Treatment of cancer with allogeneic natural killer (NK) cell therapies has seen rapid development, especially use against hematologic malignancies. Clinical trials of NK cell-based adoptive transfer ...to treat relapsed or refractory malignancies have used peripheral blood, umbilical cord blood and pluripotent stem cell-derived NK cells, with each approach undergoing continued clinical development. Improving the potency of these therapies relies on genetic modifications to improve tumor targeting and to enhance expansion and persistence of the NK cells. Induced pluripotent stem cell (iPSC)-derived NK cells allow for routine targeted introduction of genetic modifications and expansion of the resulting NK cells derived from a clonal starting cell population. In this review, we discuss and summarize recent important advances in the development of new iPSC-derived NK cell therapies, with a focus on improved targeting of cancer. We then discuss improvements in methods to expand iPSC-derived NK cells and how persistence of iPSC-NK cells can be enhanced. Finally, we describe how these advances may combine in future NK cell-based therapy products for the treatment of both hematologic malignancies and solid tumors.
Natural killer (NK) cells derived or isolated from different sources have been gaining in importance for cancer therapies. In this study, we evaluate and compare key characteristics between NK cells ...derived or isolated from umbilical cord blood, umbilical cord blood hematopoietic stem/progenitor cells, peripheral blood, and induced pluripotent stem cells (iPSCs). Specifically, we find CD56
NK cells isolated and expanded directly from umbilical cord blood (UCB56) and NK cells derived from CD34
hematopoietic stem/progenitors in umbilical cord blood (UCB34) differ in their expression of markers associated with differentiation including CD16, CD2, and killer Ig-like receptors (KIRs). UCB56-NK cells also displayed a more potent cytotoxicity compared to UCB34-NK cells. NK cells derived from iPSCs (iPSC-NK cells) were found to have variable KIR expression, with certain iPSC-NK cell populations expressing high levels of KIRs and others not expressing KIRs. Notably, KIR expression on UCB56 and iPSC-NK cells had limited effect on cytotoxic activity when stimulated by tumor target cells that express high levels of cognate HLA class I, suggesting that
differentiation and expansion may override the KIR-HLA class I mediated inhibition when used across HLA barriers. Together our results give a better understanding of the cell surface receptor, transcriptional, and functional differences between NK cells present in umbilical cord blood and hematopoietic progenitor-derived NK cells which may prove important in selecting the most active NK cell populations for treatment of cancer or other therapies.
In this issue of Cell Stem Cell, Woan et al., (2021) investigate the anti-cancer activity of triple gene edited iPSC-derived natural killer (NK) cells and demonstrate that expression of a modified ...CD16a and interleukin (IL)-15 receptor combined with knockout of CD38 improves NK cell-mediated activity against leukemia and multiple myeloma.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Treatment of acute myeloid leukemia (AML) has changed dramatically in the past ten years with the approval of targeted agents, the first of which was the anti-CD33 antibody-drug conjugate gemtuzumab ...ozogamicin (GO). Despite withdrawal from the market after accelerated approval, GO was reapproved and now has a well-established role in treating select AML patients. CD33 has proven to be an important target for drug development in AML as evidenced by the improvement in survival with GO treatment.
The review summarizes the development of GO, its mechanism of action, initial studies and approval, withdrawal from the market, and subsequent reapproval after the results of several large randomized studies became available. We also provide an overview of its current role in the treatment landscape of AML.
Multiple phase 3 trials with GO have established a significant benefit with GO in induction therapy for favorable risk AML. Additional studies support the use of GO in relapsed/refractory AML and APL. Despite the withdrawal of GO from the market after initial approval, GO has proven to improve survival of select AML patients when added to induction chemotherapy and in relapsed disease.
Acute megakaryocytic leukemia (AMKL) is one of the most deadly and least treatable leukemias. In AMKL, the leukemia blasts possess megakaryocyte characteristics, but unlike normal megakaryocytes they ...fail to differentiate and exit the proliferative cycle (1). The prognosis for many patients with AMKL is poor, and new treatment approaches are needed. In 2012 the Crispino lab completed a high content screen to attempt to identify new AMKL therapeutics. The small molecule screen identified several promising compounds that induced proliferation arrest and polyploidization of malignant megakaryocytes. The most effective molecule, dimethylfasudil (diMF), selectively induced polyploidy, differentiation, and proliferation arrest of AMKL blasts in vitro and in vivo (2). To identify the relevant cellular targets of diMF, genetic and proteomic experiments were performed. These studies pointed to aurora kinase A (AURKA) as the critical target. Additional experiments with the highly selective and potent AURKA inhibitor MLN8237 confirmed that AURKA inhibition leads to polyploidization of malignant megakaryocytes and can effectively treat AMKL in several disease models. To investigate the function of AURKA in normal hematopoiesis, megakaryocyte development and myelofibrosis, AURKA tissue specific knockout studies were completed. We found that loss of AURKA in hematopoietic cells causes profound, cell autonomous defects in the peripheral blood and bone marrow. In addition, we discovered that loss of just one allele of AURKA retards the development of myelofibrosis. AURKA inhibitors induced differentiation and cell death of MPN cells as well and with JAK2 inhibitors synergistically induced cell death. Surprisingly, in contrast to the survival defects of nearly all hematopoietic lineages, deletion of AURKA resulted in increased differentiation and polyploidization of megakaryocytes. With respect to the mechanism of megakaryocyte differentiation, we determined that AURKA phosphorylates the transcription factor NF-E2. AURKA phosphorylation of NF-E2 impaired its chromatin occupancy and transcriptional activity. Taken together, our data show that AURKA is required for adult hematopoiesis, development of myelofibrosis and that AURKA functions to suppress megakaryocyte maturation by maintaining phosphorylation of NF-E2. Thus, in addition to its cell cycle functions, AURKA controls the activity of an essential hematopoietic transcription factor to regulate differentiation.
BackgroundNatural killer (NK) cells are key effector cells of antitumor immunity. However, tumors can acquire resistance programs to escape NK cell-mediated immunosurveillance. Identifying mechanisms ...that mediate this resistance enables us to define approaches to improve immune-mediate antitumor activity. In previous studies from our group, a genome-wide CRISPR-Cas9 screen identified Charged Multivesicular Body Protein 2A (CHMP2A) as a novel mechanism that mediates tumor intrinsic resistance to NK cell activity.MethodsHere, we use an immunocompetent mouse model to demonstrate that CHMP2A serves as a targetable regulator of not only NK cell-mediated immunity but also other immune cell populations. Using the recently characterized murine 4MOSC model system, a syngeneic, tobacco-signature murine head and neck squamous cell carcinoma model, we deleted mCHMP2A using CRISPR/Cas9-mediated knock-out (KO), following orthotopic transplantation into immunocompetent hosts.ResultsWe found that mCHMP2A KO in 4MOSC1 cells leads to more potent NK-mediated tumor cell killing in vitro in these tumor cells. Moreover, following orthotopic transplantation, KO of mCHMP2A in 4MOSC1 cells, but not the more immune-resistant 4MOSC2 cells enables both T cells and NK cells to better mediate antitumor activity compared with wild type (WT) tumors. However, there was no difference in tumor development between WT and mCHMP2A KO 4MOSC1 or 4MOSC2 tumors when implanted in immunodeficient mice. Mechanistically, we find that mCHMP2A KO 4MOSC1 tumors transplanted into the immunocompetent mice had significantly increased CD4+T cells, CD8+T cells. NK cell, as well as fewer myeloid-derived suppressor cells (MDSC).ConclusionsTogether, these studies demonstrate that CHMP2A is a targetable inhibitor of cellular antitumor immunity.
Predicting future climate change over a region of complex terrain, such as the western United States (US), remains challenging due to the low resolution of global climate models (GCMs). Yet the ...climate extremes of recent years in this region, such as floods, wildfires, and drought, are likely to intensify further as climate warms, underscoring the need for high-quality and high-resolution predictions. Here, we present an ensemble of dynamically downscaled simulations over the western US from 1980-2100 at 9 km grid spacing, driven by 16 latest-generation GCMs. This dataset is titled the Western US Dynamically Downscaled Dataset (WUS-D3).
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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