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Background Natural killer (NK) cell immunotherapy has shown promising therapeutic potential for acute myeloid leukemia (AML), especially with advancements in chimeric antigen receptor-engineered NK cells (CAR-NK) and artificial intelligence (AI). Despite these developments, the field lacks comprehensive bibliometric analyses to identify research hotspots and trends, which could guide future precision treatments. Methods A bibliometric analysis of NK cell immunotherapy for AML was conducted using literature from 2000 to 2023 retrieved from the Web of Science Core Collection database. Data visualization tools like CiteSpace, VOSviewer, and RStudio were employed to analyze publication trends, country contributions, institutional collaborations, influential authors, and research themes. Results The analysis identified 1513 studies, with the United States and China leading global contributions. Notable institutions include the University of Minnesota and MD Anderson Cancer Center. Hot topics include allogeneic NK therapy, CAR-NK cell therapy, and memory-like NK cells. Emerging trends highlight the integration of intelligent NK cells and combinatory therapies, offering promising avenues for AML treatment. Despite progress, challenges such as NK cell expansion, activation, and resistance mechanisms remain critical areas for research. Conclusion This study provides a comprehensive overview of the research landscape, highlighting the transformative potential of NK cell immunotherapy in AML. It underscores the need for international collaboration and continued innovation to overcome existing challenges and advance precision therapies.

Introduction A new type of immune cell transplantation called allogeneic NK cell infusion is proposed as a potential universal off-the-shelf cell product for adoptive immune cell therapy in hematologic malignancies. Design A multicentral phase I non-randomized clinical trial was conducted to assess the safety, feasibility, and potential efficacy of adoptively infused NK cells in patients with refractory/relapsed AML. We evaluated the feasibility of the trial by considering cell production, patient selection, and treatment protocol. Method Allogeneic NK cells were produced from random healthy unrelated donors; 10 patients were selected according to the inclusion criteria and were included in two groups in case of NK cell dose escalation. Two cell infusions were given, spaced 7 days apart, following a lymphodepletion conditioning regimen of fludarabin-endoxan administered 7 days before the first infusion. The intervention safety was scored using Common Terminology Criteria for Adverse Events (CTCAE) based on variations in vital signs due to cell infusion. NK cell chimerism, tumor burden, and duration of relapse were considered to be components of efficacy. The pilot feasibility evaluation was checked using the CONSORT platform. Results The NK cell infusion procedure was well tolerated, and no grade 2–5 toxicities related (possible or probable) to PB-NK cell infusion were observed. Four patients developed grade 1 transient chills, headaches, vomiting, and bone pain following each PB-NK cell infusion that were not required hospitalization. One of these patients (p01) died because of severe acute respiratory syndrome. Of 9 evaluable patients, 6 (66.6%) showed stable disease (SD) and 3 (33.3%) presented progressive disease (PD). Of 6 SD patients, 2 (p08 and p09) remained alive in SD and 3 patients (p04, p05 and p07) converted to PD at 9 months after infusion of NK cells, and 1 (p03) was not evaluable due to follow-up loss. No patient achieved complete remission. Conclusion The study demonstrated the feasibility and safety of adoptive transfer of random healthy unrelated donor PB-NK cells in refractory/relapsed AML patients and supports continued study in phase II clinical trials in relapsed/refractory AML patients.

Natural killer cells (NK cells) are the first line of the innate immune defense system, primarily located in peripheral circulation and lymphoid tissues. They kill virally infected and malignant cells through a balancing play of inhibitory and stimulatory receptors. In pre-clinical investigational studies, NK cells show promising anti-tumor effects and are used in adoptive transfer of activated and expanded cells, ex-vivo . NK cells express co-stimulatory molecules that are attractive targets for the immunotherapy of cancers. Recent clinical trials are investigating the use of CAR-NK for different cancers to determine the efficiency. Herein, we review NK cell therapy approaches (NK cell preparation from tissue sources, ways of expansion ex-vivo for “off-the-shelf” allogeneic cell-doses for therapies, and how different vector delivery systems are used to engineer NK cells with CARs) for cancer immunotherapy.

Natural killer (NK) cells are unique immune effectors able to kill cancer cells by direct recognition of surface ligands, without prior sensitization. Allogeneic NK transfer is a highly valuable treatment option for cancer and has recently emerged with hundreds of clinical trials paving the way to finally achieve market authorization. Advantages of NK cell therapies include the use of allogenic cell sources, off-the-shelf availability, and no risk of graft-versus-host disease (GvHD). Allogeneic NK cell therapies have reached the clinical stage as ex vivo expanded and differentiated non-engineered cells, as chimeric antigen receptor (CAR)-engineered or CD16-engineered products, or as combination therapies with antibodies, priming agents, and other drugs. This review summarizes the recent clinical status of allogeneic NK cell-based therapies for the treatment of hematological and solid tumors, discussing the main characteristics of the different cell sources used for NK product development, their use in cell manufacturing processes, the engineering methods and strategies adopted for genetically modified products, and the chosen approaches for combination therapies. A comparative analysis between NK-based non-engineered, engineered, and combination therapies is presented, examining the choices made by product developers regarding the NK cell source and the targeted tumor indications, for both solid and hematological cancers. Clinical trial outcomes are discussed and, when available, assessed in comparison with preclinical data. Regulatory challenges for product approval are reviewed, highlighting the lack of specificity of requirements and standardization between products. Additionally, the competitive landscape and business field is presented. This review offers a comprehensive overview of the effort driven by biotech and pharmaceutical companies and by academic centers to bring NK cell therapies to pivotal clinical trial stages and to market authorization.

IntroductionNatural killer 92 (NK-92) cells are an attractive therapeutic approach as alternative chimeric antigen receptor (CAR) carriers, different from T cells, once they can be used in the allogeneic setting. The modest in vivo outcomes observed with NK-92 cells continue to present hurdles in successfully translating NK-92 cell therapies into clinical applications. Adoptive transfer of CAR-NK-92 cells holds out the promise of therapeutic benefit at a lower rate of adverse events due to the absence of GvHD and cytokine release syndrome. However, it has not achieved breakthrough clinical results yet, and further improvement of CAR-NK-92 cells is necessary.MethodsIn this study, we conducted a comparative analysis between CD19-targeted CAR (CAR.19) co-expressing IL-15 (CAR.19-IL15) with IL-15/IL-15Rα (CAR.19-IL15/IL15Rα) to promote NK cell proliferation, activation, and cytotoxic activity against B-cell leukemia. CAR constructs were cloned into lentiviral vector and transduced into NK-92 cell line. Potency of CAR-NK cells were assessed against CD19-expressing cell lines NALM-6 or Raji in vitro and in vivo in a murine model. Tumor burden was measured by bioluminescence.ResultsWe demonstrated that a fourth- generation CD19-targeted CAR (CAR.19) co-expressing IL-15 linked to its receptor IL-15/IL-15Rα (CAR.19-IL-15/IL-15Rα) significantly enhanced NK-92 cell proliferation, proinflammatory cytokine secretion, and cytotoxic activity against B-cell cancer cell lines in vitro and in a xenograft mouse model.ConclusionTogether with the results of the systematic analysis of the transcriptome of activated NK-92 CAR variants, this supports the notion that IL-15/IL-15Rα comprising fourth-generation CARs may overcome the limitations of NK-92 cell-based targeted tumor therapies in vivo by providing the necessary growth and activation signals.

Relapsed/refractory (r/r) large B-cell lymphoma (LBCL) remains a difficult-to-treat disease with limited treatment options and high unmet clinical need, necessitating the development of new therapies with greater potency and broader applicability. While autologous chimeric antigen receptor (CAR)-T cell therapies have transformed the treatment landscape, 60-65% of patients receiving these therapies eventually relapse, underscoring the need for improved approaches. Allogeneic CAR-T and CAR-NK cell therapies have recently emerged as promising alternatives, offering the potential to shorten manufacturing times, reduce costs, and expand access to a broader patient population. This systematic review and meta-analysis compiles the currently available clinical trial data on the efficacy and safety of these novel therapies in adult patients with r/r LBCL. A systematic search of MEDLINE, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials was conducted for studies published up to January 12, 2025, involving allogeneic CAR-T and CAR-NK cell therapies in R/R LBCL. The primary outcomes assessed were the best overall response rate (bORR) and best complete response rate (bCRR) at any time point. Secondary outcomes included rates of grade 1-2 and grade 3+ cytokine release syndrome (CRS), grade 1-2 and grade 3+ immune effector cell-associated neurotoxicity syndrome (ICANS), grade 1-2 and grade 3+ infections and incidence of graft-versus-host disease (GvHD). Nineteen studies met the inclusion and exclusion criteria, encompassing 334 patients (155 CAR-NK; 179 CAR-T) evaluable for safety and 235 patients evaluable for response (77 CAR-NK; 158 CAR-T). The pooled estimates for the best overall response rate (bORR) and the best complete response rate (bCRR) were 52.5% [95% CI, 41.0-63.9] and 32.8% [95% CI, 24.2-42.0], respectively. Safety analysis revealed very low incidences of grade 3+ CRS (0.04% [95% CI 0.00-0.49]) or grade 3+ ICANS (0.64% [95% CI 0.01-2.23]) and only one occurrence of a GvH-like reaction across 334 infused patients enrolled in the included studies, highlighting the remarkable safety profile of CAR-engineered \"off-the-shelf\" allogeneic approaches. The estimated overall incidence of low-grade CRS was 30% [95% CI, 14-48], while the estimated overall incidence of low-grade ICANS was 1% [95% CI, 0%-4%], markedly lower than current-generation autologous CAR-T cell products. The incidence of low-grade and severe infections was 25% [95% CI 14-36%) (n=252) and 7% [95% CI 2-14%] (n=291), respectively. Together, allogeneic CAR-T and CAR-NK cell therapies demonstrate encouraging efficacy in heavily pretreated patients with r/r LBCL. Coupled with their favorable safety profiles and the potential for off-the-shelf availability, allogeneic cell therapies hold great promise to broaden the reach of live cell-based treatments, delivering impactful results to a wider patient population in the coming years.

Multiple myeloma (MM) is a clonal malignancy of plasma cells that remains largely incurable despite major advances in proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies. Chimeric antigen receptor (CAR)-engineered immune cells have transformed the therapeutic landscape, but CAR-T cell therapy faces challenges such as severe cytokine release syndrome (CRS), neurotoxicity, limited persistence, and logistical complexity. In recent years, natural killer (NK) cells have emerged as a promising platform for next-generation cellular immunotherapy, offering innate antitumor activity, a reduced risk of graft-versus-host disease (GvHD), and the feasibility of “off-the-shelf” allogeneic production. This review summarizes current advances in CAR-NK cell therapy for MM, focusing on two major aspects: the diversity of cell sources—including NK-92, peripheral (PB) and cord blood (CB), and induced pluripotent stem cell (iPSC)-derived NK cells—and the expanding repertoire of target antigens such as BCMA (B-cell maturation antigen), NKG2D, CD38, CD70, SLAMF7, CD138, and GPRC5D. We highlight preclinical and early clinical studies demonstrating potent cytotoxicity, favorable safety profiles, and innovative multi-targeting strategies designed to overcome antigen escape and enhance persistence. Emerging clinical data suggest that CAR-NK cell therapy may combine the specificity of CAR recognition with the inherent safety and versatility of NK biology, offering a potential paradigm shift in the treatment of relapsed or refractory MM. Further clinical validation will determine whether CAR-NK cell therapy can achieve durable remission and complement or surpass current CAR-T modalities.

Natural killer (NK) cells play a central role in the innate immune system. In allogeneic stem cell transplantation (alloSCT), alloreactive NK cells derived by the graft are discussed to mediate the elimination of leukemic cells and dendritic cells in the patient and thereby to reduce the risk for leukemic relapses and graft-versus-host reactions. The alloreactivity of NK cells is determined by various receptors including the activating CD94/NKG2C and the inhibitory CD94/NKG2A receptors, which both recognize the non-classical human leukocyte antigen E (HLA-E). Here we analyze the contribution of these receptors to NK cell alloreactivity in 26 patients over the course of the first year after alloSCT due to acute myeloid leukemia, myelodysplastic syndrome and T cell Non-Hodgkin-Lymphoma. Our results show that NK cells expressing the activating CD94/NKG2C receptor are significantly reduced in patients after alloSCT with severe acute and chronic graft-versus-host disease (GvHD). Moreover, the ratio of CD94/NKG2C to CD94/NKG2A was reduced in patients with severe acute and chronic GvHD after receiving an HLA-mismatched graft. Collectively, these results provide evidence for the first time that CD94/NKG2C is involved in GvHD prevention.

Cell-based immunotherapy, such as chimeric antigen receptor (CAR) T cell therapy, has revolutionized the treatment of hematological malignancies, especially in patients who are refractory to other therapies. However, there are critical obstacles that hinder the widespread clinical applications of current autologous therapies, such as high cost, challenging large-scale manufacturing, and inaccessibility to the therapy for lymphopenia patients. Therefore, it is in great demand to generate the universal off-the-shelf cell products with significant scalability. Human induced pluripotent stem cells (iPSCs) provide an “unlimited supply” for cell therapy because of their unique self-renewal properties and the capacity to be genetically engineered. iPSCs can be differentiated into different immune cells, such as T cells, natural killer (NK) cells, invariant natural killer T (iNKT) cells, gamma delta T (γδ T), mucosal-associated invariant T (MAIT) cells, and macrophages (Mφs). In this review, we describe iPSC-based allogeneic cell therapy, the different culture methods of generating iPSC-derived immune cells (e.g., iPSC-T, iPSC-NK, iPSC-iNKT, iPSC-γδT, iPSC-MAIT and iPSC-Mφ), as well as the recent advances in iPSC-T and iPSC-NK cell therapies, particularly in combinations with CAR-engineering. We also discuss the current challenges and the future perspectives in this field towards the foreseeable applications of iPSC-based immune therapy.

T cells engineered to express chimeric antigen receptors (CARs) have revolutionised the field of cellular therapy for cancer. Despite its success, this strategy has some recognised limitations and toxicities. Hence, there is growing interest in developing novel cellular therapies based on non‐αβ T‐cell immune effector cells, including NK cells that offer clear advantages in cancer immunotherapy. As a result, NK cells are being explored as an alternative platform for CAR engineering and are becoming recognised as important players in the next generation of cellular therapies targeting cancer. In this review, we highlight preclinical and clinical studies of CAR‐NK cells derived from different sources and discuss strategies under investigation to enhance the antitumor activity of these engineered innate immune cells. NK cells can be derived from various sources (PB, UCB, HSC, iPSC, NK cell lines) and can be engineered to express a chimeric antigen receptor (CAR) to target various surface antigens on cancer cells. These CAR‐NK cells can be used as off‐the‐shelf adoptive cellular therapy to treat patients with various malignancies.