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  • 1
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    A phase 1b study of blinatumomab in Japanese children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia
    Springer Science and Business Media LLC ; 2020
    In:  International Journal of Hematology Vol. 112, No. 2 ( 2020-08), p. 223-233
    Details
    In: International Journal of Hematology, Springer Science and Business Media LLC, Vol. 112, No. 2 ( 2020-08), p. 223-233
    Type of Medium: Online Resource
    ISSN: 0925-5710 , 1865-3774
    URL: Article
    DOI: 10.1007/s12185-020-02907-9
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
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  • 2
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    Abstract LB-334: CpG- STAT3 siRNA for two-pronged immunotherapy of acute myeloid leukemia .
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. LB-334-LB-334
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. LB-334-LB-334
    Abstract: STAT3 transcription factor plays central role for survival, metastasis and immune evasion of many solid and blood tumors. In acute myeloid leukemia (AML), STAT3 is a critical node in signaling from numerous tyrosine kinases. Thus, it is an attractive but also elusive pharmacological target. We have recently shown that linking siRNA molecules to Toll-like receptor 9 (TLR9) ligands, CpG oligonucleotides, allows for cell-specific siRNA delivery in vivo. CpG-STAT3 siRNA conjugates induce RNAi in both mouse and human immune cells resulting in potent immunostimulatory effects. TLR9 is also commonly expressed in blood cancers, such as AML. We assessed whether targeting STAT3 in both leukemic and in tumor-associated immune cells using CpG-STAT3 siRNA can augment antitumor effects. We used orthotopic models of mouse Cbfb-MYH11 leukemia on 129Sv and C57BL/6 genetic backgrounds, which closely mimic human inv(16) AML. Our results demonstrated that intravenous injections of CpG-STAT3 siRNA (5 mg/kg), but not control oligonucleotides, into mice with established leukemia (1-2 weeks after challenge) resulted in elimination of leukemic cells from bone marrow, spleen, lymph nodes and blood. Furthermore, prior in vivo CpG-STAT3 siRNA treatment inhibited the engraftment and leukemia onset in secondary recipient mice. We found that these therapeutic effects depended on intact immune system, as CpG-STAT3 siRNA failed to eliminate leukemia in immunodeficient mice. In fact, systemic STAT3 targeting led to immune activation not only of DCs but also of AML cells as measured by cell surface expression of immune markers (MHC II, CD40, CD80 and CD86), secretion of IL-12 and IFNγ as well as induction of T cell proliferation. CpG-STAT3 siRNA treatment also reduced accumulation of tolerogenic regulatory T cells and myeloid-derived suppressor cells. The antibody-mediated depletion experiments confirmed the critical role of CD8 T cells in CpG-STAT3 siRNA-induced antitumor immunity. Finally, our preliminary studies confirmed that this strategy allows for targeting STAT3 also in primary human CD34+ AML cells. These findings indicate the potential of using CpG-STAT3 siRNA alone or in combination with T cell-based immunotherapeutic strategies for treatment of AML and potentially other TLR9-positive blood cancers. This project described was supported by the National Cancer Institute of the National Institutes of Health under award number R01CA155367 awarded to M.K. Citation Format: Sakib D M Hossain, Cedric Dos Santos, Qifang Zhang, Hongjun Liu, Piotr Swiderski, Claudia Kowolik, Stephen Forman, Ravi Bhatia, Ya-Huei Kuo, Marcin Kortylewski. CpG-STAT3 siRNA for two-pronged immunotherapy of acute myeloid leukemia . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-334. doi:10.1158/1538-7445.AM2013-LB-334
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-LB-334
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 3
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    Phase 1b/2 study of blinatumomab in Japanese adults with relapsed/refractory acute lymphoblastic leukemia
    Wiley ; 2020
    In:  Cancer Science Vol. 111, No. 4 ( 2020-04), p. 1314-1323
    Details
    In: Cancer Science, Wiley, Vol. 111, No. 4 ( 2020-04), p. 1314-1323
    Abstract: Adult patients with relapsed/refractory (R/R) B‐precursor acute lymphoblastic leukemia (ALL) have a poor prognosis. Blinatumomab is a bispecific T‐cell engager (BiTE) immuno‐oncology therapy with dual specificity for CD19 and CD3 that redirects patients’ CD3‐positive cytotoxic T cells to lyse malignant and normal B cells. We conducted an open‐label, phase 1b/2 study to determine the safety, pharmacokinetics, efficacy and recommended dose of blinatumomab in Japanese adults with R/R B‐precursor ALL. Patients received 9 μg/day blinatumomab during week 1 and 28 μg/day during weeks 2‐4, with a 2‐week treatment‐free interval (6‐week cycle); patients received 28 μg/day blinatumomab in subsequent cycles. Primary endpoints were the incidence of dose‐limiting toxicities (DLT) in phase 1b and complete remission (CR)/CR with partial hematologic recovery (CRh) within the first two cycles in phase 2. A total of 26 patients enrolled and 25 (96%) reported grade ≥3 adverse events (mostly cytopenias). There were no DLT. CR/CRh within two cycles was achieved by 4 of 5 patients (80%) in phase 1b and 8 of 21 patients (38%) in phase 2. Among patients with evaluable minimal residual disease, 4 (100%) in phase 1b and 3 (38%) in phase 2 had a complete MRD response. Median RFS for 8 patients who achieved CR/CRh in phase 2 was 5 (95% CI: 3.5‐6.4) months; median OS was not estimable. There were no significant associations between maximum cytokine levels or percentage of specific cell types during cycle 1 and response. Consistent with global studies, blinatumomab appeared to be safe and efficacious in Japanese adults with R/R ALL.
    Type of Medium: Online Resource
    ISSN: 1347-9032 , 1349-7006
    URL: Issue
    URL: Article
    DOI: 10.1111/cas.v111.4
    DOI: 10.1111/cas.14322
    Language: English
    Publisher: Wiley
    Publication Date: 2020
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  • 4
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    Antileukemic activity of rapamycin in acute myeloid leukemia
    American Society of Hematology ; 2005
    In:  Blood Vol. 105, No. 6 ( 2005-03-15), p. 2527-2534
    Details
    In: Blood, American Society of Hematology, Vol. 105, No. 6 ( 2005-03-15), p. 2527-2534
    Abstract: The mammalian target of rapamycin (mTOR) is a key regulator of growth and survival in many cell types. Its constitutive activation has been involved in the pathogenesis of various cancers. In this study, we show that mTOR inhibition by rapamycin strongly inhibits the growth of the most immature acute myeloid leukemia (AML) cell lines through blockade in G0/G1 phase of the cell cycle. Accordingly, 2 downstream effectors of mTOR, 4E-BP1 and p70S6K, are phosphorylated in a rapamycin-sensitive manner in a series of 23 AML cases. Interestingly, the mTOR inhibitor markedly impairs the clonogenic properties of fresh AML cells while sparing normal hematopoietic progenitors. Moreover, rapamycin induces significant clinical responses in 4 of 9 patients with either refractory/relapsed de novo AML or secondary AML. Overall, our data strongly suggest that mTOR is aberrantly regulated in most AML cells and that rapamycin and analogs, by targeting the clonogenic compartment of the leukemic clone, may be used as new compounds in AML therapy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2004-06-2494
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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  • 5
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    Dasatinib Enhances Targeting of Human AML Leukemia Stem Cells by Chemotherapeutic Agents Via Activation of p53
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 3590-3590
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 3590-3590
    Abstract: Abstract 3590 Tyrosine kinases play a critical role in regulating cellular proliferation, differentiation and survival in acute myeloid leukemia (AML). Tyrosine kinase inhibitors (TKI) can induce remissions of AML patients by reducing leukemia burden, but fail to eradicate primitive leukemia stem cells (LSC) that likely contribute to AML relapse after completion of treatment. Therefore, new strategies to enhance targeting of AML LSCs and increase probability of cure are required. We have previously reported that pharmacological inhibition of Src Family Kinases (SFKs) using Dasatinib selectively reduced AML progenitor growth in vitro (Dos Santos et al, Blood 2011, 118:4270A). Since Dasatinib monotherapy has had limited success in malignancies other than CML, we evaluated whether Dasatinib treatment could enhance targeting of AML LSCs by the commonly used chemotherapeutic agents Daunorubicin (DNR) and Cytarabine (Ara-C). Combined treatment with Dasatinib and DNR or Ara-C resulted in a significantly greater inhibition of AML CD34+ cell proliferation compared to Dasatinib, DNR or Ara-C alone (PI=3.1±0.3 for control, 2.3±0.6 for Dasatinib, 2.3±0.9 for DNR, 1.6±0.7 for Ara-C n=5; 1.3±0.4 for Dasatinib and DNR, and 1.1±0.1 for Dasatinib and Ara-C). The combination of Dasatinib with DNR or Ara-C also resulted in significantly increased AML CD34+ cell apoptosis, and significantly greater reduction of AML colony forming cells (CFC), compared to Dasatinib, Ara-C or DNR alone. Importantly, AML CD34+ cells treated with the combination of Dasatinib with DNR (p=0.0006) or Ara-C (p=0.008) and transplanted into NSG mice demonstrated significantly reduced engraftment in murine BM compared with cells treated with Dasatinib, DNR or Ara-C alone. The combination of Dasatinib with DNR or Ara-C did not inhibit engraftment of normal HSC compared to DNR and Ara-C alone, suggesting that Dasatinib specifically enhanced chemotherapy-induced targeting of AML LSC. To evaluate the efficacy of the Dasatinib and chemotherapy combination in vivo, we used a conditional knock-in mouse model (Cbfb56M/+/Mx1-Cre) of inversion 16 AML (Kuo et al, Cancer Cell 2006, 9:57). Although leukemic cells were reduced in BM and spleen of mice treated with chemotherapy alone, compared to controls, they were further significantly reduced with the combination of Dasatinib and chemotherapy (p 〈 0.0039 compared to chemotherapy alone). To determine treatment effects on LSC capable of regenerating leukemia, BM cells from treated mice were transplanted into secondary recipients. Treatment with the combination of Dasatinib and chemotherapy resulted in significantly enhanced survival in secondary transplant recipients (after 40 days, 0% survival for controls and 10% for Dasatinib treated mice, 45% survival for chemotherapy treated mice and 91% survival for the Dasatinib plus chemotherapy combination treated mice, p=0.0008), indicating enhanced elimination of cells with LSC capacity. AML CD34+ cells treated with the combination of Dasatinib with DNR showed enhanced expression of p53 mRNA (n=8, p=0.008) and protein, and several p53 target genes, including BAX (p=0.01), PUMA (=0.03), P21 (p=0.04), NOXA (p=0.03) and DR5 (p=0.01), compared to untreated cells or cells treated with Dasatinib or DNR alone. We show that p53 knockdown results in a significant reduction in apoptosis in cells treated with the combination of Dasatinib and chemotherapy (54.4±11.4% apoptosis with combination treatment and control siRNA 37.2±12.5% apoptosis with p53 siRNA, p=0.01). Our results suggest that the increased p53 response is related to inhibition of the important p53 regulatory gene MDM2 by the combination of Dasatinib and DNR, resulting from reduced AKT-mediated phosphorylation of MDM2 on the Ser166 regulatory site. In conclusion, we have found that co-treatment with the SFK inhibitor Dasatinib enhances p53 activation in response to chemotherapy in AML LSC, and lead to their increased elimination. These promising preclinical studies are being applied to a clinical trial of Dasatinib in combination with chemotherapy in high risk AML patients. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.3590.3590
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 6
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    Activity of Rapamycin in Patients with Relapsed, Refractory or Poor-Risk Acute Myeloid Leukemia.
    American Society of Hematology ; 2004
    In:  Blood Vol. 104, No. 11 ( 2004-11-16), p. 1791-1791
    Details
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 1791-1791
    Abstract: We have recently demonstrated that the mammalian Target of Rapamycin (mTOR) pathway is constitutively activated in most AML cases and that rapamycin (RAPA) selectively inhibits the clonogenic properties of AML progenitors while sparing their normal counterparts (ASH 2003, #331). We report here the results of a pilot study evaluating the activity of RAPA in relapsed, refractory or poor-risk AML patients. Twelve patients have been enrolled from October 2003 to March 2004. Patients’ characteristics were: median age, 72 years (range, 55-77); refractory AML (n=4), first relapse (n=5, 4 after autologous stem cell transplantation), secondary AML (n=3), median WBC (23.8 x 109/L, range, 1.8–103), cytogenetic (intermediate, n=11; unfavorable, n=1), performans status (PS 〉 2; n=5). Patients received RAPA (6 mg at day 1 then 2 mg per day) for 28 days on an outpatient basis. The primary study objective was to determine the overall response rate after 28 days of treatment. RAPA was well tolerated. Whole blood sirolimus concentrations were measured at day 7 and day 21. The range of sirolimus concentrations was highly variable according to patients (trace amounts to 31.4 μg/L). At day 28, hematologic response (HR), defined as a greater than 50% reduction in the absolute number of blood blasts or at least a 50% reduction in the percentage of marrow blasts, occurred in 4 pts, while 7 patients progressed and one had stable disease. The median duration of response was 38 days (range, 35–120). The median duration of treatment was 50 days (range, 21–240) and 90 days (range, 55–240) for all patients and responders, respectively. Two responding patients are alive at 8 and 10 months, respectively. The anti-leukemic activity of RAPA was accompanied by a restoration of normal neutrophils counts and a loss of transfusion requirement in these two responders. No correlations between clinical data, in vitro sensitivity to RAPA assessed by clonogenic assays and HR were found. In a responding patient, the phosphorylation of mTOR targets (p70S6K and 4E-BP1) in blood blasts was inhibited upon RAPA treatment, demonstrating that RAPA targets mTOR in vivo. As an example, a previously autografted 55 years patient with second relapse, displayed a very good response to RAPA. At d28, he had less than 5% of blasts in the marrow (vs 35% before RAPA) and restored normal absolute neutrophils counts. Moreover, cytogenetic response was documented by the disappearance of a pretreatment chromosomal abnormality (del 5q). However, CR was not truly obtained because of persistent mild thrombopenia. The duration of response in this heavily pre-treated patient was 3 months with RAPA alone. He then relapsed and is still alive (10 months +). This study demonstrate that inhibition of mTOR can induce significant responses in high-risk AML patients and warrant further studies assessing the role of RAPA or analogues in combination with chemotherapy in this disease.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V104.11.1791.1791
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
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  • 7
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    In Vivo Targeting Of Acute Myeloid Leukemia Using CpG-Stat3 siRNA Results In T Cell-Dependent Tumor Eradication
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 4212-4212
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 4212-4212
    Abstract: Signal Transducer and Activator of Transcription-3 (STAT3) is an oncogene and immune checkpoint commonly activated in cancer cells and in tumor-associated immune cells. As a focal point of downstream signaling from numerous cytokines and growth factors present in the tumor microenvironment, STAT3 is an attractive but also elusive pharmacological target. We previously developed an immunostimulatory strategy based on targeted Stat3 gene silencing in Toll-like Receptor (TLR9)-positive hematopoietic cells using CpG-siRNA conjugates. Here, we assessed therapeutic effect of systemic STAT3 blocking/TLR9 triggering in disseminated acute myeloid leukemia (AML). We used a model of mouse Cbfb/MYH11/Mpl-induced leukemia, which mimics human inv(16) AML. Our results demonstrate that intravenously delivered CpG-Stat3 siRNA, but not control oligonucleotides, can eradicate established AML and impair leukemia-initiating potential. These antitumor effects require host’s effector T cells but not TLR9-positive antigen-presenting cells. Instead, CpG-Stat3 siRNA has direct immunogenic effect on AML cells in vivo leading to up regulation of MHC class II, co-stimulatory molecules and proinflammatory mediators, such as IL-12 and IFNγ, while down regulating expression of co-inhibitory PD-L1 molecule. Systemic injections of CpG-Stat3 siRNA generate potent tumor antigen specific immune responses, increase the ratio of tumor-infiltrating CD8+ T cells to T regulatory cells (Tregs) in various organs and result in CD8+ T cell-dependent regression of leukemia. Targeted STAT3 inhibition/TLR9 triggering also enhances immunogenicity of primary patients’ AML cells which gain ability to stimulate T cell proliferation. Our findings underscore the potential of using targeted STAT3 inhibition/TLR9 triggering to break tumor tolerance and induce potent immunity against AML and potentially other TLR9-positive blood cancers. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.4212.4212
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 8
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    Pharmacological Inhibition Of The SIRT1 Deacetylase With The Small Molecule Inhibitor Tenovin-6 Enhances Ablation Of FLT3-ITD+ LSC In Combination With TKI Treatment
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 2685-2685
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 2685-2685
    Abstract: Acute myeloid leukemia (AML) is propagated by small populations of leukemia stem cells (LSC). Internal tandem duplication (ITD) in the FMS-like tyrosine kinase-3 (FLT3) is the most frequent mutation seen in AML patients, and is associated with poor prognosis. However, FLT3 tyrosine kinase inhibitors (TKI) demonstrate only moderate clinical activity in FLT3-ITD AML patients. Persistent FLT3-ITD+ AML LSC may represent a source of relapse after treatment. Additional therapeutic strategies are required to target LSC and improve outcomes for FLT3-ITD+ AML patients. We have shown that the stress-related deacetylase SIRT1 is expressed at high levels in FLT3-ITD+ AML stem/progenitor cells and in cord blood CD34+ cells ectopically expressing FLT3-ITD. Inhibition of SIRT1 using RNAi or a potent small molecule inhibitor Tenovin-6 (TV-6) induces apoptosis in FLT3-ITD+ AML progenitors via p53-dependent mechanisms while sparing normal CD34+ cells suggesting a potential role for SIRT1 in FLT3-ITD+ AML LSC maintenance (Blood 2012,120: A1368). We now show that treatment of FLT3-ITD+ AML CD34+ cells with the TKI AC220 (20 nM) did not significantly reduce SIRT1 levels, increase p53 acetylation, or increase p53 target gene expression (p21, Bax, Puma, DR5, Noxa), suggesting that kinase independent mechanisms maintain SIRT1 expression and activity in TKI-treated cells. The combination of TV-6 (1μM) with AC220 (20nM) significantly reduced survival of primary human FLT3-ITD+ AML CD34+ cells compared with AC220 or TV-6 alone (combination 47±8% inhibition, AC220 alone 21±7%, TV-6 alone 25±5%, p=0.03, n=7), and significantly increased inhibition of AML CD34+ cell growth compared to AC220 and TV-6 alone (TV-6 44±7% inhibition; AC220 30±6%, TV+AC220 59±8%, p=0.04, n=7). TV-6 treatment increased p53 expression and activity in AC220-treated FLT3-ITD+ AML CD34+ cells, but did not affect FLT3 phosphorylation or STAT5 activation. Interestingly, TV-6 treatment also reduced survival of FLT3-ITD+ AML CD34+ cells expressing the D835Y mutation associated with TKI resistance (AC220 5±5% inhibition, TV 33±8%, p=0.04, n=3], suggesting SIRT1 inhibition can target TKI-resistant FLT3-ITD+ AML cells. We next tested the effect of TV-6, AC220 and the combination on primary cells from one untreated cytogenetically normal and FLT3-ITD+ patient engrafted in NSG mice (2×106 cells/mouse).12 weeks after transplantation, mice were treated with vehicle, AC220 (10mg/kg, gavage), TV-6 (100mg/kg, intraperitoneal), or the combination (n=7 per group) for 4 weeks. Treatment with TV reduced human cell engrafted in NSG mice (TV-6 2.9*107±1.2*107 human CD45+ cells/2 femurs vs. Control 5.3*107±2.6*107, after 4 weeks treatment, p=0.04). Importantly, the combination of TV and AC220 significantly reduced AML cell engraftment compared with AC220 alone (AC220 2.4*107±0.9*107 human CD45+ cells. Combination 1.2*107±0.6*107, p=0.01). Residual functional LSC were assessed by transplantation into secondary recipients. BM cells from the combination treatment group demonstrated significantly reduced engraftment of leukemia cells after secondary transplantation compared to AC220 treatment alone (16 weeks after secondary transplantation, AC220 1.8*106±0.6*106 human CD45+ cells/2 femurs, Combination 0.4*106±0.1*106, p=0.02, n=6). To determine the potential of this combination for FLT3-ITD+ AML patients refractory to standard chemotherapy, AML xenografts established using cells from a chemotherapy-resistant patient (n = 36) were treated with TV-6, AC220, or the combination vs. Standard of care (SOC, Ara-C + DNR), and vehicle control. Molecular imaging of primary patient xenografts with fluorescently labeled monoclonal antibodies after 4 weeks of therapy revealed significant differences between combination and single arm groups (vs. TV-6, p=0.0005, n=8; vs. AC220, p=0.003, n=7). Furthermore, TV-6 alone increased survival over controls (TV-6 vs. Control, p =0.02, n=6), and the combination demonstrated significantly improved survival over AC220 (p=0.02) and SOC (p=0.006. n=6). In conclusion, our studies indicate that elevated SIRT1 expression in FLT3-ITD AML cells is maintained after FLT3 TKI treatment. Inhibition of SIRT1 with TV-6 can enhance ablation of FLT3-ITD+ AML LSC in combination with FLT3 TKI treatment. Our results support further evaluation of inhibition of SIRT1 as a therapeutic strategy in FLT3-ITD+ AML. Disclosures: Popa: KinN Therapeutics AS: Employment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.2685.2685
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 9
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    The Combination of the Novel Syk Inhibitor TAK659 with Decitabine Exerts Synergistic Cytotoxic Effects Against FLT3/ITD Mutated Acute Myeloid Leukemia Cells
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 4928-4928
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 4928-4928
    Abstract: Background: Effective treatment regimens for FLT3/ITD+ AML patients are lacking. Recent data on the effects of FLT3 tyrosine kinase inhibition showed promising clinical activity, but outcomes have been stunted by drug resistance. Targeting additional signaling pathways besides FLT3 might therefore offer therapeutic benefit. Spleen tyrosine kinase (syk) is frequently overexpressed and constitutively activated in primary AML FLT3/ITD+ blasts. Pharmacologic inhibition of syk has been associated with antileukemic potential, consisting of inhibition of cell growth and induction of differentiation in AML cells. Hypomethylating agents (DNMTis) such as Decitabine (DEC) have emerged as attractive agents in the treatment of AML, partially due to their proapoptotic and differentiation inducing effects. There is a strong rationale for combining FLT3- and syk- inhibitors with DNMTis for FLT3/ITD+ AML. Here, we investigated whether the antileukemic effects of the novel, dual FLT3/syk inhibitor TAK659 (TAK) can be enhanced by the co-administration of DEC. Methods: Molm14 (M14) cells were incubated in culture medium in the presence and absence of stromal cells (MS5) for 72 hours. TAK or DEC was added in single agent or combined mode at the indicated concentrations. After the incubation period, cell growth was determined by MTT assays. Apoptosis, autophagy and cell cycle status were assessed by FACS analysis. FLT3- and syk- phosphorylation levels were detected by western blotting. Differentiation was assessed by morphology. A combination index (CI) was calculated using Calcusyn Software. Results: TAK exerted dose dependent effects against M14 cells. However, the presence of stromal cells significantly blunted TAK mediated cytotoxicity (50nM: 61.9±1.3% [off stroma] vs. 10.9±3.1% [on stroma] , p 〈 .001; 500nM: 91.2±0.5% [off stroma] vs. 17.4±2.5% [on stroma] , p 〈 .001, n=3-9; IC50: 40.6nM [off stroma] vs. 3.9µM [on stroma] ). Although less marked when stroma was present, TAK combined with DEC yielded synergistically enhanced growth inhibition (off stroma: 50.2±3.9% [TAK659 50nM], 58.1±3.0% [DEC 1µM] , 76.7±3.1% [TAK659 50nM+DEC 1µM; CI=0.77]; on stroma: 9.5±3.0%[TAK659 50nM] , 42.9±3.1% [DEC1µM], 57.0±5.2%[TAK659 50nM+DEC 1µM; CI=0.62] ) compared to single agent treatment (off stroma: p 〈 .001 vs. TAK, p 〈 .001 vs. DEC, on stroma: p 〈 .001 vs.TAK, p=.03 vs. DEC, n=3). In line with these findings, combined treatment yielded greater levels of FLT3- and syk- dephosphorylation compared to single agent treatment both when stroma was present and absent. When compared to untreated controls (11.6±0.7%), Annexin V/PI staining (n=3) showed that induction of apoptosis was increased with TAK (18.9±3.9%; p=NS), DEC (39.2±4.8%; p 〈 .01), and greatest when the two drugs were combined (44.2±6.7%; p 〈 .01) in the absence stoma. In the presence of stroma, single agent DEC, and when combined with TAK, increased the fraction of apoptotic cells by up to two fold whereas TAK did not induce any meaningful apoptosis. Consistent with the induction of cell death, cell cycle analysis demonstrated the greatest increase in subG0 phase when TAK and DEC were combined. Both in the presence and absence of stroma, autophagic flux was increased when M14 cells were treated with DEC, and when DEC was combined with TAK whereas no difference was observed with TAK alone. The combination of TAK and DEC led to changes consistent with differentiation, as shown by more abundant cytoplasm and nuclei with deep indentations, folds and lobulation compared to untreated cells. DEC treated cells also showed signs of differentiation although these changes were less marked. No evidence of differentiation was observed in M14 cells when treated with TAK alone. Conclusions: 1. Stroma conferred protective effects against all treatments. 2. TAK exerted dose dependent cytotoxicity against M14 cells in the nanomolar to low micromolar range in the absence and presence of stroma, respectively. 3. The cytotoxic effects of TAK were enhanced when TAK was combined with DEC. 4. The antileukemic effects of TAK combined with DEC are multifaceted and include inhibition of cell growth, induction of apoptosis, autophagy and differentiation. 5. The combination of TAK and DEC represents a potentially important novel approach for FLT3/ITD+ AML patients. 6. Clinical trials incorporating syk-inhibitors into standard AML treatment protocols are currently under way. Disclosures Dos Santos: Amgen: Employment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.4928.4928
    RVK:
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 10
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    Anti-Leukemic Activity of Daratumumab in Acute Myeloid Leukemia Cells and Patient-Derived Xenografts
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 2312-2312
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 2312-2312
    Abstract: Daratumumab is a human antibody that binds to CD38 on the cell surface and induces cell killing by multiple mechanisms including complement mediated cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cell phagocytosis (ADCP) and apoptosis. In pre-clinical and clinical studies, daratumumab has been shown to effectively kill multiple myeloma (MM) cells and to enhance the potency of other treatments against MM. The purpose of the study was to investigate in vitro and in vivo efficacy of daratumumab against 9 acute myeloid leukemia (AML) cell lines and patient-derived samples. First, we evaluated the expression of CD38, complement inhibitory proteins (CIP) CD46, CD55, CD59, and FcgR1 (CD64) on AML cell lines (n=9), AML patient cells (n=10) and healthy donor bone marrow using flow cytometry. CD38 enumeration showed a substantial variation between cell lines (12,827±19, 320 molecules/cell) and between AML patients (11,560±8, 175 molecules/cell), while CD38 expression was more consistent in bone marrow (BM) from healthy donors (1,176±355 molecules/cell). The daratumumab-induced apoptosis observed in cell lines (MOLM-13, MOLM-16, MV-4-11, NB4) in vitro was not correlated with CD38 expression levels. Daratumumab induced minimal ADCC (5-20%) and low levels of (2-5%) CDC mediated cell killing in 6 AML cell lines tested. We did not observe a direct correlation between CD38 expression and ADCC, CDC, nor between CDC and CIP expression. Interestingly, treatment of two human Acute Promyelocytic Leukemia (M3) cell lines HL-60 and NB-4 with all-trans retinoic acid (ATRA) induced a 10-30-fold increase in CD38 expression, suggesting that ATRA could be used in combination with daratumumab. While we, and others, have shown that pre-incubation of primary AML cells with anti-CD38 antibodies inhibits engraftment in NSG mice, we aimed at evaluating the anti-leukemic activity of daratumumab in a therapeutic xenograft model using 3 different AML patients. NSG mice (10/group/patient) were transplanted with T cell-depleted AML cells and BM aspirates were collected 4-6 weeks later to assess leukemia burden in each mouse prior to treatment. Animals were untreated (Ctrl) or received daratumumab (10 mg/kg), or IgG1 isotype once a week for five weeks. We assessed AML burden (% huCD45+ CD33+) in BM, spleen (SPL) and peripheral blood (PB) within 5 days after the last treatment. First, we evaluated an AML (#3406, FLT3-ITD, see figure) with high expression of CD38 (13,445 molecules/cell) and low CD64 (489/cell) was evaluated. Daratumumab significantly reduced leukemia burden in SPL and PB, but had no effect in BM. The same daratumumab-induced reduction in peripheral blasts and lack of effect in BM was observed in 2 other AML patient xenografts (#7577, M1 IDH mutant/FLT3-ITD with 6,529 CD38 molecules/cell; #8096, M2 with 335 CD38 molecules/cell). Interestingly, we observed that daratumumab treatment led to a drastic reduction in CD38 surface expression in AML blasts including in BM, indicating that daratumumab efficiently targeted CD38 in bone marrow blasts. Our results suggest that the bone marrow microenvironment can impair the anti-leukemic activity of daratumumab observed in other tissues. Ongoing xenograft studies are testing whether induction with chemotherapy (Ara-C+doxorubicin), or with other agents disrupting the bone marrow microenvironment, can enhance the anti-leukemic activity of daratumumab. Figure 1: Effect of daratumumab treatment on AML 3406 leukemia burden: Figure 1:. Effect of daratumumab treatment on AML 3406 leukemia burden: Disclosures Dos Santos: Janssen R & D: Research Funding. Xiaochuan:Janssen R & D: Research Funding. Doshi:Janssen R & D: Employment. Sasser:Janssen R & D: Employment. Danet-Desnoyers:Janssen R & D: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.2312.2312
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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