scholarly journals Adoptively Transferred Donor-Derived Cytokine Induced Memory-like NK Cells Persist and Induce Remission in Pediatric Patient with Relapsed Acute Myeloid Leukemia after Hematopoietic Cell Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3307-3307
Author(s):  
Jeffrey J. Bednarski ◽  
Clare Zimmerman ◽  
Amanda F Cashen ◽  
Sweta Desai ◽  
Mark Foster ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Nk Cells ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Nk Cell ◽  
Ex Vivo ◽  
Salvage Chemotherapy ◽  
Acute Myeloid ◽  
Refractory Aml

Acute myeloid leukemia (AML) accounts for 18% of pediatric leukemias. For high-risk AML, standard treatment includes multi-agent chemotherapy followed allogeneic hematopoietic cell transplantation (HCT). Despite a high remission rate, 50% of patients relapse and have a poor prognosis with < 20% of patients surviving more than 3 years. Salvage chemotherapy alone or combined with donor lymphocyte infusions (DLI) have little curative potential, and new treatment strategies are needed for relapsed-refractory AML. Previous studies have shown that natural killer (NK) cells can be stimulated ex vivo with IL-12/15/18 to generate a memory-like phenotype with enhanced anti-leukemia effect. In adults with relapsed-refractory AML, adoptive transfer of MHC-haploidentical cytokine-induced memory-like (CIML or ML) NK cells induced remission in 54% of patients (PMID27655849). The infused donor ML NK cells expand in vivo but are rapidly eliminated following recovery of recipient T cells, providing a window of therapeutic activity of 2-3 weeks. We sought to test the safety and efficacy of ML NK cells for treatment of pediatric/young adult patients with post-HCT relapsed AML. We hypothesized that ML NK cells derived from the HCT donor would be well-tolerated, exhibit anti-leukemia activity, and expand with prolonged persistence following transfer into pediatric AML patients. Here, we report the results of the first pediatric patient treated on a phase I clinical trial using ML NK cell therapy for relapsed AML after allogeneic HCT (NCT03068819). Briefly, patients are treated with FLAG (fludarabine, cytarabine and granulocyte colony stimulating factor) salvage chemotherapy to reduce the bulk of AML and provide lymphodepletion for ML NK cell expansion. Two weeks after chemotherapy, a non-mobilized leukapheresis product is collected from the original HCT donor and processed into a T cell-based DLI and ML NK cells. The T cell DLI (1 x 106 T cells/kg) is immediately infused, and the ML NK cells are generated by stimulation with IL-12/15/18 ex vivo for 12-16 hours and then infused (10x106/kg). An 18-month-old male with infant AML had relapse of his leukemia 3 months after MHC-haploidentical HCT. Treatment with chemotherapy, including mitoxantrone and daunorubicin-cytarabine liposome, failed to induce remission. At the time of enrollment on the phase I trial, he had AML blasts in his bone marrow (Table 1). He was treated with FLAG chemotherapy followed by infusion of DLI and ML NK cells from the original haploidentical HCT donor. Assessment at 30 days, 3 months and 6 months post NK cell infusion showed complete remission with no evidence of leukemia and full donor engraftment. Remarkably, donor-derived ML NK cells expanded to 77% of donor lymphocytes on day 28 and still comprised 24% percent of lymphocytes at 6 months post infusion (Figure 1A-C). The expanded donor NK cell phenotype was consistent with ML NK cells (e.g., NKG2A+KIR+) utilizing CyTOF multidimensional analysis previously confirmed to identify ML NK cells (Figure 1D). The ML NK cells were functional as demonstrated by leukemia-triggered IFN-γ production immediately ex vivo from day 7-28 samples (Figure 1E-F). The patient's clinical course was complicated by mild gastrointestinal graft-versus-host disease that resolved with low-dose steroids and tociluzimab. These early results demonstrate proof-of-principle that adoptive transfer of donor-derived ML NK cells in combination with DLI is feasible and offers a novel immunotherapy option for patients with relapsed AML after HCT. Moreover, in this T and NK cell compatible immune environment post-HCT, donor ML NK cells expand and persist robustly in vivo for > 6 months without exogenous cytokine support and have potent anti-leukemic activity. Thus, ML NK cells are a cellular therapy platform to treat AML that has relapsed after allogeneic HCT. Disclosures Cashen: Celgene: Other: Speaker's Bureau; Seattle Genetics: Other: Speaker's Bureau; Novartis: Other: Speaker's Bureau. Fehniger:Horizon Pharma PLC: Other: Consultancy (Spouse); Cyto-Sen Therapeutics: Consultancy.

scholarly journals 852 Trifunctional NKp46/CD16a-NK cell engager targeting CD123 overcomes acute myeloid leukemia resistance to ADCC

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A893-A893
Author(s):  
Laurent Gauthier ◽  
Angela Virone-Oddos ◽  
Angela Virone-Oddos ◽  
Jochen Beninga ◽  
Benjamin Rossi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Antitumor Activity ◽  
Nk Cells ◽  
Myeloid Leukemia ◽  
Nk Cell ◽  
Ex Vivo ◽  
Activating Receptors ◽  
Acute Myeloid

BackgroundThere is a clear need for targeted therapies to treat acute myeloid leukemia (AML), the most common acute leukemia in adults. CD123 (IL-3 receptor alpha chain) is an attractive target for AML treatment.1 However, cytotoxic antibody targeting CD123 proved insufficiently effective in a combination setting in phase II/III clinical trials.2 T-cell engagers targeting CD123 displayed some clinical efficacy but were often associated with cytokine release syndrome and neurotoxicity.3 Interest in the use of NK cells for therapeutic interventions has increased in recent years, as a potential safer alternative to T cells. Several NK-cell activating receptors, such as CD16a, NKG2D, and the natural cytotoxicity receptors NKp30 and NKp46, can be targeted to induce antitumor immunity. We previously reported the development of trifunctional NK-cell engagers (NKCEs) targeting a tumor antigen on cancer cells and co-engaging NKp46 and CD16a on NK cells.4MethodsWe report here the design, characterization and preclinical development of a novel trifunctional NK cell engager (NKCE) targeting CD123 on AML cells and engaging the activating receptors NKp46 and CD16a on NK cells. The CD123 NKCE therapeutic molecule was engineered with humanized antibodies targeting NKp464 and CD123.5 We compared CD123-NKCE and a cytotoxic ADCC-enhanced antibody (Ab) targeting CD123, in terms of antitumor activity in vitro, ex vivo and in vivo. Pharmacokinetic, pharmacodynamic and safety profile of CD123-NKCE were evaluated in non-human primate (NHP) studies.ResultsThe expression of the high affinity Fc gamma receptor CD64 on patient-derived AML cells inhibited the ADCC of the Ab targeting CD123 in vitro and ex vivo, but not the antitumor activity of CD123-NKCE. CD123-NKCE had potent antitumor activity against primary AML blasts and AML cell lines, promoted strong NK-cell activation and induced cytokine secretion only in the presence of AML target cells. Its antitumor activity in mouse model was greater than that of the comparator antibody. Moreover, CD123-NKCE had strong and prolonged pharmacodynamic effects in NHP when used at very low doses, was well-tolerated up to high 3 mg/kg dose and triggered only minor cytokine release.ConclusionsThe data for activity, safety, pharmacokinetics, and pharmacodynamics provided here demonstrate the superiority of CD123-NKCE over comparator cytotoxic antibody, in terms of antitumor activity in vitro, ex vivo, in vivo, and its favorable safety profile, as compared to T-cell therapies. These results constitute proof-of-principle for the efficacy of CD123-NKCE for controlling AML tumors in vivo, and provide consistent support for their clinical development.ReferencesEhninger A, Kramer M, Rollig C, et al. Distribution and levels of cell surface expression of CD33 and CD123 in acute myeloid leukemia. Blood Cancer J 2014;4:e218.Montesinos P, Gail J Roboz GJ, et al. Safety and efficacy of talacotuzumab plus decitabine or decitabine alone in patients with acute myeloid leukemia not eligible for chemotherapy: results from a multicenter, randomized, phase 2/3 study. Leukemia 2021;35(1):62–74.Uy GL, Aldoss I, Foster MC, et al. Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia. Blood 2021;137(6):751–762.Gauthier L, Morel A, Anceriz N, et al. Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity. Cell 2019;177(7):1701–13.Jin L, Lee EM, Ramshaw HS, et al. Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells. Cell Stem Cell 2009;5:31–42.

Successful transfer of alloreactive haploidentical KIR ligand-mismatched natural killer cells after infusion in elderly high risk acute myeloid leukemia patients

Blood ◽  
2011 ◽  
Vol 118 (12) ◽  
pp. 3273-3279 ◽  
Author(s):  
Antonio Curti ◽  
Loredana Ruggeri ◽  
Alessandra D'Addio ◽  
Andrea Bontadini ◽  
Elisa Dan ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Nk Cells ◽  
Natural Killer ◽  
Myeloid Leukemia ◽  
Nk Cell ◽  
Median Number ◽  
Active Disease ◽  
Acute Myeloid

Abstract Thirteen patients with acute myeloid leukemia, 5 with active disease, 2 in molecular relapse, and 6 in morphologic complete remission (CR; median age, 62 years; range, 53-73 years) received highly purified CD56+CD3− natural killer (NK) cells from haploidentical killer immunoglobulin-like receptor–ligand mismatched donors after fludarabine/cyclophosphamide immunosuppressive chemotherapy, followed by IL-2. The median number of infused NK cells was 2.74 × 106/Kg. T cells were < 105/Kg. No NK cell–related toxicity, including GVHD, was observed. One of the 5 patients with active disease achieved transient CR, whereas 4 of 5 patients had no clinical benefit. Both patients in molecular relapse achieved CR that lasted for 9 and 4 months, respectively. Three of 6 patients in CR are disease free after 34, 32, and 18 months. After infusion, donor NK cells were found in the peripheral blood of all evaluable patients (peak value on day 10). They were also detected in BM in some cases. Donor-versus-recipient alloreactive NK cells were shown in vivo by the detection of donor-derived NK clones that killed recipient's targets. Adoptively transferred NK cells were alloreactive against recipient's cells, including leukemia. In conclusion, infusion of purified NK cells is feasible in elderly patients with high-risk acute myeloid leukemia. This trial was registered at www.clinicaltrial.gov as NCT00799799.

scholarly journals Acute Myeloid Leukemia Epigenetic Immune Escape From Nature Killer Cells by ICAM-1

2021 ◽  
Vol 11 ◽  
Author(s):  
Yang Xiao ◽  
Jinghong Chen ◽  
Jia Wang ◽  
Wei Guan ◽  
Mengzhen Wang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Nk Cells ◽  
Myeloid Leukemia ◽  
Immune Escape ◽  
Nk Cell ◽  
Epigenetic Modification ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Acute Myeloid

Acute myeloid leukemia (AML), a malignant disorder of hemopoietic stem cells. AML can escape immunosurveillance of natural killer (NK) by gene mutation, fusions, and epigenetic modification, while the mechanism is not clearly understood. Here we show that the expression of Intercellular adhesion molecule‐1 (ICAM‐1, CD54) is silenced in AML cells. Decitabine could upregulate ICAM-1 expression, which contributes to the NK-AML cell conjugates and helps NK cells kill AML cells. We also show that ICAM-1 high expression can reverse the AML immune evasion and activate NK cells function in vivo. This study suggests that a combination of the hypomethylating agent and NK cell infusion could be a new strategy to cure AML.

scholarly journals Early and Transient Microchimerism Associated with Complete Remission after Adoptively Transferred Haploidentical NK Cells Against High Risk Myelodysplastic Syndrome and Refractory Acute Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1120-1120
Author(s):  
Andreas T Björklund ◽  
Mattias Carlsten ◽  
Marie Schaffer ◽  
Lisa Liu ◽  
Sarah A. Cooley ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
High Risk ◽  
Nk Cells ◽  
Myeloid Leukemia ◽  
Progressive Disease ◽  
Nk Cell ◽  
Nk Cell Therapy ◽  
Acute Myeloid

Abstract Introduction: We here report from an ongoing phase I/II study of HLA-haploidentical NK cell therapy to patients with high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) not eligible for standard therapies. The preparative regimen consisted of intermediate doses of Cyklophosphamide (Cy), Fludarabin (Flu) and titrated doses of total lymphoid irradiation (TLI). The trial design excluded systemic IL-2 treatment to avoid expansion of regulatory T cells and to test if in vivo expansion could be obtained without IL-2 support. Patients:The first 12 patients were treated with Cy/Flu and an escalating dose of TLI (2 Gy and 4 Gy), followed by infusion of short-term IL-2 activated (16 hours) NK cells. Three patients received daily cyclosporine A after the conditioning. Three had relapsed, chemotherapy-refractory, primary AML, seven had secondary relapsed or refractory MDS-AML and two had high risk MDS with fibrosis. Results: The treatment was well tolerated and no severe non-infectious toxicity could be observed in the patients. The endpoint of expansion (>100 donor NK cells/ul at day 14) was not reached, but six patients had positive microchimerism, NK cells of donor origin detectable by RT-PCR at day 7-14, that thereafter became undetectable within 7-14 days. Four of these six patients achieved complete remission (CR) whereafter they become eligible for and could proceed to allogeneic stem cell transplantation. None of the patients with negative microchimerism obtained CR. Four patients died from progressive disease and three patients, with minor response and progressive disease, died in infections within three months of therapy. Discussion: Although the long-term efficacy needs to be evaluated, the results suggest that a combined regimen with mild conditioning followed by NK cell therapy may induce remission in patients with chemo-refractory disease and provide a bridge to allogeneic stem cell transplantation. Notably, clinical responses were observed after only a minimal in vivo NK cell expansion and were independent on KIR-ligand mismatch. Disclosures Blomberg: VECURA: Employment. Hellström-Lindberg:Celgene: Research Funding.

scholarly journals Impact of CMV reactivation on relapse of acute myeloid leukemia after HCT is dependent on disease stage and ATG

2021 ◽  
Author(s):  
Amin T. Turki ◽  
Nikolaos Tsachakis-Mück ◽  
Saskia Leserer ◽  
Pietro Crivello ◽  
Tobias Liebregts ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Advanced Disease ◽  
Survival Rates ◽  
Disease Stage ◽  
The Impact ◽  
Cmv Reactivation ◽  
Acute Myeloid

Cytomegalovirus (CMV) reactivation is a frequent complication after allogeneic hematopoietic cell transplantation (HCT), whose impact on clinical outcome, in particular on leukemic relapse is controversial. We retrospectively analyzed 687 HCT recipients with acute myeloid leukemia (AML) and ciclosporin-based immunosuppression to better understand the differential impact of CMV on transplant outcomes depending on AML disease stage and in-vivo T-cell depletion with anti-thymocyte globulin (ATG). Without ATG, CMV reactivation associated with significantly reduced relapse, yet its effect was more pronounced for advanced disease AML (p=0.0002) than for patients in first complete remission (CR1, p=0.0169). Depending on the disease stage, ATG exposure abrogated relapse protection following CMV reactivation in advanced stages (p=0.796), while it inverted its effect into increased relapse for CR1 patients (p=0.0428). CMV reactivation was associated with significantly increased non-relapse mortality in CR1 patients without ATG (p=0.0187), but not in those with advanced disease and ATG. Following CMV reactivation, only patients with advanced disease had significantly higher event-free survival rates as compared to patients without CMV. Overall, our data suggest that both ATG and disease stage modulate the impact of post-HCT CMV reactivation in opposite directions, revealing a level of complexity that warrants future studies regarding the interplay between anti-virus and anti-tumor immunity.

scholarly journals APR-246 induces early cell death by ferroptosis in acute myeloid leukemia.

Haematologica ◽  
2021 ◽  
Author(s):  
Rudy Birsen ◽  
Clement Larrue ◽  
Justine Decroocq ◽  
Natacha Johnson ◽  
Nathan Guiraud ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Ex Vivo ◽  
Lipid Peroxides ◽  
Death Process ◽  
Glutathione Biosynthesis ◽  
Acute Myeloid

APR-246 is a promising new therapeutic agent that targets p53 mutated proteins in myelodysplastic syndromes and in acute myeloid leukemia. APR-246 reactivates the transcriptional activity of p53 mutants by facilitating their binding to DNA target sites. Recent studies in solid cancers have found that APR-246 can also induce p53-independent cell death. In this study, we demonstrate that AML cell death occurring early after APR-246 exposure is suppressed by iron chelators, lipophilic antioxidants and inhibitors of lipid peroxidation, and correlates with the accumulation of markers of lipid peroxidation, thus fulfilling the definition of ferroptosis, a recently described cell death process. The capacity of AML cells to detoxify lipid peroxides by increasing their cystine uptake to maintain major antioxidant molecule glutathione biosynthesis after exposure to APR-246 may be a key determinant of sensitivity to this compound. The association of APR-246 with induction of ferroptosis (either by pharmacological compounds, or genetic inactivation of SLC7A11 or GPX4) had a synergistic effect on the promotion of cell death, both in vivo and ex vivo.

scholarly journals PVRIG is a novel NK cell immune checkpoint receptor in acute myeloid leukemia

Haematologica ◽  
2020 ◽  
pp. 0-0
Author(s):  
Jessica Li ◽  
Sarah Whelan ◽  
Maya F. Kotturi ◽  
Deborah Meyran ◽  
Criselle D’Souza ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Surface ◽  
Nk Cells ◽  
Immune Checkpoint ◽  
Myeloid Leukemia ◽  
Cell Activation ◽  
Nk Cell ◽  
Blocking Antibody ◽  
Poliovirus Receptor ◽  
Acute Myeloid

This study explored the novel immune checkpoint poliovirus receptor-related immunoglobulin domain-containing (PVRIG) in acute myeloid leukemia (AML). We showed that AML patient blasts consistently expressed the PVRIG ligand (poliovirus receptor-related 2, PVRL2). Furthermore, PVRIG blockade significantly enhanced NK cell killing of PVRL2+, poliovirus receptor (PVR)lo AML cell lines, and significantly increased NK cell activation and degranulation in the context of patient primary AML blasts. However, in AML patient bone marrow, NK cell PVRIG expression levels were not increased. To understand how PVRIG blockade might potentially be exploited therapeutically, we investigated the biology of PVRIG and revealed that NK cell activation resulted in reduced PVRIG expression on the cell surface. This occurred whether NK cells were activated by tumour cell recognition, cytokines (IL-2 and IL-12) or activating receptor stimulation (CD16 and NKp46). PVRIG was present at higher levels in the cytoplasm than on the cell surface, particularly on CD56bright NK cells, which further increased cytoplasmic PVRIG levels following IL-2 and IL-12 activation. PVRIG was continually transported to the cell surface via the endoplasmic reticulum (ER) and Golgi in both unstimulated and activated NK cells. Taken together, our findings suggest that anti- PVRIG blocking antibody functions by binding to surface-bound PVRIG, which undergoes rapid turnover in both unstimulated and activated NK cells. We conclude that the PVRIGPVRL2 immune checkpoint axis can feasibly be targeted with PVRIG blocking antibody for NK-mediated immunotherapy of PVRL2+ AML.

scholarly journals Characterization of the DNAM-1, TIGIT and TACTILE Axis on Circulating NK, NKT-Like and T Cell Subsets in Patients with Acute Myeloid Leukemia

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2171
Author(s):  
Isabel Valhondo ◽  
Fakhri Hassouneh ◽  
Nelson Lopez-Sejas ◽  
Alejandra Pera ◽  
Beatriz Sanchez-Correa ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Healthy Volunteers ◽  
Nk Cells ◽  
Myeloid Leukemia ◽  
Cell Activation ◽  
Nk Cell ◽  
T Cell Subsets ◽  
Acute Myeloid

Background: Acute myeloid leukemia (AML) remains a major clinical challenge due to poor overall survival, which is even more dramatic in elderly patients. TIGIT, an inhibitory receptor that interacts with CD155 and CD112 molecules, is considered as a checkpoint in T and NK cell activation. This receptor shares ligands with the co-stimulatory receptor DNAM-1 and with TACTILE. The aim of this work was to analyze the expression of DNAM-1, TIGIT and TACTILE in NK cells and T cell subsets in AML patients. Methods: We have studied 36 patients at the time of diagnosis of AML and 20 healthy volunteers. The expression of DNAM-1, TIGIT and TACTILE in NK cells and T cells, according to the expression of CD3 and CD56, was performed by flow cytometry. Results: NK cells, CD56− T cells and CD56+ T (NKT-like) cells from AML patients presented a reduced expression of DNAM-1 compared with healthy volunteers. An increased expression of TIGIT was observed in mainstream CD56− T cells. No differences were observed in the expression of TACTILE. Simplified presentation of incredibly complex evaluations (SPICE) analysis of the co-expression of DNAM-1, TIGIT and TACTILE showed an increase in NK and T cells lacking DNAM-1 and co-expressing TIGIT and TACTILE. Low percentages of DNAM-1−TIGIT+TACTILE+ NK cells and DNAM-1− TIGIT+TACTILE+ CD56− T cells were associated with a better survival of AML patients. Conclusions: The expression of DNAM-1 is reduced in NK cells and in CD4+ and CD8+ T cells from AML patients compared with those from healthy volunteers. An increased percentage of NK and T cells lacking DNAM-1 and co-expressing TIGIT and TACTILE is associated with patient survival, supporting the role of TIGIT as a novel candidate for checkpoint blockade.

Role of Glucocorticoid-Induced TNF-Related Protein (GITR) Ligand in the Interaction of Acute Myeloid Leukemia with NK Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 18-18
Author(s):  
Matthias Krusch ◽  
Katrin M. Baltz ◽  
Tina Baessler ◽  
Lothar Kanz ◽  
Helmut R. Salih
Keyword(s):  
Acute Myeloid Leukemia ◽  
Nk Cells ◽  
Myeloid Leukemia ◽  
Map Kinases ◽  
Nk Cell ◽  
Immune Surveillance ◽  
Related Protein ◽  
Surface Receptors ◽  
Enhanced Production ◽  
Acute Myeloid

Abstract NK cells play an important role in the reciprocal interaction of tumor cells with the immune system and participate in the surveillance and eradication of hematological malignancies. The activity of NK cells is governed by a balance of activating and inhibitory surface receptors. Glucocorticoid-induced TNF-related protein (GITR) and its ligand (GITRL) are members of the TNF/TNF receptor (TNFR) superfamily, which mediates multiple cellular functions including proliferation, differentiation, and cell death. Recently we reported that NK cells express GITR while cancer cells express GITRL and GITR-GITRL interaction down regulates NK cell-mediated anti-tumor immunity (Baltz et al., FASEB J 2007). Here we demonstrate that GITRL is expressed on 6 of 7 investigated acute myeloid leukemia (AML) cell lines and on primary AML cells in 30 of 52 (59%) patients, while no GITRL expression was detected on CD34+ cells of healthy donors (n=5). GITRL expression was not restricted to a specific French-American-British (FAB) subtype, but was significantly (p&lt;0.05, one-way ANOVA) associated with monocytic (FAB M4, M5) differentiation. In addition, no association with a particular cytogenetic abnormality or with expression of MHC class I was observed. Reverse signaling via GITRL led to phosphorylation of ERK and JNK resulting in significantly (p&lt;0.05, Mann-Whitney U-test) enhanced production of IL-10 and TNF by patient AML cells (n=10). In line, specific inhibitors for JNK and ERK1/2 blocked the cytokine release by AML cells demonstrating that activation of MAP kinases is responsible for the production of the immunoregulatory cytokines following GITRL stimulation. Importantly, blocking GITR-GITRL interaction in cocultures of AML and NK cells significantly (both &lt;0.05 Mann-Whitney U-test) increased cellular cytotoxicity about 70% and IFN-γ production about 60%, and this was due to restored NK cell NF-κB activity. Thus, GITRL substantially influences immunoediting by AML cells and enables the escape of AML cells from NK cell-mediated immune surveillance. The correlation found between GITRL expression and NK cell susceptibility may provide useful information for NK cell-based immunotherapy.

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