scholarly journals NK Cells as Possible Prognostic Factor in Childhood Acute Lymphoblastic Leukemia

2019 ◽  
Vol 2019 ◽  
pp. 1-4 ◽  
Author(s):  
Agnieszka Mizia-Malarz ◽  
Grażyna Sobol-Milejska
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Prognostic Factor ◽  
Nk Cells ◽  
Nk Cell ◽  
Lymphoblastic Leukemia ◽  
Cell Percentage ◽  
Group I ◽  
Group Ii ◽  
Cluster Of Differentiation

Deficiency or impaired function natural killer (NK) cells might result in the development of serious infections and promote the development of malignancies. The aim of our study was to assess the prognostic role of NK cell percentage in bone marrow on the day of acute lymphoblastic leukemia (ALL) diagnosis. 84 children (49 males=58%; median age 5 yrs) with ALL were enrolled. The NK cell percentage was assessed using flow cytometry with antibodies against the cluster of differentiation (CD): CD3, CD56, and CD16. We evaluated two groups: group I (NK+), patients with NK cells in the bone marrow (n=74), and group II (NK-), patients without NK cells in the bone marrow (n=10) (cut-off value of negative <1%). In the patients from group I, the prednisone good response on day 8 and the remission on day 15 of treatment were observed significantly more often (p=.01, p=.03). The children from group I had significantly better survival as compared to those from group II (p=.02) (HR 2.59; 95% CI: 1.38-4.85). The presence of NK cells in the bone marrow at diagnosis can be a prognostic factor in children with ALL. The presented results should be the basis for further research.

Protective role of black seed oil in doxorubicin-induced cardiac toxicity in children with acute lymphoblastic leukemia

2020 ◽  
Vol 26 (6) ◽  
pp. 1397-1406 ◽  
Author(s):  
Adel A Hagag ◽  
Ibrahim M Badraia ◽  
Walid A El-Shehaby ◽  
Maaly M Mabrouk
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Dose Group ◽  
Seed Oil ◽  
Lymphoblastic Leukemia ◽  
Protective Role ◽  
Black Seed ◽  
Group I ◽  
Black Seed Oil ◽  
Group Ii

Background Leukemia is the most common pediatric malignancy. It affects bone marrow cells especially lymphoid cell precursor. Leukemia is treated mainly by chemotherapy. Doxorubicin is a well-established chemotherapeutic agent included in treatment protocols of acute lymphoblastic leukemia. Its efficacy is often limited by its cardiotoxic side effects. Many studies are directed to overcome this problem. Black seed oil was found to have a potent cardioprotective effect. Aim of the study: To assess the protective role of black seed oil against doxorubicin-induced cardiotoxicity in children with acute lymphoblastic leukemia. Subjects and methods This study was carried out on 40 children with acute lymphoblastic leukemia including 20 patients under doxorubicin therapy and black seed oil 80 mg/kg/dose divided into 3 doses starting at the same moment of beginning of doxorubicin infusion therapy and continued for 1 week after each doxorubicin dose [group I] and 20 patients under doxorubicin and placebo for 1 week after each doxorubicin dose [group II]. They underwent conventional echo-Doppler measures of left ventricular systolic and diastolic functions and pulsed wave tissue Doppler of lateral mitral annulus. Results No significant differences were found in parameters of electrocardiograph including S-T segment and Q-T interval either before or after doxorubicin therapy. No significant differences in echocardiographic parameters were found between group I and group II before therapy. Non-significant changes in parameters of diastolic function [E/A ratio or e/a ratio] were found after doxorubicin therapy in group I and II, but there were significant reduction in parameters of systolic function [EF, FS and s wave] after doxorubicin therapy more in group II than group I. Conclusion and recommendation: From this study, we concluded that: Black seed oil improves some cardiac side effects of doxorubicin as shown by better systolic functions in children with acute lymphoblastic leukemia who were treated with Doxorubicin and black seed (group I) than in children with acute lymphoblastic leukemia who were treated with doxorubicin alone with no black seeds (group II), and therefore multi center studies is recommended to be done before we can recommend the use of black seed oil as an adjuvant therapy in patients with acute lymphoblastic leukemia under doxorubicin-based treatment protocol.

CpG Oligonucleotides Induce Anti-Leukemia Activity in a Syngeneic Murine Model of Acute Lymphoblastic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2830-2830
Author(s):  
Alix E. Seif ◽  
Marlo D. Bruno ◽  
Junior Hall ◽  
Valerie I. Brown ◽  
Stephan A. Grupp ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Nk Cells ◽  
Bone Marrow Cells ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Intensive Therapy ◽  
Significant Proportion ◽  
Cpg Odn

Abstract Acute lymphoblastic leukemia (ALL) accounts for 80% of all pediatric leukemias and is the most common form of childhood cancer. While most children with ALL are cured by current therapies, refractory and relapsed ALL comprise a significant proportion of all pediatric cancers. Furthermore, nearly half of all ALL diagnoses occur in adults, who carry a much poorer prognosis, with the majority dying of relapsed disease. Relapsed ALL generally requires intensive therapy with significant associated morbidity and mortality. Development of novel therapies is essential to improving outcomes. DNA oligodeoxynucleotides containing CpG motifs (CpG ODN) stimulate anti-tumor immune activity via Toll-like receptor 9 (TLR9) activation and are currently in clinical trials for a variety of solid tumors. We have previously reported that CpG ODN stimulation alters antigen presentation by human ALL cells, enhancing allogeneic Th1 responses. In addition, we have shown that CpG ODN administration in vivo reduces the leukemic burden of primary human ALL xenografts in Nod-SCID mice, and that this activity is mediated in part by NK cells. To further the development of CpG ODN as a novel therapeutic agent for ALL, we have investigated the induction of anti-ALL activity by CpG ODN in a syngeneic ALL setting. CpG ODN did not exhibit direct toxicity against cell lines derived from leukemic Eμ-ret transgenic mice in vitro, nor did it alter CD40 or CD86 expression or cytokine production. However, using a flow cytometry-based in vitro killing assay we observed CpG ODN-induced elimination of leukemia cells when cultured with splenocytes or bone marrow cells from Eμ-ret transgene-negative mice (P=0.0388). The difference between CpG ODN-treated and untreated controls became more pronounced with increasing effector:target ratios (P<0.0001). Preliminary data show that depletion of NK cells markedly decreases the magnitude of the observed effect, supporting the hypothesis that this cell type is involved in targeted control of ALL in this model. The ability of CpG ODN to exert anti-leukemia activity in a syngeneic setting suggests that it may have utility as an adjuvant therapy. To test this hypothesis we administered CpG ODN (or PBS) to syngeneic leukemia-bearing mice 2 days after completion of a chemotherapy regimen used to reduce leukemia burden. When mice were sacrificed 3 weeks after treatment, we found significantly reduced leukemia burden in bone marrow (P=0.0019), spleen (P<0.00001) and blood (P=0.00028) of CpG ODN-treated mice. Cell-depletion and cytokine-neutralization assays are currently ongoing to define the mechanism of action of CpG ODN in these settings. To our knowledge, this is the first demonstration of CpG ODN-induced anti-ALL activity in a post-chemotherapy syngeneic model, suggesting that this agent has the potential to treat minimal residual disease and to reduce the incidence of relapse.

Incidence of Post-Thrombotic Syndrome Following Asymptomatic Thrombosis in Survivors of Childhood Acute Lymphoblastic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1631-1631
Author(s):  
Stefan Kuhle ◽  
Maria Spavour ◽  
Jacqueline Halton ◽  
Patricia Massicotte ◽  
Irene Cherrick ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Group I ◽  
Arm Circumference ◽  
History Of ◽  
Group Ii

Abstract BACKGROUND: Asymptomatic deep venous thrombosis (DVT) are well-known complications of treatment of acute lymphoblastic leukemia (ALL) in children. However, the clinical significance of radiographically detected, asymptomatic DVT is unclear and controversial, as there are no studies on long-term outcome of asymptomatic DVT in children available. There are two likely reasons for the studies not being done in this area. First, there is a lack of defined cohorts of pediatric patients screened for DVT and secondly, there is a great deal of difficulty in following patients over many years. The study, Prophylaxis with Antithrombin Replacement in Kids with ALL treated with L-Asparaginase (PARKAA) was a multicentre randomized controlled trial in which children with ALL were screened for DVT. As survivors of childhood cancer, the PARKAA cohort continues to be followed in their respective centers. Therefore, establishment of the PARKAA cohort (1997–99) and the ability to locate these patients provided a unique opportunity to study the long-term outcome of asymptomatic DVT. OBJECTIVE: To assess the incidence of PTS in children with ALL who previously had an asymptomatic DVT. The objective were approached in two ways. Firstly, to assess the outcome of asymptomatic DVT by determining the prevalence of PTS in children with a history of ALL with radiographically diagnosed DVT (PARKAA cohort); secondly, to corroborate the findings by determining the prevalence of PTS in an unselected group of survivors of childhood ALL. METHODS: Cross-sectional study in two separate populations: Group I comprised of children enrolled in the PARKAA multicentre study who had been screened for, and diagnosed with, DVT in the upper venous system. Group II consisted of non-selected patients &lt; 21 years with a history of ALL followed at Stollery Children’s Hospital, Edmonton. Patients were invited for a follow-up at their treatment centre (Group I) or were assessed for PTS childhood cancer survivor clinic (Group II). PTS was assessed by two of the investigators (Group I) or by the attending oncologist (Group II), respectively, using a standardized scoring sheet. RESULTS: Group I: 13 PARKAA patients with a history of ALL and objectively diagnosed DVT were assessed for PTS (4 males; median age 11.9 years; median age at diagnosis of ALL 4.4 years). 7/13 patients had PTS (54%, 95%CI 25;81). All patients with PTS had collaterals on examination, 3 also had increased arm circumference. Group II: 41 patients with a history of ALL were enrolled (61% males; median age at diagnosis 3.0 years; 28% high-risk, 67% standard risk). Mean length of follow-up since diagnosis was 9.5 years. PTS was diagnosed in 10/41 (24%; 95%CI 11–38) patients. All patients with PTS had collaterals on examination, 5 (50%) also had increased arm circumference. CONCLUSIONS: There is a clinically significant prevalence of PTS in children with a history of ALL and radiographically diagnosed DVT. A significant proportion of survivors of ALL develop PTS, indicating previously undiagnosed DVT in this population.

Natural Killer Cells In Pediatric Acute Lymphoblastic Leukemia Patients At Diagnosis Demonstrate An Inhibitory Phenotype and Reduced Cytolytic Capacity

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1397-1397 ◽  
Author(s):  
Rayne H. Rouce ◽  
Takuya Sekine ◽  
Gerrit Weber ◽  
Claude Chew ◽  
Katayoun Rezvani ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Nk Cells ◽  
Nk Cell ◽  
Lymphoblastic Leukemia ◽  
Target Cells ◽  
Healthy Controls ◽  
Cytokine Release ◽  
Absolute Count ◽  
Flow Cytometric ◽  
Pediatric All

Abstract Background Natural killer (NK) cells are a key component of innate immunity, with the potential to recognize and kill transformed malignant cells without prior sensitization. A balance between activating and inhibitory signals from cell surface receptors determines NK cell cytotoxicity and cytokine release. Therapeutic approaches to augmenting NK cell function are being explored in various malignancies. Little is known about NK phenotype and function in patients with childhood acute lymphoblastic leukemia (ALL), the most common childhood cancer. Here we describe an inhibitory phenotype and impaired cytolytic function in NK cells from pediatric ALL patients at diagnosis, compared with healthy pediatric controls. Restoring NK function may be a useful therapeutic approach in ALL. Methods Peripheral blood mononuclear cells (PBMCs) were isolated from 25 patients with newly diagnosed B-ALL, age 1-16 years, and 7 healthy controls, age 2-13 years, in order to compare NK cell frequency, immunophenotype, and functional activity. NK frequency was assessed by flow cytometric staining for CD56+CD3- cells. NK phenotype was assessed by surface expression of activating receptors NKp30, NKp44, NKp46 and NKG2D and inhibitory receptors KIR2DL1/S1, KIR2DL2/S2, KIR3DL1 and NKG2A. Functional activity was determined by incubation of NKs with target cells, followed by flow cytometric measurement of degranulation (surface CD107a) and cytokine release (intracellular IFNg and TNFa). Targets included the MHC class I deficient K562 cell line and, where available, autologous ALL blasts. Results ALL patients demonstrated significantly lower absolute NK cell counts compared with healthy controls (mean absolute count 168 vs. 406 cells/uL, p = 0.0002). They also exhibited significantly fewer NK cells expressing the activating marker NKp46 (mean absolute count 70 vs. 165, p = 0.016); and a significantly higher percentage of cells expressing the inhibitory marker NKG2A (mean 20.5% vs. 1.95% in controls, p = 0.012) (Fig 1A). In co-culture assays with K562 target cells, ALL patients' NK cells demonstrated inferior degranulation and cytokine release compared to healthy controls (representative data in Fig 1B; mean IFNγ production of 1.2% vs. 4.8%, p = 0.02; mean TNFα production of 1.8% vs. 3.8%, p = 0.06; and mean surface CD107a of 5.4% vs. 15.1%, p = 0.08). ALL samples (n = 3) demonstrated little to no cytokine release when incubated with autologous blasts compared with the response elicited by PMA-ionomycin (representative data in Fig 1C; mean CD107a 0.92% vs. 7.85%, p = 0.04; mean IFNγ 0.26% vs 40.47%, p = 0.10; mean TNFα 0.2% vs 41%, p = 0.008). Conclusion At diagnosis, pediatric ALL patients exhibit a lower frequency of NK cells, an inhibitory phenotype, and decreased cytolytic activity compared to healthy pediatric controls, particularly against autologous leukemic blasts. These results suggest that augmentation of the NK response may be useful therapeutically to improve outcomes in childhood ALL. Disclosures: No relevant conflicts of interest to declare.

A Novel Method for Propagating Primary Natural Killer (NK) Cells Allows Highly Efficient Expression of Anti-CD19 Chimeric Receptors and Generation of Powerful Cytotoxicity Against NK-Resistant Acute Lymphoblastic Leukemia Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 306-306
Author(s):  
Chihaya Imai ◽  
Shotaro Iwamoto ◽  
Dario Campana
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Lymphocytes ◽  
Nk Cells ◽  
Treatment Option ◽  
Nk Cell ◽  
Lymphoblastic Leukemia ◽  
Chimeric Receptors ◽  
Membrane Bound

Abstract Despite intensive chemotherapy, acute lymphoblastic leukemia (ALL) recurs in approximately 20% of children and 65% of adults. For most of these patients, allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment option but risk of relapse after transplantation is high. Donor lymphocyte infusions can suppress leukemia relapse but they are generally ineffective in ALL. We and others have shown that T lymphocytes transduced with anti-CD19 chimeric receptors have remarkable anti-ALL capacity in vitro and in vivo, suggesting the clinical testing of receptor-modified autologous T cells in patients with persistent minimal residual disease. However, the use of allogeneic receptor-modified T lymphocytes after HCT might carry the risk of severe graft-versus-host disease (GvHD). In this setting, the use of CD3-negative NK cells is attractive because they should not cause GvHD. Spontaneous cytotoxicity of NK cells against ALL is weak, if measurable at all. To test whether anti-CD19 chimeric receptors could enhance it, we developed a method to specifically expand human primary NK cells and induce high levels of receptor expression. Specific NK cell expansion has been problematic to achieve with established methods, because CD3+ T cells expand preferentially; even with T-cell depletion, residual T cells typically become prominent after stimulation. We overcame this obstacle by generating a genetically-modified K562 myeloid leukemia cell line that expresses membrane-bound interleukin-15 (IL-15) and 4-1BB ligand (CD137L) (K562-mb15-137L). Peripheral blood mononuclear cells from 8 donors were cultured with K562-mb15-137L in the presence of 10 IU/mL IL-2. After 1 week of culture with K562-mb15-137L, CD3- CD56+ NK cells expanded by 16.3 ± 5.9 fold, whereas CD3+ T cells did not expand. The stimulatory effect of K562-mb15-137L was much higher than that of K562 cells transduced with control vectors, K562 expressing membrane-bound IL-15 or CD137L alone, or K562 expressing wild-type IL-15 instead of membrane-bound IL-15. NK cell exposed to K562-mb15-137L were transduced with a retroviral vector and the anti-CD19-BB-ζ receptor, consisting of the single-chain variable domain of an anti-CD19 monoclonal antibody, the hinge and transmembrane domains of CD8α, and the signaling domains of CD3ζ and 4-1BB. 4-1BB mediates signals that are crucial for immune response to tumors in vivo and significantly improves chimeric receptor signaling. In 27 experiments, mean (± SD) transduction efficiency after 7–14 days was 67.5% ± 16.7%. Seven days after transduction, 92.3% (range 84.7%–99.4%) of cells were CD3- CD56+ NK cells; expression of receptors on the cell surface was high. NK cells expressing anti-CD19-BB-ζ had powerful cytotoxicity against NK-resistant B-lineage ALL cell lines and primary ALL cells. NK cells transduced with anti-CD19-BB-ζ had consistently higher cytotoxicity than those transduced with receptors lacking 4-1BB. The method described here allows specific expansion of primary NK cells and highly efficient transduction of chimeric receptors. Expression of anti-CD19-BB-ζ receptors in NK cells markedly enhances their anti-ALL activity. This approach could be a valuable treatment option for patients with refractory or relapsed B-cell malignancies after HCT.

Pre-Clinical Activity of a Novel FcγRIIIa Engineered CD19 Monoclonal Antibody in B Cell Chronic Lymphocytic Leukemia and Acute Lymphoblastic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2351-2351
Author(s):  
Julie M. Roda ◽  
Rosa Lapalombella ◽  
Robert Baiocchi ◽  
Eugene Zhukocsky ◽  
John Desjarlais ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Nk Cells ◽  
Nk Cell ◽  
Lymphoblastic Leukemia ◽  
Negative Control ◽  
Lymphocytic Leukemia ◽  
Adcc Activity ◽  
Specific Lysis

Abstract CD19 is a B cell lineage-specific transmembrane signaling protein that controls differentiation and proliferation. CD19 is an attractive therapeutic target due to its high level of expression in numerous B cell malignancies, as well as its lack of expression on non-B cells. Here we report the in vitro anti-tumor activity of a novel humanized monoclonal anti-CD19 Ab (CD19-IgG1, aka XENP5603) and its Fc engineered counterpart (XmAb™CD19, aka XENP5574). XENP5603 induced direct apoptosis in normal CD19+ B cells, but not NK cells, T cells, or monocytes, as determined by flow cytometric staining with annexin V and propidium iodide. XENP5603 also induced significant levels of apoptosis in a number of lymphoblastoid cell lines, including Ramos, Raji, 697, NALM6, and RS4;11 cells. Treatment of primary chronic lymphocytic leukemia (CLL) cells with XENP5603 induced significant cell death in all patients tested (mean, 36% apoptotic cells at 24 hours; range, 13–66%, p &lt; 0.001). Similar apoptosis was noted in cells from a subset of patients (4 of 9) with CD19+ primary acute lymphoblastic leukemia (ALL). Apoptosis of CLL cells treated with XENP5603 was not associated with cleavage of caspase-3, caspase-8, caspase-9, or PARP, but was associated with upregulation of Bim, suggesting a caspase-independent mechanism of cell death. NK cells from normal donors exhibited high levels of ADCC in response to B cell lines coated with XENP5603. Furthermore, NK cells from CLL patients mediated significant ADCC against autologous CLL cells in the presence of XENP5603 (mean, 15% specific lysis at an E:T ratio of 25:1; range, 8–24%; p = 0.04 vs. the negative control Ab). ADCC activity was further increased in the presence of XENP5574, which has the same antigen-recognition sequences as XENP5603 but which contains two mutations in the Fc region that increase FcγRIIIa affinity (mean, 39% specific lysis at an E:T ratio of 25:1; range, 29–51%; p = 0.02 vs. the negative control Ab). ADCC mediated by either CD19 Ab was also significantly higher than that mediated by an equivalent concentration of rituximab (mean, 39% specific lysis with XENP5574 vs. 12% with rituximab; p &lt; 0.001). ADCC in the presence of either Ab was further increased in the presence of the NK cell-activating cytokine IL-2, suggesting that these antibodies might be effectively combined with immune stimulatory adjuvants. Furthermore, NK cell ADCC against CLL cells in the presence of CD19 Abs was found to be dependent on perforin/granzyme release, as treatment with 3,4-dichloroisocoumarin (which inhibits granzyme enzymatic activity) or EGTA (which prevents release of cytotoxic vesicles) potently inhibited ADCC activity. Collectively, these studies provide evidence of the autologous innate immune-mediated cytotoxicity and direct apoptotic activity of XENP5603 and XENP5574. In addition, engineering to enhance FcγRIIIa binding enhances autologous ADCC, providing support for further pre-clinical development of XENP5574 in CD19+ malignancies, including CLL and ALL.

scholarly journals NK Cell Subpopulation Is Altered and the Expression of TLR1 and TLR9 Is Decreased in Patients with Acute Lymphoblastic Leukemia

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
David Sánchez-Herrera ◽  
Alejandra Contreras-Ramos ◽  
Elva Jiménez-Hernández ◽  
Aurora Medina-Sansón ◽  
Silvia Giono-Cerezo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Acute Lymphoblastic Leukemia ◽  
Nk Cells ◽  
Peripheral Blood ◽  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
Innate Immune ◽  
Cell Subpopulation ◽  
Hematological Cancers

NK cells represent a heterogeneous subpopulation of lymphocytes of the innate immune system, which possess powerful antitumor activity. NK cells exhibit their function through a complex collection of receptors that act synergistically to recognize, regulate, or amplify the immune response. TLRs allow cells to detect PAMPs, MAMPs, or DAMPs, which are essential for the initiation of the immune response. Studies on the different subpopulations of NK cells and their expression profile of innate immune receptors in hematological cancers are limited. In this study, the specific subpopulations of NK cells in pediatric patients with acute lymphoblastic leukemia (ALL) and the repertoire and level of expression of TLRs in cytotoxic NK cells were assessed. The results suggested that pediatric patients with ALL exhibited a significant decrease in NK cells in peripheral blood and bone marrow, in addition to alterations in the distribution of the subpopulations of cells. Regulatory and cytotoxic NK cells were diminished, whereas dysfunctional phenotype was considerably increased. Cytotoxic NK cells from children with ALL expressed all 10 TLRs, and expression of TLR1 and TLR9 was decreased compared with the controls. Interestingly, cytotoxic NK cells exhibited a higher expression of TLR1 in the bone marrow than in the peripheral blood of patients with ALL. The present study is the first to show that TLR10 was expressed in the cytotoxic NK cells and the first to assess the profile and levels of the 10 known TLRs in cytotoxic NK cells from patients with ALL. The alterations in expression levels and cellular distribution may be involved in the immune response.

Artificial Antigen Presenting Cells (aAPC) Expanded NK-Mediated Enhanced Lysis of Allogeneic Tumor Cells Regardless of HLA Class I/KIR Mismatch and Its Implication of Use in Eradicating Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3023-3023
Author(s):  
Hua Zhang ◽  
Bruce Levine ◽  
Nga Voong ◽  
Alan S. Wayne ◽  
Carl H. June ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Nk Cells ◽  
Natural Killer ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Fusion Proteins ◽  
Nk Cell ◽  
Lymphoblastic Leukemia ◽  
Target Cells ◽  
Activating Receptors

Abstract Abstract 3023 Poster Board II-999 NK Killer cell immunoglobulin-like receptors (KIRs) and their human leukocyte antigen (HLA) ligands play critical roles in maintaining natural killer (NK) cell tolerance, while providing surveillance against pathogens and malignant transformation. Natural killer (NK) cells have been explored as tools for adoptive anti-tumor or leukemia immunotherapy and current models hold that a mismatch or absence of KIR ligands on target cells is essential for efficient NK cell mediated cytolysis. However, new approaches are now available to activate NK cells and the role for KIR mediated signaling in regulating cytotoxicity of activated NK cells has not been well studied. In this study, aAPCs comprising IL15Ra+K562 cells engineered to express 4-1BBL activated and expanded peripheral NK cells in the presence of exogenous IL15 up to 1000-fold in 3 weeks. Compared to resting NK cells, 4-1BBL/IL15-activated NK cells upregulated TRAIL and NKp30, 44, 46 expression, and showed significantly enhanced cytotoxicity against a multitude of tumor targets including K562, Daudi, Ewing's tumors, osteosarcoma, as well as autologous tumors (50%-90% killing vs. 0%-8% with non-activated NK cells). Meanwhile we could detect little to no influence of KIR signaling in regulating cytotoxicity by aAPC activated NK cells, since sorted CD158a+ and CD158b+ activated NK cells showed similar killing of tumor cells expressing HLA group C1 (CD158b ligand) and/or C2 (CD158a ligand) antigens. In contrast, killer activating receptors (KARs) were indispensable for the cytolysis of solid pediatric tumors by aAPC-activated NK cells, since the killing was significantly inhibited by fusion proteins binding to the ligands of NKG2D, NK p30, p44, p46, p80 (KARs). About 20-40% inhibition of the killing was accomplished when all four activating receptors were blocked, though other activating receptors have not been well defined. Although acute lymphoblastic leukemia (ALL) blasts were refractory to fresh NK cytotoxicity, 4-1BBL/IL15 activated NK cells demonstrated higher lytic activities (20%-50%) against ALL blasts from either patients or cell lines. ALL blast lysis could be completely or partially inhibited by KAR-blocking fusion proteins, indicating that expression levels of KAR ligands vary among ALL cases and other solid tumors. We conclude that KIR ligand mismatch or absence is not essential for effective NK cytotoxicities on either solid tumors or ALL when fully activated NK cells are utilized. This suggests that adoptive therapy with autologous aAPC-activated NK cells may prove effective in some clinical settings, such as ALL, AML, or certain solid tumors. Further studies to assess the impact of KAR ligand expression on aAPC-activated NK killing of ALL blasts are in progress. Percentage of Activated NK Killings vs. Fresh NK's with/without KAR-Ig Fusion Proteins Activated NK (E:T=2.5:1) Fresh NK (E:T=25:1) -KAR-Ig Fc +KAR-Ig Fc SB tumor (Ewing's) 48% 30% 0.5% HOS (Osteo sarcoma) 63% 36% 0.7% Daudi (B. lymphoma) 78% 46% 0.2% REH (ALL) 54% 8% 3% Disclosures No relevant conflicts of interest to declare.

scholarly journals Activated Natural Killer Cells Predict Poor Clinical Prognosis in High-risk B- and T- cell Acute Lymphoblastic Leukemia

Blood ◽  
2021 ◽  
Author(s):  
Caroline Duault ◽  
Anil Kumar ◽  
Adeleh Taghi Khani ◽  
Sung June Lee ◽  
Lu Yang ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
High Risk ◽  
Clinical Outcome ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Lymphoblastic Leukemia ◽  
Clinical Prognosis ◽  
Cell Acute Lymphoblastic Leukemia

B- and T- cell acute lymphoblastic leukemia (B/T-ALL) may be refractory or recur after therapy by suppressing host anti-cancer immune surveillance mediated specifically by natural killer (NK) cells. We delineated the phenotypic and functional defects in NK cells of high-risk B/T-ALL patients using mass, flow, and in silico cytometry, with the goal of further elucidating the role of NK cells in sustaining ALL regression. We found that, compared to normal counterparts, NK cells in B/T-ALL patients are less cytotoxic, but exhibit an activated signature characterized by high CD56, high CD69, production of activated NK-origin cytokines, and calcium signaling. We demonstrated that defective maturation of NK cells into cytotoxic effectors prevents NK cells of ALL patients from lysing NK-sensitive targets as efficiently as normal NK cells. Additionally, we showed that NK cells in ALL are exhausted, which is likely caused by their chronic activation. We found that increased frequencies of activated cytokine-producing NK cells are associated with increased disease severity and independently predict poor clinical outcome in ALL patients. Our studies highlight the benefits of developing NK cell profiling as a diagnostic tool to predict clinical outcome in patients with ALL and underscore the clinical potential of allogeneic NK infusions to prevent ALL recurrence.

Sign in / Sign up

Export Citation Format

Share Document