD28, or CD8α. The NKp30 CAR expressing T cells produced IFN-γ and killed B7-H6 ligand-expressing tumor cells. This response was dependent upon ligand expression on target cells but not on MHC expression. The inclusion of other signaling domains enhanced chimeric NKp30 CAR-mediated activity compared to CD3ζ alone. Adoptive transfer of T cells expressing a chimeric NKp30 receptor containing a CD28 signaling domain inhibited the growth of a B7-H6-expressing murine lymphoma (RMA/B7-H6) in vivo. Moreover, mice that remained tumor-free were resistant to a subsequent challenge with the wild-type RMA tumor cells, suggesting the generation of immunity against other tumor antigens. Overall, this study demonstrates the therapeutic potential of adoptive immunotherapy with NKp30 CAR-expressing T cells against B7-H6+ tumor cells.
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Hu, Yuan, Zhi-gang Tian, and Cai Zhang. "Chimeric antigen receptor (CAR)-transduced natural killer cells in tumor immunotherapy." Acta Pharmacologica Sinica 39, no. 2 (2017): 167–76. http://dx.doi.org/10.1038/aps.2017.125.
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Robbins, Gabrielle, Kenta Yamomoto, Walker Lahr, and Joseph Skeate. "Abstract A021: Chimeric antigen receptor armored natural killer cell immunotherapy for osteosarcoma." Clinical Cancer Research 28, no. 18_Supplement (2022): A021. http://dx.doi.org/10.1158/1557-3265.sarcomas22-a021.
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Abstract Over the last decade, Chimeric Antigen Receptor based T cell (CAR-T) therapy has developed into an effective immunotherapy for several cancers, primarily limited to those of hematological origin. In other cancers, especially solid tumors, CAR-T cell therapies have several shortcomings and clinical success has been underwhelming. Challenges of CAR-T cell therapy include tumor immune evasion through loss of target antigen expression by tumor cells and inhibition of CAR-T cell function by tumor expressed inhibitory molecules. Natural killer (NK) cells present an alternative to T cells that could be more effective due to their ability to perform both antigen dependent and independent killing. NK cells can mediate the direct killing of transformed cells with reduced or absent MHC expression in addition to carrying out antibody dependent cell mediated cytotoxicity (ADCC) of cells bound by antibodies via the NK cell CD16A receptor. Engineering NK cells to express CARs will effectively enable them with additional antigen specific killing. Due to the multiple modalities for cancer cell killing, there is an increased interest in NK cells for cancer immunotherapy. As NK cells are not associated with graft versus host disease, neurotoxicity, long-term autoimmunity, nor cytokine release syndrome, they are more suited for use in allogeneic settings than T cells and have significant clinical potential for use as off-the-shelf products. However, previous publications and clinical trials have demonstrated that the use of unmanipulated NK cells to treat cancer is minimally effective, likely due to limited engraftment, little in vivo expansion or persistence, and suppression by the tumor microenvironment. NK cells activated and expanded with engineered feeder cells expressing membrane bound interleukin-21 (mbIL-21) and 4-1BBL have shown promising results clinically with high-risk myeloid malignancies and preclinically in several solid tumor models. Therefore, we hypothesize that activated/expanded CAR-NK cells that have been genetically edited can be used to successfully treat osteosarcoma, a disease for which patient outcome has not improved in over forty years. Our proposed objective is to evaluate the non-viral KI of several CARs, either alone or in combination, that optimally activate NK cell antigen-specific killing. Genetically engineered CAR-NK cells will be evaluated for enhanced therapeutic efficacy and safety in osteosarcoma models. Our preliminary data strongly supports the hypothesis that CAR-NK cell-based cancer immunotherapy can be fully realized using activated, genome engineered CAR-NK cells. Citation Format: Gabrielle Robbins, Kenta Yamomoto, Walker Lahr, Joseph Skeate. Chimeric antigen receptor armored natural killer cell immunotherapy for osteosarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A021.
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Iyoda, Tomonori, Satoru Yamasaki, Shogo Ueda, Kanako Shimizu, and Shin-ichiro Fujii. "Natural Killer T and Natural Killer Cell-Based Immunotherapy Strategies Targeting Cancer." Biomolecules 13, no. 2 (2023): 348. http://dx.doi.org/10.3390/biom13020348.
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Both natural killer T (NKT) and natural killer (NK) cells are innate cytotoxic lymphoid cells that produce inflammatory cytokines and chemokines, and their role in the innate immune response to tumors and microorganisms has been investigated. Especially, emerging evidence has revealed their status and function in the tumor microenvironment (TME) of tumor cells. Some bacteria producing NKT cell ligands have been identified to exert antitumor effects, even in the TME. By contrast, tumor-derived lipids or metabolites may reportedly suppress NKT and NK cells in situ. Since NKT and NK cells recognize stress-inducible molecules or inhibitory molecules on cancer cells, their status or function depends on the balance between inhibitory and activating receptor signals. As a recent strategy in cancer immunotherapy, the mobilization or restoration of endogenous NKT or NK cells by novel vaccines or therapies has become a focus of research. As a new biological evidence, after activation, effector memory-type NKT cells lasted in tumor-bearing models, and NK cell-based immune checkpoint inhibition potentiated the enhancement of NK cell cytotoxicity against cancer cells in preclinical and clinical trials. Furthermore, several new modalities based on the characteristics of NKT and NK cells, including artificial adjuvant vector cells, chimeric antigen receptor-expressing NK or NKT cell therapy, or their combination with immune checkpoint blockade have been developed. This review examines challenges and future directions for improving these therapies.
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Zhang, Tong, Bethany A. Lemoi, and Charles L. Sentman. "Chimeric NK-receptor–bearing T cells mediate antitumor immunotherapy." Blood 106, no. 5 (2005): 1544–51. http://dx.doi.org/10.1182/blood-2004-11-4365.
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Abstract NKG2D is an activating cell-surface receptor expressed on natural killer (NK) cells and some T-cell subsets. Its ligands are primarily expressed on tumor cells. The aim of this study was to determine whether chimeric NK-receptor—bearing T cells would directly kill tumor cells and lead to induction of host immunity against tumors. Chimeric NK receptors were produced by linking NKG2D or DNAX activating protein of 10 kDa (Dap10) to the cytoplasmic portion of the CD3ζ chain. Our results showed that chimeric (ch) NKG2D-bearing T cells responded to NKG2D-ligand–bearing tumor cells (RMA/Rae-1β, EG7) but not to wild-type tumor cells (RMA). This response was dependent upon ligand expression on the target cells but not on expression of major histocompatibility complex (MHC) molecules, and the response could be blocked by anti-NKG2D antibodies. These T cells produced large amounts of T-helper 1 (Th1) cytokines and proinflammatory chemokines and killed ligand–expressing tumor cells. Adoptive transfer of chNKG2D-bearing T cells inhibited RMA/Rae-1β tumor growth in vivo. Moreover, mice that had remained tumor-free were resistant to subsequent challenge with the wild-type RMA tumor cells, suggesting the generation of immunity against other tumor antigens. Taken together, our findings indicate that modification of T cells with chimeric NKG2D receptors represents a promising approach for immunotherapy against cancer.
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St-Pierre, Frederique, Shailender Bhatia, and Sunandana Chandra. "Harnessing Natural Killer Cells in Cancer Immunotherapy: A Review of Mechanisms and Novel Therapies." Cancers 13, no. 8 (2021): 1988. http://dx.doi.org/10.3390/cancers13081988.
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Natural killer (NK) cells are lymphocytes that are integral to the body’s innate immunity, resulting in a rapid immune response to stressed or infected cells in an antigen-independent manner. The innate immune system plays an important role in the recognition of tumor-derived stress-related factors and is critical to subsequent adaptive immune responses against tumor antigens. The aim of this review is to discuss mechanisms by which tumor cells evade NK cells and to outline strategies that harness NK cells for cancer immunotherapy. We discuss strategies to relieve the exhausted state of NK cells, recent therapies focused on targeting NK-cell-specific activating and inhibitory receptors, the use of cytokines IL-2 and IL-15 to stimulate autologous or allogeneic NK cells, and ongoing trials exploring the use of genetically modified NK cells and chimeric antigen-receptor-modified NK (CAR-NK) cells.
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Sherpally, Deepak, and Ashish Manne. "Advancing Immunotherapy in Pancreatic Cancer: A Brief Review of Emerging Adoptive Cell Therapies." Cancers 17, no. 4 (2025): 589. https://doi.org/10.3390/cancers17040589.
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Pancreatic cancer has the lowest 5-year survival rate (13%) among major cancers and is the third leading cause of cancer-related deaths in the United States. The high lethality of this cancer is attributed to its insidious onset, late-stage diagnosis, rapid progression, and limited treatment options. Addressing these challenges requires a deeper understanding of the complex tumor microenvironment to identify novel therapeutic targets. Newer approaches like adoptive cell therapy have shown remarkable success in treating hematological malignancies, but their application in solid tumors, particularly pancreatic cancer, is still in the early stages of development. ACT broadly involves isolating immune cells (T lymphocytes, Natural Killer cells, and macrophages) from the patient, followed by genetic engineering to enhance and mount a specific anti-tumor response. Various ACT modalities are under investigation for pancreatic cancer, including chimeric antigen receptor T cells (CAR-T), chimeric antigen receptor NK cells (CAR-NK), tumor-infiltrating lymphocytes (TIL), T-cell receptor (TCR)-engineered T cells, and cytokine-induced killer cells (CIK). Major hurdles have been identifying actionable tumor antigens and delivering focused cellular therapies to overcome the immunosuppressive and dense fibrotic stroma surrounding the pancreatic cancer. Further studies are needed to explore the limitations faced by cellular therapy in pancreatic cancer and identify novel combination treatment approaches in order to improve clinical outcomes.
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Zhurman, V. N., and E. V. Eliseeva. "Vaccination strategies and adoptive immunotherapy for ovarian cancer. Literature review." Hirurg (Surgeon), no. 3 (June 23, 2023): 58–64. http://dx.doi.org/10.33920/med-15-2303-06.
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The review considers modern cancer vaccines consisting of autologous whole cells, dendritic cells loaded with autologous tumor-specific antigens, or plasmids, which lead to antigen expression and immune activation after repeated exposure. Each vaccination strategy can be supplemented with various immunomodulatory agents. Engineering autologous immunotherapy of tumor cells is an approach to restoring the effector function of T cells. Other tumor-associated antigens (TAAs) are also of interest in ovarian can cer. Adoptive immunotherapy is based on infusion of autologous or allogeneic tumor-targeted immune cells that have been expanded and/or activated exvivo. Adoptive immunotherapy can be based on antigen-dependent (innate immunity, for example, natural killer (NK) and cytokine-induced killer (CIK) cells) or antigen-independent (adaptive immunity, for instance, TILs, chimeric antigen receptor (CAR) T cells) strategies. NK cells can kill tumor cells without prior sensitization and play an important role in tumor immunosuppression. Adoptive T-cell immunotherapy, CAR-T-cell immunotherapy, allows combining antigen specificity through conjugation of a specific antibody with T-cell activating properties in a single fused molecule. CARs bypass the immune mechanism of cancer cell release as they endow T-lymphocytes with cytotoxic effector properties. In order to reduce mortality and improve prognosis, further study and refinement of immunotherapeutic strategies for the treatment of ovarian cancer is required.
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Borobova, E. A., and A. A. Zheravin. "Natural killer cels in immunotherapy for cancer." Siberian journal of oncology 17, no. 6 (2019): 97–104. http://dx.doi.org/10.21294/1814-4861-2018-17-6-97-104.
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Cancer is the second leading cause of death worldwide behind cardiovascular diseases. Late stage of cancer at diagnosis and low efficacy of traditional cancer treatments result in low survival rate in cancer patients. Modern techniques to kill tumor cells are therefore needed. Over the last decade novel anticancer treatments have emerged from advances in our understanding of tumor cell biology, and a number of molecular and biologic targets have been identified. Chimeric antigen receptor T cell (CAR-T cell) therapy is a novel adoptive immunotherapy, which is used predominantly in the treatment of hematological malignancies. Moreover, it has been evidenced that cells of the innate immune system are key players at initiating and regulating adaptive immune responses. Studies focusing on innate immune cells for cancer immunotherapy show promising results. In this review, we describe functions of natural killer cells and analyze the rationale for using natural killer cells in cancer therapy.
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Fedorova, P. O. "CAR natural killer cell therapy: Natural killer cell activation and expansion." Acta Biomedica Scientifica 9, no. 5 (2024): 53–65. http://dx.doi.org/10.29413/abs.2024-9.5.6.
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Currently, chimeric antigen receptor (CAR) T-cell therapy is an effective treatment method of hematological malignancies. However, T-lymphocyte-based immunotherapy has certain limitations for the scope of application of this approach. A promising alternative is CAR therapy based on natural killer (NK) cells, since it does not require detailed donor selection according to the human leukocyte antigen system; NK cells have a unique mechanism for recognizing and destroying tumor cells. In addition, NK cells do not cause severe toxic reactions when infused. The creation of a CAR NK product is a complex task includes cell culturing, using genetic engineering methods, and quality control testing of the resulting biomedical cell product (BMCP). For proliferation and effector function enhancement, NK cells require the presence of interleukins, feeder cells or their components, and immune system activators in the nutrient medium. This review focuses on various approaches to the activation and expansion of natural killer cells during cultivation, and also addresses the issues of the advantages and disadvantages of the chosen therapy and the regulatory aspects of creating a full-fledged BMCP.
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Morimoto, Takayuki, Tsutomu Nakazawa, Ryosuke Maeoka, Ichiro Nakagawa, Takahiro Tsujimura, and Ryosuke Matsuda. "Natural Killer Cell-Based Immunotherapy against Glioblastoma." International Journal of Molecular Sciences 24, no. 3 (2023): 2111. http://dx.doi.org/10.3390/ijms24032111.
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Glioblastoma (GBM) is the most aggressive and malignant primary brain tumor in adults. Despite multimodality treatment involving surgical resection, radiation therapy, chemotherapy, and tumor-treating fields, the median overall survival (OS) after diagnosis is approximately 2 years and the 5-year OS is poor. Considering the poor prognosis, novel treatment strategies are needed, such as immunotherapies, which include chimeric antigen receptor T-cell therapy, immune checkpoint inhibitors, vaccine therapy, and oncolytic virus therapy. However, these therapies have not achieved satisfactory outcomes. One reason for this is that these therapies are mainly based on activating T cells and controlling GBM progression. Natural killer (NK) cell-based immunotherapy involves the new feature of recognizing GBM via differing mechanisms from that of T cell-based immunotherapy. In this review, we focused on NK cell-based immunotherapy as a novel GBM treatment strategy.
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Simon, Bianca, Manuel Wiesinger, Johannes März, et al. "The Generation of CAR-Transfected Natural Killer T Cells for the Immunotherapy of Melanoma." International Journal of Molecular Sciences 19, no. 8 (2018): 2365. http://dx.doi.org/10.3390/ijms19082365.
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Natural killer T (NKT) cells represent a cell subpopulation that combines characteristics of natural killer (NK) cells and T cells. Through their endogenous T-cell receptors (TCRs), they reveal a pronounced intrinsic anti-tumor activity. Thus, a NKT cell transfected with a chimeric antigen receptor (CAR), which recognizes a tumor-specific surface antigen, could attack tumor cells antigen-specifically via the CAR and additionally through its endogenous TCR. NKT cells were isolated from peripheral blood mononuclear cells (PBMCs), expanded, and electroporated with mRNA encoding a chondroitin sulfate proteoglycan 4 (CSPG4)-specific CAR. The CAR expression on NKT cells and their in vitro functionality were analyzed. A transfection efficiency of more than 80% was achieved. Upon stimulation with melanoma cells, CAR-NKT cells produced cytokines antigen-specifically. Compared with conventional CAR-T cells, cytokine secretion of CAR-NKT cells was generally lower. Specific cytotoxicity, however, was similar with CAR-NKT cells showing a trend towards improved cytotoxicity. Additionally, CAR-NKT cells could kill target cells through their endogenous TCRs. In summary, it is feasible to generate CAR-NKT cells by using mRNA electroporation. Their CAR-mediated cytotoxicity is at least equal to that of conventional CAR-T cells, while their intrinsic cytotoxic activity is maintained. Thus, CAR-NKT cells may represent a valuable alternative to conventional CAR-T cells for cancer immunotherapy.
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Vu, Binh Thanh, Dat Tan Le, and Phuc Van Pham. "Synergistic effect of chimeric antigen receptors and cytokine-induced killer cells: An innovative combination for cancer therapy." Biomedical Research and Therapy 3, no. 06 (2016): 653–65. http://dx.doi.org/10.15419/bmrat.v3i06.99.
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In recent years, the combination of gene and immunotherapy for cancer treatment has been regarded as innovative and promising; together, both therapies can help overcome limitations associated with conventional treatments. In order to augment anti-cancer efficacy and to maintain the specificity of antibody therapy, chimeric antigen receptor (CAR)-modified T cells, directed toward tumor-specific antigens, have emerged as a novel and promising therapeutic platform. CARs consist of a B cell receptor (BCR)-derived extracellular domain and T cell receptor (TCR)-associated signaling elements. Cytokine-induced killer (CIK) cells are the effector immune cells that can be activated ex vivo and possess both the anti-tumor potency of T lymphocytes and the non-major histocompatibility complex-restricted elimination of natural killer cells. With their pre-eminent ability for robust proliferation, CIK cells may overcome the main limitations of adoptive immunotherapy strategies. CIK cells have strong tumor cell killing capacity; they are effective against a wide variety of malignant tumors and have been shown to be safe in cancer patients. This review summarizes the characteristics of CARs which make them attractive for in cancer treatment strategies. In addition, the role of CIK cells and the advantages of combining CIK cells with CAR-based therapy will be discussed. Scientific evidence to support their combined therapeutic application will be highlighted, with a focus on how their innovative combination may be translated into cancer clinical trials.
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Thadi, Anusha, Marian Khalili, William Morano, Scott Richard, Steven Katz, and Wilbur Bowne. "Early Investigations and Recent Advances in Intraperitoneal Immunotherapy for Peritoneal Metastasis." Vaccines 6, no. 3 (2018): 54. http://dx.doi.org/10.3390/vaccines6030054.
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Peritoneal metastasis (PM) is an advanced stage malignancy largely refractory to modern therapy. Intraperitoneal (IP) immunotherapy offers a novel approach for the control of regional disease of the peritoneal cavity by breaking immune tolerance. These strategies include heightening T-cell response and vaccine induction of anti-cancer memory against tumor-associated antigens. Early investigations with chimeric antigen receptor T cells (CAR-T cells), vaccine-based therapies, dendritic cells (DCs) in combination with pro-inflammatory cytokines and natural killer cells (NKs), adoptive cell transfer, and immune checkpoint inhibitors represent significant advances in the treatment of PM. IP delivery of CAR-T cells has shown demonstrable suppression of tumors expressing carcinoembryonic antigen. This response was enhanced when IP injected CAR-T cells were combined with anti-PD-L1 or anti-Gr1. Similarly, CAR-T cells against folate receptor α expressing tumors improved T-cell tumor localization and survival when combined with CD137 co-stimulatory signaling. Moreover, IP immunotherapy with catumaxomab, a trifunctional antibody approved in Europe, targets epithelial cell adhesion molecule (EpCAM) and has shown considerable promise with control of malignant ascites. Herein, we discuss immunologic approaches under investigation for treatment of PM.
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Bachiller, Mireia, Anthony M. Battram, Lorena Perez-Amill, and Beatriz Martín-Antonio. "Natural Killer Cells in Immunotherapy: Are We Nearly There?" Cancers 12, no. 11 (2020): 3139. http://dx.doi.org/10.3390/cancers12113139.
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Natural killer (NK) cells are potent anti-tumor and anti-microbial cells of our innate immune system. They are equipped with a vast array of receptors that recognize tumor cells and other pathogens. The innate immune activity of NK cells develops faster than the adaptive one performed by T cells, and studies suggest an important immunoregulatory role for each population against the other. The association, observed in acute myeloid leukemia patients receiving haploidentical killer-immunoglobulin-like-receptor-mismatched NK cells, with induction of complete remission was the determinant to begin an increasing number of clinical studies administering NK cells for the treatment of cancer patients. Unfortunately, even though transfused NK cells demonstrated safety, their observed efficacy was poor. In recent years, novel studies have emerged, combining NK cells with other immunotherapeutic agents, such as monoclonal antibodies, which might improve clinical efficacy. Moreover, genetically-modified NK cells aimed at arming NK cells with better efficacy and persistence have appeared as another option. Here, we review novel pre-clinical and clinical studies published in the last five years administering NK cells as a monotherapy and combined with other agents, and we also review chimeric antigen receptor-modified NK cells for the treatment of cancer patients. We then describe studies regarding the role of NK cells as anti-microbial effectors, as lessons that we could learn and apply in immunotherapy applications of NK cells; these studies highlight an important immunoregulatory role performed between T cells and NK cells that should be considered when designing immunotherapeutic strategies. Lastly, we highlight novel strategies that could be combined with NK cell immunotherapy to improve their targeting, activity, and persistence.
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Ahmadnia, Ali, Saeed Mohammadi, Ahad Yamchi, et al. "Augmenting the Antitumor Efficacy of Natural Killer Cells via SynNotch Receptor Engineering for Targeted IL-12 Secretion." Current Issues in Molecular Biology 46, no. 4 (2024): 2931–45. http://dx.doi.org/10.3390/cimb46040183.
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Natural killer (NK) cells are crucial components of innate immunity, known for their potent tumor surveillance abilities. Chimeric antigen receptors (CARs) have shown promise in cancer targeting, but optimizing CAR designs for NK cell functionality remains challenging. CAR-NK cells have gained attention for their potential to reduce side effects and enable scalable production in cancer immunotherapy. This study aimed to enhance NK cell anti-tumor activity by incorporating PD1-synthetic Notch (synNotch) receptors. A chimeric receptor was designed using UniProt database sequences, and 3D structure models were generated for optimization. Lentiviral transduction was used to introduce PD1-Syn receptors into NK cells. The expression of PD1-Syn receptors on NK cell surfaces was assessed. Engineered NK cells were co-cultured with PDL1+ breast cancer cells to evaluate their cytotoxic activity and ability to produce interleukin-12 (IL-12) and interferon-gamma (IFNγ) upon interaction with the target cells. This study successfully expressed the PD1-Syn receptors on NK cells. CAR-NK cells secreted IL-12 and exhibited target-dependent IFNγ production when engaging PDL1+ cells. Their cytotoxic activity was significantly enhanced in a target-dependent manner. This study demonstrates the potential of synNotch receptor-engineered NK cells in enhancing anti-tumor responses, especially in breast cancer cases with high PDL1 expression.
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Qin, Vicky Mengfei, Criselle D’Souza, Paul J. Neeson, and Joe Jiang Zhu. "Chimeric Antigen Receptor beyond CAR-T Cells." Cancers 13, no. 3 (2021): 404. http://dx.doi.org/10.3390/cancers13030404.
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Chimeric antigen receptors (CAR) are genetically engineered receptors that can recognise specific antigens and subsequently activate downstream signalling. Human T cells engineered to express a CAR, also known as CAR-T cells, can target a specific tumour antigen on the cell surface to mediate a cytotoxic response against the tumour. CAR-T cell therapy has achieved remarkable success in treating hematologic malignancies, but not in solid tumours. Currently, extensive research is being carried out to make CAR-T cells a therapy for solid tumours. To date, most of the research interest in the field has focused on cytotoxic T lymphocytes as the carrier of CAR products. However, in addition to T cells, the CAR design can be introduced in other immune cells, such as natural killer (NK)/NKT cells, γδ T cells, mucosal-associated invariant T (MAIT) cells, dendritic cells (DC), macrophages, regulatory T cells (Treg), B cells, etc. Some of the CAR-engineered immune cells, such as CAR- γδ T and CAR-NK/NK-T cells, are directly involved in the anti-tumour response, demonstrated in preclinical studies and/or clinical trials. CAR-Tregs showed promising therapeutic potential in treating autoimmune diseases. In particular, B cells engineered with chimeric receptors can be used as a platform for long-term delivery of therapeutic proteins, such as recombinant antibodies or protein replacement, in an antigen-specific manner. CAR technology is one of the most powerful engineering platforms in immunotherapy, especially for the treatment of cancers. In this review, we will discuss the recent application of the CAR design in non-CAR-T cells and future opportunities in immunotherapy.
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Hermanson, David L., Zhenya Ni, David A. Knorr, et al. "Functional Chimeric Antigen Receptor-Expressing Natural Killer Cells Derived From Human Pluripotent Stem Cells." Blood 122, no. 21 (2013): 896. http://dx.doi.org/10.1182/blood.v122.21.896.896.
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Abstract Natural killer (NK) cells are a key part in the innate immune system and have the ability to recognize diverse types of tumors and virally-infected targets. NK cells represent an attractive cell population for adoptive immunotherapy due to their ability to kill target cells in a human leukocyte antigen (HLA) non-restricted manner and without prior sensitization. Clinical studies using IL-2 activated NK cells demonstrate significant anti-tumor effects when adoptively transferred into patients with refractory leukemia (mainly AML). However, there has been a more limited response observed in clinical trials for the treatment of ovarian cancer and other solid malignancies. Chimeric antigen receptors (CARs) consist of an antigen-specific single chain antibody variable fragment fused to intracellular signaling domains derived from receptors involved in lymphocyte activation. CARs targeting various tumor-associated antigens have been developed and tested via expression in primary T cells with promising clinical results. However, engineering these T cells must be done on a patient-specific basis, thus limiting the number of patients who can be treated. In order to produce a potential targeted, “off-the-shelf” product suitable to treat patients with diverse tumors or chronic infections, we have generated human pluripotent stem cells with stable CAR expression. Previous studies by our group demonstrate that human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) provide an accessible, genetically tractable, and homogenous starting cell population to develop NK cells. We use a combined approach using “Spin-EB”- mediated differentiation of hESCs/iPSCs, followed by co-culture with artificial antigen presenting cells (aAPCs) that express mbIL-21. Using this strategy, we can generate 109 NK cells from a population of approximately 106 undifferentiated hESCs or iPSCs. This GMP compatible method is fully defined, without xenogeneic stromal cells or serum. Here, we have expressed both an anti-CD19 (targeting B cell malignancies) and an anti-mesothelin CAR (targeting ovarian cancer cells and other adenocarcinomas) in both hESCs and iPSCs. Using the Sleeping Beauty transposon system, both hESCs and iPSCs have been genetically engineered to express 3rd generation CARs, which express a single chain antibody fragment recognizing either CD19 or mesothelin, a CD8α hinge region, the transmembrane protein CD28, a co-stimulatory protein 4-1BB, and the activating domain CD3ζ. NK cells derived from hESCs/iPSCs with or without CAR expression are phenotypically similar to NK cells isolated from peripheral blood. These NK cells are CD56+, CD94+/CD117-, Nkp44+, Nkp46+, NKG2A+, NKG2D+, and KIR+. In 51Cr release assays against tumor targets expressing either CD19 or mesothelin, NK cells expressing the corresponding CAR show an enhanced killing ability. In cell lines lacking CD19 or mesothelin expression, the engineered cell lines exhibit equal activity compared to their non-engineered counterparts. Specifically, at a 10:1 effector:target ratio, anti-CD19 CAR+ iPSC-NK cells kill 58% of Lax7R cells (a CD19+ ALL cell line) compared to just 5% cell killing by CAR- iPSC-NK cells. Anti-CD19 CAR+ iPSC-NK cells also killed 2 other CD19+ ALL cell lines (018Z and Raji) better than CAR- iPSC-NK cells killing 63% vs 18% and 61% vs 8%, respectively. Similar results are seen against the mesothelin+ ovarian tumor line A1847. Here, anti-mesothelin CAR+ iPSC-NK cells kill 39% vs 14% for CAR- iPSC-NK cells. Currently, CAR-expressing NK cells derived from hESCs and iPSCs are being tested in vivo against both mesothelin+ ovarian tumor lines and CD19+ leukemia cells. Together, these studies demonstrate engineering hESCs and iPSCs with tumor-specific receptors provides a novel strategy to produce targeted NK cells suitable for immune therapies against refractory malignancies. Disclosures: No relevant conflicts of interest to declare.
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Zhang, Congcong, Jasmin Röder, Anne Scherer, et al. "Bispecific antibody-mediated redirection of NKG2D-CAR natural killer cells facilitates dual targeting and enhances antitumor activity." Journal for ImmunoTherapy of Cancer 9, no. 10 (2021): e002980. http://dx.doi.org/10.1136/jitc-2021-002980.
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BackgroundNatural killer group 2D (NKG2D) is an activating receptor of natural killer (NK) cells and other lymphocytes that mediates lysis of malignant cells through recognition of stress-induced ligands such as MICA and MICB. Such ligands are broadly expressed by cancer cells of various origins and serve as targets for adoptive immunotherapy with effector cells endogenously expressing NKG2D or carrying an NKG2D-based chimeric antigen receptor (CAR). However, shedding or downregulation of NKG2D ligands (NKG2DL) can prevent NKG2D activation, resulting in escape of cancer cells from NKG2D-dependent immune surveillance.MethodsTo enable tumor-specific targeting of NKG2D-expressing effector cells independent of membrane-anchored NKG2DLs, we generated a homodimeric recombinant antibody which harbors an N-terminal single-chain fragment variable (scFv) antibody domain for binding to NKG2D, linked via a human IgG4 Fc region to a second C-terminal scFv antibody domain for recognition of the tumor-associated antigen ErbB2 (HER2). The ability of this molecule, termed NKAB-ErbB2, to redirect NKG2D-expressing effector cells to ErbB2-positive tumor cells of different origins was investigated using peripheral blood mononuclear cells, ex vivo expanded NK cells, and NK and T cells engineered with an NKG2D-based chimeric receptor.ResultsOn its own, bispecific NKAB-ErbB2 increased lysis of ErbB2-positive breast carcinoma cells by peripheral blood-derived NK cells endogenously expressing NKG2D more effectively than an ErbB2-specific IgG1 mini-antibody able to induce antibody-dependent cell-mediated cytotoxicity via activation of CD16. Furthermore, NKAB-ErbB2 synergized with NK-92 cells or primary T cells engineered to express an NKG2D-CD3ζ chimeric antigen receptor (NKAR), leading to targeted cell killing and greatly enhanced antitumor activity, which remained unaffected by soluble MICA known as an inhibitor of NKG2D-mediated natural cytotoxicity. In an immunocompetent mouse glioblastoma model mimicking low or absent NKG2DL expression, the combination of NKAR-NK-92 cells and NKAB-ErbB2 effectively suppressed outgrowth of ErbB2-positive tumors, resulting in treatment-induced endogenous antitumor immunity and cures in the majority of animals.ConclusionsOur results demonstrate that combining an NKAB antibody with effector cells expressing an activating NKAR receptor represents a powerful and versatile approach to simultaneously enhance tumor antigen-specific as well as NKG2D-CAR and natural NKG2D-mediated cytotoxicity, which may be particularly useful to target tumors with heterogeneous target antigen expression.
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Robbins, Gabrielle M., Kenta Yamamoto, Joshua Krueger, Walker Lahr, Joseph Skeate, and Branden Moriarity. "Abstract 2836: Genome engineered natural killer cell immunotherapy against osteosarcoma." Cancer Research 82, no. 12_Supplement (2022): 2836. http://dx.doi.org/10.1158/1538-7445.am2022-2836.
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Abstract Over the last decade Chimeric Antigen Receptor based T cell therapy (CAR-T) has developed into an effective immunotherapy for some cancers. Unfortunately, CAR-T cell therapies have several shortcomings and clinical success has primarily been limited to hematological cancers. Challenges of CAR-T cell therapy include tumor immune evasion through loss of target antigen expression by tumor cells and inhibition of CAR-T cell function by tumor expressed inhibitory molecules. Natural killer (NK) cells present an alternative to T cells that could be more effective due to their ability to perform both antigen dependent and independent killing. NK cells have demonstrated antigen specific killing when engineered to express CARs and NK cells also mediate the direct killing of transformed cells with reduced or absent MHC expression. Moreover, NK cells carry out antibody dependent cell mediated cytotoxicity (ACDD) of cells bound by antibodies via the NK cell CD16A receptor. Due to the multiple modalities for cancer cell killing, there is an increased interest in NK cells for cancer immunotherapy. As NK cells are not associated with graft versus host disease, neurotoxicity, long-term autoimmunity, nor cytokine release syndrome, they are more suited for use in allogeneic settings than T cells and have significant clinical potential for use as off-the-shelf products. However, previous publications and clinical trials have demonstrated that the use of unmanipulated NK cells to treat cancer is minimally effective, likely due to limited engraftment, little in vivo expansion or persistence, and suppression by the tumor microenvironment. NK cells activated and expanded with engineered feeder cells expressing membrane bound interleukin-21 (mbIL-21) and 4-1BBL have shown promising results clinically with high-risk myeloid malignancies and preclinically in several solid tumor models. Therefore, we hypothesize that activated/expanded CAR-NK cells that have been genetically edited can be used to successfully treat osteosarcoma, a disease for which patient outcome has not improved in over forty years. Our proposed objectives are to evaluate the baseline response of rested- and activated/expanded-NK cells against various osteosarcoma cell lines, knockout negative regulators of NK cell function (specifically, c-CBL, IL-1R8, and SMAD3), and implement several CARs alone or in combination that optimally activate NK cell antigen-specific killing. Genetically engineered CAR-NK cells will be evaluated for enhanced therapeutic efficacy and safety in osteosarcoma models. Our preliminary data strongly supports the hypothesis that CAR-NK cell-based cancer immunotherapy can be fully realized using activated, genome engineered CAR-NK cells. Citation Format: Gabrielle M. Robbins, Kenta Yamamoto, Joshua Krueger, Walker Lahr, Joseph Skeate, Branden Moriarity. Genome engineered natural killer cell immunotherapy against osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2836.
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Hege, Kristen M., Keegan S. Cooke, Mitchell H. Finer, Krisztina M. Zsebo, and Margo R. Roberts. "Systemic T Cell–independent Tumor Immunity after Transplantation of Universal Receptor–modified Bone Marrow into SCID Mice." Journal of Experimental Medicine 184, no. 6 (1996): 2261–70. http://dx.doi.org/10.1084/jem.184.6.2261.
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Gene modification of hematopoietic stem cells (HSC) with antigen-specific, chimeric, or “universal” immune receptors (URs) is a novel but untested form of targeted immunotherapy. A human immunodeficiency virus (HIV) envelope–specific UR consisting of the extracellular domain of human CD4 linked to the ζ chain of the T cell receptor (CD4ζ) was introduced ex vivo into murine HSC by retroviral transduction. After transplantation into immunodeficient SCID mice, sustained high level expression of CD4ζ was observed in circulating myeloid and natural killer cells. CD4ζ-transplanted mice were protected from challenge with a lethal dose of a disseminated human leukemia expressing HIV envelope. These results demonstrate the ability of chimeric receptors bearing ζ-signaling domains to activate non–T cell effector populations in vivo and thereby mediate systemic immunity.
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Shin, Min Hwa, Eunha Oh, Yunjeong Kim, et al. "Recent Advances in CAR-Based Solid Tumor Immunotherapy." Cells 12, no. 12 (2023): 1606. http://dx.doi.org/10.3390/cells12121606.
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Adoptive cell therapy using chimeric antigen receptor (CAR) technology is one of the most advanced engineering platforms for cancer immunotherapy. CAR-T cells have shown remarkable efficacy in the treatment of hematological malignancies. However, their limitations in solid tumors include an immunosuppressive tumor microenvironment (TME), insufficient tumor infiltration, toxicity, and the absence of tumor-specific antigens. Although recent advances in CAR-T cell design—such as the incorporation of co-stimulatory domains and the development of armored CAR-T cells—have shown promising results in treating solid tumors, there are still challenges that need to be addressed. To overcome these limitations, other immune cells, such as natural killer (NK) cells and macrophages (M), have been developed as attractive options for efficient cancer immunotherapy of solid tumors. CAR-NK cells exhibit substantial clinical improvements with "off-the-shelf" availability and low toxicity. CAR-M cells have promising therapeutic potential because macrophages can infiltrate the TME of solid tumors. Here, we review the recent advances and future perspectives associated with engineered immune cell-based cancer immunotherapies for solid tumors. We also summarize ongoing clinical trials investigating the safety and efficacy of engineered immune cells, such as CAR-T, CAR-NK, and CAR-M, for targeting solid tumors.
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Shimizu, Kanako, Tomonori Iyoda, Satoru Yamasaki, Norimitsu Kadowaki, Arinobu Tojo, and Shin-ichiro Fujii. "NK and NKT Cell-Mediated Immune Surveillance against Hematological Malignancies." Cancers 12, no. 4 (2020): 817. http://dx.doi.org/10.3390/cancers12040817.
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Recent cancer treatment modalities have been intensively focused on immunotherapy. The success of chimeric antigen receptor T cell therapy for treatment of refractory B cell acute lymphoblastic leukemia has pushed forward research on hematological malignancies. Among the effector types of innate lymphocytes, natural killer (NK) cells show great importance in immune surveillance against infectious and tumor diseases. Particularly, the role of NK cells has been argued in either elimination of target tumor cells or escape of tumor cells from immune surveillance. Therefore, an NK cell activation approach has been explored. Recent findings demonstrate that invariant natural killer T (iNKT) cells capable of producing IFN-γ when optimally activated can promptly trigger NK cells. Here, we review the role of NKT and/or NK cells and their interaction in anti-tumor responses by highlighting how innate immune cells recognize tumors, exert effector functions, and amplify adaptive immune responses. In addition, we discuss these innate lymphocytes in hematological disorders, particularly multiple myeloma and acute myeloid leukemia. The immune balance at different stages of both diseases is explored in light of disease progression. Various types of innate immunity-mediated therapeutic approaches, recent advances in clinical immunotherapies, and iNKT-mediated cancer immunotherapy as next-generation immunotherapy are then discussed.
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Lee, Maxwell Y., Yvette Robbins, Cem Sievers, et al. "Chimeric antigen receptor engineered NK cellular immunotherapy overcomes the selection of T-cell escape variant cancer cells." Journal for ImmunoTherapy of Cancer 9, no. 3 (2021): e002128. http://dx.doi.org/10.1136/jitc-2020-002128.
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BackgroundAs heterogeneous tumors develop in the face of intact immunity, tumor cells harboring genomic or expression defects that favor evasion from T-cell detection or elimination are selected. For patients with such tumors, T cell-based immunotherapy alone infrequently results in durable tumor control.MethodsHere, we developed experimental models to study mechanisms of T-cell escape and demonstrated that resistance to T-cell killing can be overcome by the addition of natural killer (NK) cells engineered to express a chimeric antigen receptor (CAR) targeting programmed death ligand-1 (PD-L1).ResultsIn engineered models of tumor heterogeneity, PD-L1 CAR-engineered NK cells (PD-L1 t-haNKs) prevented the clonal selection of T cell-resistant tumor cells observed with T-cell treatment alone in multiple models. Treatment of heterogenous cancer cell populations with T cells resulted in interferon gamma (IFN-γ) release and subsequent upregulation of PD-L1 on tumor cells that escaped T-cell killing through defects in antigen processing and presentation, priming escape cell populations for PD-L1 dependent killing by PD-L1 t-haNKs in vitro and in vivo.ConclusionsThese results describe the underlying mechanisms governing synergistic antitumor activity between T cell-based immunotherapy that results in IFN-γ production, upregulation of PD-L1 on T-cell escape cells, and the use of PD-L1 CAR-engineered NK cells to target and eliminate resistant tumor cell populations.
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Kravchenko, Yu E., D. I. Gagarinskaya, E. I. Frolova, and S. P. Chumakov. "Chimeric antigen receptor expression in natural killer cell line NK-92 by transduction with lentiviral particles pseudotyped with the surface glycoproteins of the measles virus vaccine strain." NANOMEDICINE, no. 6 (December 31, 2018): 155–61. http://dx.doi.org/10.24075/brsmu.2018.091.
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Cancer immunotherapy with T-cells that carry chimeric antigen receptors is currently on cutting edge of modern oncology. Autotransplantation of T-lymphocytes with chimeric receptor specific for certain tumor antigen proves to be clinically effective, but costly. Linear carriers of chimeric antigen receptors based on natural killer NK-92 cell culture may be an affordable alternative, however, this culture is resistant to lentiviral transduction. Recently, lentiviral vectors, pseudotyped with surface glycoproteins of the measles virus vaccine strain, have recently been successfully applied for transduction of primary immune cells. The aim of the work was to assess the efficiency of transduction of NK-92 cells with lentivirus vectors, pseudotyped with measles F and H surface glycoproteins, as well as to establish optimal conditions for selection of NK-92 transduced with the chimeric receptor against CD20 and to evaluate the culture’s cytotoxic potential. The results showed that the maximum infectious titer is achieved using the H∆18 variant in combination with F∆30, and the use of the TBK1/IKKɛ inhibitor BX795 results in additional 3-fold increase in the infectious titer. CAR-expressing NK-92 were able to suppress the proliferation of CD20+ cell line Raji in lower effector-to-target ratios than unmodified NK-92.
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Temme, Achim, and Marc Schmitz. "Chimeric antigen receptor-engineered primary natural killer cells: a tool to improve adoptive tumor immunotherapy." Immunotherapy 8, no. 9 (2016): 983–86. http://dx.doi.org/10.2217/imt-2016-0072.
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Zhang, Jianguang, Huifang Zheng, and Yong Diao. "Natural Killer Cells and Current Applications of Chimeric Antigen Receptor-Modified NK-92 Cells in Tumor Immunotherapy." International Journal of Molecular Sciences 20, no. 2 (2019): 317. http://dx.doi.org/10.3390/ijms20020317.
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Natural killer (NK) cells are innate immune cells that can be activated rapidly to target abnormal and virus-infected cells without prior sensitization. With significant advancements in cell biology technologies, many NK cell lines have been established. Among these cell lines, NK-92 cells are not only the most widely used but have also been approved for clinical applications. Additionally, chimeric antigen receptor-modified NK-92 cells (CAR-NK-92 cells) have shown strong antitumor effects. In this review, we summarize established human NK cell lines and their biological characteristics, and highlight the applications of NK-92 cells and CAR-NK-92 cells in tumor immunotherapy.
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Della Chiesa, Mariella, Chiara Setti, Chiara Giordano, et al. "NK Cell-Based Immunotherapy in Colorectal Cancer." Vaccines 10, no. 7 (2022): 1033. http://dx.doi.org/10.3390/vaccines10071033.
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Human Natural Killer (NK) cells are all round players in immunity thanks to their powerful and immediate response against transformed cells and the ability to modulate the subsequent adaptive immune response. The potential of immunotherapies based on NK cell involvement has been initially revealed in the hematological setting but has inspired the design of different immune tools to also be applied against solid tumors, including colorectal cancer (CRC). Indeed, despite cancer prevention screening plans, surgery, and chemotherapy strategies, CRC is one of the most widespread cancers and with the highest mortality rate. Therefore, further efficient and complementary immune-based therapies are in urgent need. In this review, we gathered the most recent advances in NK cell-based immunotherapies aimed at fighting CRC, in particular, the use of monoclonal antibodies targeting tumor-associated antigens (TAAs), immune checkpoint blockade, and adoptive NK cell therapy, including NK cells modified with chimeric antigen receptor (CAR-NK).
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Kusmartsev, Sergei, Johaness Vieweg та Victor Prima. "Development of human NKG2D-CD3ε chimeric antigen receptor (CAR) for T-cell-mediated cancer immunotherapy." Journal of Clinical Oncology 35, № 7_suppl (2017): 150. http://dx.doi.org/10.1200/jco.2017.35.7_suppl.150.
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150 Background: NKG2D is a lectin-like type 2 transmembrane receptor that expressed by natural killer cells and some T cell subsets. Stimulation of NKG2D receptor with specific agonistic ligands produces activating signals through signaling adaptor protein DAP10 leading to the enhanced cytokine production, proliferation, and cytotoxicity against tumor cells. There is strong evidence that NKG2D ligands are expressed in many human tumors, including melanoma, leukemia, myeloma, glioma, and carcinomas of the prostate, breast, lung, and colon. Recent studies also demonstrated that T cells bearing chimeric antigen receptor (CAR) NKG2D linked to CD3ζ (zeta) chain produce marked in vitro and in vivo anti-tumor effects. The aim of current study was to determine whether human T cells bearing chimeric antigen receptor (CAR) NKGD2 linked to CD3ε (epsilon) chain could be activated by the NKG2D-specific stimulation and able to kill human cancer cells. Given the important role of CD3ε in activation and survival of T cells, we hypothesized that NKG2D-CDε-bearing T cells could exert strong in vitro and in vivo anti-tumor effects. Methods: NKG2D CAR was produced by linking human NKG2D to DAP10 and the cytoplasmic portion of the CD3ε chain. Original full-length human cDNA clones were obtained from NIH Mammalian Gene Collection (MGC). Functional domain analysis and oligonucleotide design in the in-Fusion system of DNA cloning (Clontech) was used to generate the retroviral expression constructs. Results: Human PBMC-derived T cells were retrovirally transduced with newly generated NKG2D-CD3ε CAR DNA construct. These NKG2D CAR-expressing human T cells responded to NKG2D-specific activation by producing IFN-γ and exhibited significant cellular cytotoxicity against human tumor cells in vitro. In vivo studies demonstrated that NKG2D-CD3ε-bearing cells are capable of inhibiting growth of DU-145 human prostate cancer in the immunodeficient mice. Conclusions: Collectively, our data indicate the feasibility of developing chimeric antigen receptor NKG2D-CD3ε for T cells and suggest that adoptive transfer of T cells bearing NKG2D-CD3ε CAR could be potentially effective for immunotherapy of cancer patients.
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Xian, Yunjia, та Lu Wen. "CARBeyond αβ T Cells: Unleashing NK Cells, Macrophages, and γδ T Lymphocytes Against Solid Tumors". Vaccines 13, № 6 (2025): 654. https://doi.org/10.3390/vaccines13060654.
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Chimeric antigen receptor (CAR)-engineered cell therapy represents a landmark advancement in cancer immunotherapy. While αβ CAR-T therapy has demonstrated remarkable success in hematological malignancies, its efficacy in solid tumors remains constrained mainly by factors such as antigen heterogeneity, immunosuppressive microenvironments, and on-target/off-tumor toxicity. To overcome these limitations, emerging CAR platforms that utilize alternative immune effectors, including natural killer (NK) cells, macrophages, and γδ T lymphocytes, are rapidly gaining traction. This review systematically analyzes the mechanistic advantages of CAR-NK, CAR-M, and CAR-γδ T cell therapies, while critically evaluating persistent challenges in clinical translation, including limited cell persistence, manufacturing scalability, and dynamic immune evasion mechanisms. We further discuss innovative strategies to enhance therapeutic efficacy through some viable strategies. By bridging fundamental immunology with translational engineering, this work provides a roadmap for developing CAR therapies capable of addressing the complexities of solid tumor eradication.
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Sayegh, Mark, Shoubao Ma, and Jianhua Yu. "Application of natural killer immunotherapy in blood cancers and solid tumors." Current Opinion in Oncology 35, no. 5 (2023): 446–52. http://dx.doi.org/10.1097/cco.0000000000000968.
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Purpose of review Natural killer (NK) cells are innate lymphoid cells characterized by their ability to attack aberrant and cancerous cells. In contrast to the activation of T-cells, NK cell activation is controlled by the interaction of NK cell receptors and their target cells in a manner independent of antigen organization. Due to NK cells’ broad array of activation cues, they have gained great attention as a potential therapeutic agent in cancer immunotherapy. Recent findings Ex vivo activation, expansion, and genetic modifications, such as the addition of a chimeric antigen receptor (CAR), will allow the next generation of NK cells to enhance cytotoxicity, promote survival, and create “off-the-shelf” products. In addition to these that are poised to greatly enhance their clinical activity, the inherent lack of potential for causing graft-versus-host disease (GVHD) and cytokine release syndrome (CRS) suggest that CAR NK cells have the potential to be complementary to CAR-T cells as a component of therapeutic strategies for cancer. Summary In this review, we will provide a general understanding of NK cell biology, CAR-NK cell advantages over CAR-T cell therapy, barriers to making NK cell immunotherapy viable, and current NK cell clinical trials for hematological malignancies and solid tumors. The next generation of NK cells has potential to change the circumstances guiding present cancer immunotherapies.
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Feng, Yachan, Haojie Zhang, Jiangtao Shao, et al. "Research Progress of Nanomaterials Acting on NK Cells in Tumor Immunotherapy and Imaging." Biology 13, no. 3 (2024): 153. http://dx.doi.org/10.3390/biology13030153.
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The prognosis for cancer patients has declined dramatically in recent years due to the challenges in treating malignant tumors. Tumor immunotherapy, which includes immune target inhibition and chimeric antigen receptor cell treatment, is currently evolving quickly. Among them, natural killer (NK) cells are gradually becoming another preferred cell immunotherapy after T cell immunotherapy due to their unique killing effects in innate and adaptive immunity. NK cell therapy has shown encouraging outcomes in clinical studies; however, there are still some problems, including limited efficacy in solid tumors, inadequate NK cell penetration, and expensive treatment expenses. Noteworthy benefits of nanomaterials include their chemical specificity, biocompatibility, and ease of manufacturing; these make them promising instruments for enhancing NK cell anti-tumor immune responses. Nanomaterials can promote NK cell homing and infiltration, participate in NK cell modification and non-invasive cell tracking and imaging modes, and greatly increase the effectiveness of NK cell immunotherapy. The introduction of NK cell-based immunotherapy research and a more detailed discussion of nanomaterial research in NK cell-based immunotherapy and molecular imaging will be the main topics of this review.
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Xiao, Jiani, Tianxiang Zhang, Fei Gao, et al. "Natural Killer Cells: A Promising Kit in the Adoptive Cell Therapy Toolbox." Cancers 14, no. 22 (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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Li, Wangshu, Xiuying Wang, Xu Zhang, Aziz ur Rehman Aziz, and Daqing Wang. "CAR-NK Cell Therapy: A Transformative Approach to Overcoming Oncological Challenges." Biomolecules 14, no. 8 (2024): 1035. http://dx.doi.org/10.3390/biom14081035.
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The use of chimeric antigen receptor (CAR) in natural killer (NK) cells for cancer therapy is gaining momentum, marking a significant shift in cancer treatment. This review aims to explore the potential of CAR-NK cell therapy in cancer immunotherapy, providing a fresh perspective. It discusses the innovative approaches in CAR-NK cell design and engineering, particularly targeting refractory or recurrent cancers. By comparing CAR-NK cells with traditional therapies, the review highlights their unique ability to tackle tumor heterogeneity and immune system suppression. Additionally, it explains how novel cytokines and receptors can enhance CAR-NK cell efficacy, specificity, and functionality. This review underscores the advantages of CAR-NK cells, including reduced toxicity, lower cost, and broader accessibility compared to CAR-T cells, along with their potential in treating both blood cancers and solid tumors.
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Gossel, Leonie D. H., Catrin Heim, Lisa-Marie Pfeffermann, et al. "Retargeting of NK-92 Cells against High-Risk Rhabdomyosarcomas by Means of an ERBB2 (HER2/Neu)-Specific Chimeric Antigen Receptor." Cancers 13, no. 6 (2021): 1443. http://dx.doi.org/10.3390/cancers13061443.
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The dismal prognosis of pediatric and young adult patients with high-risk rhabdomyosarcoma (RMS) underscores the need for novel treatment options for this patient group. In previous studies, the tumor-associated surface antigen ERBB2 (HER2/neu) was identified as targetable in high-risk RMS. As a proof of concept, in this study, a novel treatment approach against RMS tumors using a genetically modified natural killer (NK)-92 cell line (NK-92/5.28.z) as an off-the-shelf ERBB2-chimeric antigen receptor (CAR)-engineered cell product was preclinically explored. In cytotoxicity assays, NK-92/5.28.z cells specifically recognized and efficiently eliminated RMS cell suspensions, tumor cell monolayers, and 3D tumor spheroids via the ERBB2-CAR even at effector-to-target ratios as low as 1:1. In contrast to unmodified parental NK-92 cells, which failed to lyse RMS cells, NK-92/5.28.z cells proliferated and became further activated through contact with ERBB2-positive tumor cells. Furthermore, high amounts of effector molecules, such as proinflammatory and antitumoral cytokines, were found in cocultures of NK-92/5.28.z cells with tumor cells. Taken together, our data suggest the enormous potential of this approach for improving the immunotherapy of treatment-resistant tumors, revealing the dual role of NK-92/5.28.z cells as CAR-targeted killers and modulators of endogenous adaptive immunity even in the inhibitory tumor microenvironment of high-risk RMS.
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Klaihmon, Phatchanat, Xing Kang, Surapol Issaragrisil, and Sudjit Luanpitpong. "Generation and Functional Characterization of Anti-CD19 Chimeric Antigen Receptor-Natural Killer Cells from Human Induced Pluripotent Stem Cells." International Journal of Molecular Sciences 24, no. 13 (2023): 10508. http://dx.doi.org/10.3390/ijms241310508.
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Natural killer (NK) cells are a part of innate immunity that can be activated rapidly in response to malignant transformed cells without prior sensitization. Engineering NK cells to express chimeric antigen receptors (CARs) allows them to be directed against corresponding target tumor antigens. CAR-NK cells are regarded as a promising candidate for cellular immunotherapy alternatives to conventional CAR-T cells, due to the relatively low risk of graft-versus-host disease and safer clinical profile. Human induced pluripotent stem cells (iPSCs) are a promising renewable cell source of clinical NK cells. In the present study, we successfully introduced a third-generation CAR targeting CD19, which was validated to have effective signaling domains suitable for NK cells, into umbilical cord blood NK-derived iPSCs, followed by a single-cell clone selection and thorough iPSC characterization. The established single-cell clone of CAR19-NK/iPSCs, which is highly desirable for clinical application, can be differentiated using serum- and feeder-free protocols into functional CAR19-iNK-like cells with improved anti-tumor activity against CD19-positive hematologic cancer cells when compared with wild-type (WT)-iNK-like cells. With the feasibility of being an alternative source for off-the-shelf CAR-NK cells, a library of single-cell clones of CAR-engineered NK/iPSCs targeting different tumor antigens may be created for future clinical application.
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Heczey, Andras, Daofeng Liu, Amy Courtney, et al. "NKT cells as a novel platform for cancer immunotherapy with chimeric antigen receptors (P2038)." Journal of Immunology 190, no. 1_Supplement (2013): 132.9. http://dx.doi.org/10.4049/jimmunol.190.supp.132.9.
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Abstract Transgenic expression of chimeric antigen receptors (CARs) in primary T cells is an attractive strategy for cancer immunotherapy. However, poor homing of CAR T cells to the tumor site limits their therapeutic potential. Because Vα24-invariant Natural Killer T cells (NKTs) naturally localize to solid tumors, we examined their ability to serve as a cellular carrier for anti-tumor CARs. We genetically modified primary human NKTs to express a CAR against GD2 ganglioside, which is highly expressed in tumors of neuroectodermal origin such as neuroblastoma or melanoma. CAR expression rendered NKTs highly cytotoxic against GD2-positive neuroblastoma cells without affecting their native CD1d-restricted reactivity. The comparison of CAR constructs encoding different co-stimulatory endodomains revealed a striking Th2-like or Th1-like polarization of NKTs by CARs with CD28 or CD137, respectively. CAR NKTs had potent and long-lasting anti-tumor activity in a metastatic model of neuroblastoma in humanized NOD/SCID/IL-2γ(null) mice. Furthermore, in contrast to CAR T cells from the same donor, CAR NKTs did not induce graft-versus-host disease. These results establish the potential of NKTs to serve as an effective cellular platform for anti-tumor CAR therapy.
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Wang, Yuxiao, Michele Gerber, Michael Gorgievski, et al. "Abstract 3612: Preclinical & clinical activity of autologous mRNA engineered chimeric antigen receptor monocytes for targeted cancer immunotherapy." Cancer Research 84, no. 6_Supplement (2024): 3612. http://dx.doi.org/10.1158/1538-7445.am2024-3612.
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Abstract Introduction: The tumor microenvironment (TME) is a dynamic and multifaceted system that comprises largely myeloid lineage immune cells including neutrophils, macrophages, dendritic cells and monocytes. When activated, these cells are can effectively infiltrate TME and orchestrate anti-tumor immune response. Reprogramming myeloid cells by arming them with a tumor specific chimeric antigen receptor (CAR) presents an attractive strategy to overcome current limitations in solid tumor treatment. In this study, we present the isolation and mRNA-based engineering of monocytes with chimeric antigen receptors (CARs), followed by their in vivo application for cancer treatment in rodent models and in human T cell lymphoma patients. Results: Engineered monocytes demonstrated the abilities to infiltrate the TME, undergo activation, and differentiate into macrophages and dendritic cells. Upon CAR activation, these reprogrammed myeloid cells utilized both direct and indirect mechanisms to eliminate tumor cells. This included direct tumor cell killing through phagocytosis and TNF-associated mechanisms. Furthermore, engineered monocytes exhibited the capacity to recruit natural killer (NK) cells and T cells to the TME. In the case of T cells, these engineered myeloid cells facilitated the presentation of neoantigens to T cells and stimulate an adaptive immune response. In patients with T cell lymphoma, treatment with engineered monocytes expressing a CAR targeting CD5 exhibited a favorable safety profile and was associated with TME remodeling, expansion of novel T cell clones, and promising survival outcomes. Conclusions: These findings underscore the potential of reprogrammed myeloid cells as a novel avenue for cancer immunotherapy, offering hope for improved treatments and outcomes in the fight against cancer. Citation Format: Yuxiao Wang, Michele Gerber, Michael Gorgievski, Josephine D'Alessandro, Neha Diwanji, Ronald Vale, Siddhartha Mukherjee, Daniel Getts. Preclinical & clinical activity of autologous mRNA engineered chimeric antigen receptor monocytes for targeted cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3612.
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Winidmanokul, Peeranut, Aussara Panya, and Seiji Okada. "Tri-specific killer engager: unleashing multi-synergic power against cancer." Exploration of Targeted Anti-tumor Therapy 5, no. 2 (2024): 432–48. http://dx.doi.org/10.37349/etat.2024.00227.
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Cancer continues to be a global health concern, necessitating innovative solutions for treatment. Tri-specific killer engagers (TriKEs) have emerged as a promising class of immunotherapeutic agents, offering a multifaceted approach to cancer treatment. TriKEs simultaneously engage and activate natural killer (NK) cells while specifically targeting cancer cells, representing an outstanding advancement in immunotherapy. This review explores the generation and mechanisms of TriKEs, highlighting their advantages over other immunotherapies and discussing their potential impact on clinical trials and cancer treatment. TriKEs are composed of three distinct domains, primarily antibody-derived building blocks, linked together by short amino acid sequences. They incorporate critical elements, anti-cluster of differentiation 16 (CD16) and interleukin-15 (IL-15), which activate and enhance NK cell function, together with specific antibody to target each cancer. TriKEs exhibit remarkable potential in preclinical and early clinical studies across various cancer types, making them a versatile tool in cancer immunotherapy. Comparative analyses with other immunotherapies, such as chimeric antigen receptor-T (CAR-T) cell therapy, immune checkpoint inhibitors (ICIs), cytokine therapies, and monoclonal antibodies (mAbs), reveal the unique advantages of TriKEs. They offer a safer pathway for immunotherapy by targeting cancer cells without hyperactivating T cells, reducing off-target effects and complications. The future of TriKEs involves addressing challenges related to dosing, tumor-associated antigen (TAA) expression, and NK cell suppression. Researchers are exploring innovative dosing strategies, enhancing specificity through tumor-specific antigens (TSAs), and combining TriKEs with other therapies for increased efficacy.
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Rotolo, Ramona, Valeria Leuci, Chiara Donini, et al. "CAR-Based Strategies beyond T Lymphocytes: Integrative Opportunities for Cancer Adoptive Immunotherapy." International Journal of Molecular Sciences 20, no. 11 (2019): 2839. http://dx.doi.org/10.3390/ijms20112839.
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Chimeric antigen receptor (CAR)-engineered T lymphocytes (CAR Ts) produced impressive clinical results against selected hematological malignancies, but the extension of CAR T cell therapy to the challenging field of solid tumors has not, so far, replicated similar clinical outcomes. Many efforts are currently dedicated to improve the efficacy and safety of CAR-based adoptive immunotherapies, including application against solid tumors. A promising approach is CAR engineering of immune effectors different from αβT lymphocytes. Herein we reviewed biological features, therapeutic potential, and safety of alternative effectors to conventional CAR T cells: γδT, natural killer (NK), NKT, or cytokine-induced killer (CIK) cells. The intrinsic CAR-independent antitumor activities, safety profile, and ex vivo expansibility of these alternative immune effectors may favorably contribute to the clinical development of CAR strategies. The proper biological features of innate immune response effectors may represent an added value in tumor settings with heterogeneous CAR target expression, limiting the risk of tumor clonal escape. All these properties bring out CAR engineering of alternative immune effectors as a promising integrative option to be explored in future clinical studies.
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Morcillo-Martín-Romo, Paula, Javier Valverde-Pozo, María Ortiz-Bueno, et al. "The Role of NK Cells in Cancer Immunotherapy: Mechanisms, Evasion Strategies, and Therapeutic Advances." Biomedicines 13, no. 4 (2025): 857. https://doi.org/10.3390/biomedicines13040857.
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Background/Objectives: Natural killer (NK) cells play a crucial role in tumor surveillance by exerting cytotoxic activity and modulating immune responses. However, tumors employ diverse evasion strategies that limit NK cell effectiveness. This review aims to explore the molecular mechanisms of NK cell activation and inhibition in cancer, the influence of the tumor microenvironment, and the latest advancements in NK cell-based immunotherapies, including adoptive NK cell transfer and Chimeric Antigen Receptor-Natural Killer (CAR-NK) cell therapies. Methods: A comprehensive literature review was conducted, prioritizing peer-reviewed studies from the last decade on NK cell biology, tumor immune evasion, and immunotherapeutic applications. The analysis includes data from preclinical models and clinical trials evaluating NK cell expansion strategies, cytokine-based stimulation, and CAR-NK cell therapy developments. Results: NK cells eliminate tumors through cytotoxic granule release, death receptor pathways, and cytokine secretion. However, tumor cells evade NK-mediated immunity by downregulating activating ligands, secreting immunosuppressive molecules, and altering the tumor microenvironment. Novel NK cell-based therapies, such as CAR-NK cells and combination approaches with immune checkpoint inhibitors, enhance NK cell persistence and therapeutic efficacy against both hematologic and solid malignancies. Clinical trials suggest improved safety profiles compared to CAR-T therapies, with reduced cytokine release syndrome and graft-versus-host disease. Conclusions: While NK cell-based immunotherapies hold great promise, challenges remain, including limited persistence and tumor-induced immunosuppression. Addressing these hurdles will be critical for optimizing NK cell therapies and advancing next-generation, off-the-shelf immunotherapeutics for broader clinical applications.
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Zhuang, Xiaoxuan, and Eric O. Long. "CD28 homolog is a strong activator of natural killer cells for lysis of B7H7-positive tumor cells." Journal of Immunology 202, no. 1_Supplement (2019): 134.5. http://dx.doi.org/10.4049/jimmunol.202.supp.134.5.
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Abstract The CD28–B7 family of receptor–ligand pairs regulate lymphocyte responses through costimulation and coinhibition. It includes checkpoint inhibitors, such as PD-1, which limit anti-tumor and anti-virus T cell responses. CD28 homolog (CD28H) and B7H7 have been identified as a new receptor–ligand pair in this family, which has costimulatory activity in T cells. Here we show that CD28H is expressed in primary natural killer (NK) cells and that it is a strong activator of NK cells through selective synergy with receptors NKp46 and 2B4 to induce degranulation, lysis of target cells, and production of pro-inflammatory cytokines. Expression of B7H7 on target cells enhanced both natural and antibody-dependent cellular cytotoxicity (ADCC) of NK cells. Mutation of tyrosine 192 on the CD28H cytoplasmic tail abolished NK cell activation through CD28H. As B7H7 is broadly expressed in tumor tissues, we engineered a CD28H chimeric antigen receptor (CD28H-CAR) consisting of full-length CD28H fused to the cytoplasmic domain of T cell receptor zeta chain. NK cell activation is controlled by dominant “self-inhibition” mediated by inhibitory receptors for MHC class I, which has been a constraint for NK cellular cancer therapy. Remarkably, expression of CD28H-CAR in NK cells triggered lysis of tumor cells expressing HLA-E and B7H7 by overriding inhibition mediated by the HLA-E receptor NKG2A. The cytoplasmic domains of both CD28H and TCR zeta chain were required for this activity. Thus, CD28H is a powerful activation receptor of NK cells that broadens their anti-tumor activity and holds promise as a component of NK-based CARs for cancer immunotherapy.
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Gunduz, Mehmet, Pinar Ataca Atilla, and Erden Atilla. "New Orders to an Old Soldier: Optimizing NK Cells for Adoptive Immunotherapy in Hematology." Biomedicines 9, no. 9 (2021): 1201. http://dx.doi.org/10.3390/biomedicines9091201.
Full textAbstract:
NK (Natural Killer) cell-mediated adoptive immunotherapy has gained attention in hematology due to the progressing knowledge of NK cell receptor structure, biology and function. Today, challenges related to NK cell expansion and persistence in vivo as well as low cytotoxicity have been mostly overcome by pioneering trials that focused on harnessing NK cell functions. Recent technological advancements in gene delivery, gene editing and chimeric antigen receptors (CARs) have made it possible to generate genetically modified NK cells that enhance the anti-tumor efficacy and represent suitable “off-the-shelf” products with fewer side effects. In this review, we highlight recent advances in NK cell biology along with current approaches for potentiating NK cell proliferation and activity, redirecting NK cells using CARs and optimizing the procedure to manufacture clinical-grade NK and CAR NK cells for adoptive immunotherapy.
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Su, Yinghan, Jiang Li, Weidan Ji, et al. "Triple-serotype chimeric oncolytic adenovirus exerts multiple synergistic mechanisms against solid tumors." Journal for ImmunoTherapy of Cancer 10, no. 5 (2022): e004691. http://dx.doi.org/10.1136/jitc-2022-004691.
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BackgroundOncolytic virotherapy has become an important branch of cancer immunotherapy. This study investigated the efficacy of an oncolytic adenovirus (OAV), OncoViron, with synergistic mechanisms in the treatment of multiple solid tumors.MethodsAn OAV, OncoViron, was constructed and investigated by cytological experiments and implanted tumor models of multiple solid tumor cell lines to certify its anticancer efficacy, the synergistic effects of viral oncolysis and transgene anticancer activity of OncoViron, as well as oncolytic virotherapy combined with immunotherapy, were also verified.ResultsThe selective replication of OncoViron mediated high expression of anticancer factors, specifically targeted a variety of solid tumors and significantly inhibited cancer cell proliferation. On a variety of implanted solid tumor models in immunodeficient mice, immunocompetent mice, and humanized mice, OncoViron showed great anticancer effects on its own and in combination with programmed death 1 (PD-1) antibody and chimeric antigen receptor (CAR) T cells. Pathological examination, single-cell sequencing, and spatial transcriptome analysis of animal implanted tumor specimens confirmed that OncoViron significantly altered the gene expression profile of infected cancer cells, not only recruiting a large number of lymphocytes, natural killer cells, and mononuclear macrophages into tumor microenvironment (TME) and activated immune cells, especially T cells but also inducing M1 polarization of macrophages and promoting the release of more immune cytokines, thereby remodeling the TME for coordinating PD-1 antibody or CAR T therapy.ConclusionsThe chimeric OncoViron is a novel broad-spectrum anticancer product with multiple mechanisms of synergistic and potentiated immunotherapy, creating a good opportunity for combined immunotherapy against solid tumors.
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Panagiotou, Emmanouil, Nikolaos K. Syrigos, Andriani Charpidou, Elias Kotteas, and Ioannis A. Vathiotis. "CD24: A Novel Target for Cancer Immunotherapy." Journal of Personalized Medicine 12, no. 8 (2022): 1235. http://dx.doi.org/10.3390/jpm12081235.
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Cluster of differentiation 24 (CD24) is a small, highly glycosylated cell adhesion protein that is normally expressed by immune as well as epithelial, neural, and muscle cells. Tumor CD24 expression has been linked with alterations in several oncogenic signaling pathways. In addition, the CD24/Siglec-10 interaction has been implicated in tumor immune evasion, inhibiting macrophage-mediated phagocytosis as well as natural killer (NK) cell cytotoxicity. CD24 blockade has shown promising results in preclinical studies. Although there are limited data on efficacy, monoclonal antibodies against CD24 have demonstrated clinical safety and tolerability in two clinical trials. Other treatment modalities evaluated in the preclinical setting include antibody–drug conjugates and chimeric antigen receptor (CAR) T cell therapy. In this review, we summarize current evidence and future perspectives on CD24 as a potential target for cancer immunotherapy.
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Islam, Rasa, Aleta Pupovac, Vera Evtimov, et al. "Enhancing a Natural Killer: Modification of NK Cells for Cancer Immunotherapy." Cells 10, no. 5 (2021): 1058. http://dx.doi.org/10.3390/cells10051058.
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Natural killer (NK) cells are potent innate immune system effector lymphocytes armed with multiple mechanisms for killing cancer cells. Given the dynamic roles of NK cells in tumor surveillance, they are fast becoming a next-generation tool for adoptive immunotherapy. Many strategies are being employed to increase their number and improve their ability to overcome cancer resistance and the immunosuppressive tumor microenvironment. These include the use of cytokines and synthetic compounds to bolster propagation and killing capacity, targeting immune-function checkpoints, addition of chimeric antigen receptors (CARs) to provide cancer specificity and genetic ablation of inhibitory molecules. The next generation of NK cell products will ideally be readily available as an “off-the-shelf” product and stem cell derived to enable potentially unlimited supply. However, several considerations regarding NK cell source, genetic modification and scale up first need addressing. Understanding NK cell biology and interaction within specific tumor contexts will help identify necessary NK cell modifications and relevant choice of NK cell source. Further enhancement of manufacturing processes will allow for off-the-shelf NK cell immunotherapies to become key components of multifaceted therapeutic strategies for cancer.
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Ye, Ziyun A. "The Advances and Challenges of CAR-NK Cells for Tumor Immunotherapy." E3S Web of Conferences 131 (2019): 01001. http://dx.doi.org/10.1051/e3sconf/201913101001.
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Immunotherapies using chimeric antigen receptor (CAR)-T cells bring an encouraging vision to non-Hodgkin lymphoma patients who develop relapsed lymphoma or are unresponsive to standard chemotherapy, yet they also have limitations and drawbacks. Clinical trials have reported cases of neurotoxicity and cytokine release syndrome (CRS) accompanied by CAR-T cell therapies. To establish a more mature therapy, CAR incorporated into Natural Killer (NK) cells came into being. As a leukocyte involved in innate immunity, NK cell does not require MHC matching, making the production of allogeneic “off-the-shelf” CAR-NK cells possible. Moreover, the controllable life span of CAR-NK cells and little risk of graft-versus-host disease reduce side effects companion by CAR-T. This review provides an overview of CAR-NK design and production before delivery to patients. Different sources of NK cells are compared and the development of CAR molecule construction is introduced.
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Tamura, Hideto, Mariko Ishibashi, Mika Sunakawa, and Koiti Inokuchi. "Immunotherapy for Multiple Myeloma." Cancers 11, no. 12 (2019): 2009. http://dx.doi.org/10.3390/cancers11122009.
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Despite therapeutic advances over the past decades, multiple myeloma (MM) remains a largely incurable disease with poor prognosis in high-risk patients, and thus new treatment strategies are needed to achieve treatment breakthroughs. MM represents various forms of impaired immune surveillance characterized by not only disrupted antibody production but also immune dysfunction of T, natural killer cells, and dendritic cells, although immunotherapeutic interventions such as allogeneic stem-cell transplantation and dendritic cell-based tumor vaccines were reported to prolong survival in limited populations of MM patients. Recently, epoch-making immunotherapies, i.e., immunomodulatory drug-intensified monoclonal antibodies, such as daratumumab combined with lenalidomide and chimeric antigen receptor T-cell therapy targeting B-cell maturation antigen, have been developed, and was shown to improve prognosis even in advanced-stage MM patients. Clinical trials using other antibody-based treatments, such as antibody drug-conjugate and bispecific antigen-directed CD3 T-cell engager targeting, are ongoing. The manipulation of anergic T-cells by checkpoint inhibitors, including an anti-T-cell immunoglobulin and ITIM domains (TIGIT) antibody, also has the potential to prolong survival times. Those new treatments or their combination will improve prognosis and possibly point toward a cure for MM.