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Chimeric antigen receptor (CAR)‐natural killer (NK)‐cell therapy has emerged as a promising strategy in the treatment of haematological malignancies and solid cancers. Leveraging the innate immune properties of NK cells, CAR‐NK‐cell therapies offer potential advantages for cell therapy, including safety of use in the allogeneic setting and reduced risk of toxicity. This Nutshell provides an overview of the latest advancements in CAR‐NK‐cell therapy and the challenges that remain. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndrome and acute myeloid leukemia (AML) belong to a continuous disease spectrum of myeloid malignancies with poor prognosis in the relapsed/refractory setting necessitating novel therapies. Natural killer (NK) cells from patients with myeloid malignancies display global dysfunction with impaired killing capacity, altered metabolism, and an exhausted phenotype at the single-cell transcriptomic and proteomic levels. In this study, we identified that this dysfunction was mediated through a cross-talk between NK cells and myeloid blasts necessitating cell-cell contact. NK cell dysfunction could be prevented by targeting the αvβ-integrin/TGF-β/SMAD pathway but, once established, was persistent because of profound epigenetic reprogramming. We identified BATF as a core transcription factor and the main mediator of this NK cell dysfunction in AML. Mechanistically, we found that BATF was directly regulated and induced by SMAD2/3 and, in turn, bound to key genes related to NK cell exhaustion, such as HAVCR2, LAG3, TIGIT, and CTLA4. BATF deletion enhanced NK cell function against AML in vitro and in vivo. Collectively, our findings reveal a previously unidentified mechanism of NK immune evasion in AML manifested by epigenetic rewiring and inactivation of NK cells by myeloid blasts. This work highlights the importance of using healthy allogeneic NK cells as an adoptive cell therapy to treat patients with myeloid malignancies combined with strategies aimed at preventing the dysfunction by targeting the TGF-β pathway or BATF. Editor's summary: Patients with myeloid malignancies, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), often relapse after standard of care. To improve outcomes, Kumar et al. have investigated the role of natural killer (NK) cells in antitumor immunity against myeloid blasts and have identified global dysfunction of NK cells in these patients. They identified BATF as responsible for this dysfunction, and by knocking out BATF downstream of the TGF-β canonical pathway in NK cells, they were able to enhance NK cell function against AML in vitro and in vivo. This has led to the initiation of a promising clinical trial using these TGFBR2 knockout NK cells against myeloid malignancies. —Dorothy Hallberg [ABSTRACT FROM AUTHOR]

Summary: Adoptive cellular therapy using chimeric antigen receptor (CAR) T cells has led to a paradigm shift in the treatment of various hematologic malignancies. However, the broad application of this approach for myeloid malignancies and solid cancers has been limited by the paucity and heterogeneity of target antigen expression, and lack of bona fide tumor‐specific antigens that can be targeted without cross‐reactivity against normal tissues. This may lead to unwanted on‐target off‐tumor toxicities that could undermine the desired antitumor effect. Recent advances in synthetic biology and genetic engineering have enabled reprogramming of immune effector cells to enhance their selectivity toward tumors, thus mitigating on‐target off‐tumor adverse effects. In this review, we outline the current strategies being explored to improve CAR selectivity toward tumor cells with a focus on natural killer (NK) cells, and the progress made in translating these strategies to the clinic. [ABSTRACT FROM AUTHOR]

Summary: Chimeric antigen receptor (CAR) T cells are a rapidly emerging form of cancer treatment, and have resulted in remarkable responses in refractory lymphoid malignancies. However, their widespread clinical use is limited by toxicity related to cytokine release syndrome and neurotoxicity, the logistic complexity of their manufacturing, cost and time‐to‐treatment for autologous CAR‐T cells, and the risk of graft‐versus‐host disease (GvHD) associated with allogeneic CAR‐T cells. Natural killer (NK) cells have emerged as a promising source of cells for CAR‐based therapies due to their ready availability and safety profile. NK cells are part of the innate immune system, providing the first line of defence against pathogens and cancer cells. They produce cytokines and mediate cytotoxicity without the need for prior sensitisation and have the ability to interact with, and activate other immune cells. NK cells for immunotherapy can be generated from multiple sources, such as expanded autologous or allogeneic peripheral blood, umbilical cord blood, haematopoietic stem cells, induced pluripotent stem cells, as well as cell lines. Genetic engineering of NK cells to express a CAR has shown impressive preclinical results and is currently being explored in multiple clinical trials. In the present review, we discuss both the preclinical and clinical trial progress made in the field of CAR NK‐cell therapy, and the strategies to overcome the challenges encountered. [ABSTRACT FROM AUTHOR]

Keywords: cellular therapy; chimeric antigen receptor-T cell therapy; chimeric antigen receptor-natural killer cell therapy; adoptive cell therapy; T cells; natural killer cells; immune effector cells; cancer Among these, CAR T-cell therapy was the first to be approved by the US Food and Drug Administration (FDA) for the treatment of patients with B lymphoid malignancies. Cellular therapy, chimeric antigen receptor-T cell therapy, chimeric antigen receptor-natural killer cell therapy, adoptive cell therapy, T cells, natural killer cells, immune effector cells, cancer. [Extracted from the article]

Glioblastoma (GBM) is an aggressive brain cancer with limited therapeutic options. Natural killer (NK) cells are innate immune cells with strong anti-tumor activity and may offer a promising treatment strategy for GBM. We compared the anti-GBM activity of NK cells engineered to express interleukin (IL)-15 or IL-21. Using multiple in vivo models, IL-21 NK cells were superior to IL-15 NK cells both in terms of safety and long-term anti-tumor activity, with locoregionally administered IL-15 NK cells proving toxic and ineffective at tumor control. IL-21 NK cells displayed a unique chromatin accessibility signature, with CCAAT/enhancer-binding proteins (C/EBP), especially CEBPD, serving as key transcription factors regulating their enhanced function. Deletion of CEBPD resulted in loss of IL-21 NK cell potency while its overexpression increased NK cell long-term cytotoxicity and metabolic fitness. These results suggest that IL-21, through C/EBP transcription factors, drives epigenetic reprogramming of NK cells, enhancing their anti-tumor efficacy against GBM. [Display omitted] • IL-21 NK cells show superior safety and anti-tumor activity vs. IL-15 NK cells • IL-21 NK cells have a distinct epigenetic profile driven by C/EBP, mainly CEBPD • CEBPD is a key mediator of IL-21 NK cell response against glioblastoma stem cells • IL-21 engineered NK cells present a promising therapeutic strategy for glioblastoma Glioblastoma (GBM) represents an aggressive brain malignancy with limited treatments. Shanley et al. engineer NK cells to express interleukin (IL)-21, which show superior safety and long-term anti-tumor activity compared to IL-15 NK cells. Key transcription factors like CEBPD drive this enhanced function, suggesting that IL-21 reprograms NK cells epigenetically, enhancing their therapeutic efficacy against GBM. [ABSTRACT FROM AUTHOR]