- |||||||||| Latent Membrane Protein 1 Contributes to Deficient Cellular Immunity in NKTCL Patients (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_5701;
Interestingly, the extent of induction by LMP1 of Tregs and MDSCs were in line with the expression level of LMP1 on NKTCL cells (Figure o-p) . Conclusion Our study showed that LMP1 contributes to deficient cellular immunity in NKTCL patients, providing us with more insight into immunosuppressive in this entity of disease, which would lead to identification of novel treatment strategies.
- |||||||||| AMG 330 / Amgen, Blincyto (blinatumomab) / Astellas, Amgen, amatuximab (MORAb-009) / Eisai
Mesothelin Targeting Bites for Pediatric AML: In Vivo Efficacy and Specificity (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_5655;
1H), suggesting that IgG BiTE was far more efficacious than canonical BiTEs (P<0.01) . Taken together, these data indicate that MSLN-targeting BiTEs could be used as novel immunotherapy for pediatric AML with MSLN expression.
- |||||||||| mitoxantrone / Generic mfg., cytarabine / Generic mfg., Mylotarg (gemtuzumab ozogamicin) / UCB, PDL, Pfizer
Phase 1 Trial of Cladribine, High-Dose Cytarabine, G-CSF, and Dose-Escalated Mitoxantrone (CLAG-M) Plus Gemtuzumab Ozogamicin in Adults with Newly-Diagnosed Acute Myeloid Leukemia (AML) or Other High-Grade Myeloid Neoplasm (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_5621;
P1/2
CR/CRi and MRDneg CR rates were similar to what we observed with CLAG-M alone (86% and 71%, respectively). A phase 2 study based on these findings has been initiated, using event-free survival as primary efficacy endpoint.
- |||||||||| NUP98-KDM5A Fusion Induces Hematopoietic Cell Proliferation and Alters Myelo-Erythropoietic Differentiation (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_5498;
Furthermore, this fusion is sufficient to engraft in the bone marrow and spleen of NRG-SGM3 mice in vivo and cause marked splenomegaly . Taken together, these data suggest this model properly recapitulates the human disease phenotype seen in patients expressing NUP98-KDM5A and future functional assays and drug screens may provide important insights into understanding the pathophysiology and pharmacologic vulnerabilities of this fusion class.
- |||||||||| Opdivo (nivolumab) / Ono Pharma, BMS, Yervoy (ipilimumab) / Ono Pharma, BMS
Biomarker Assessment of Venous Thromboembolism in Cancer Patients Receiving Checkpoint Blockade (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_5363;
We have identified candidate cellular and plasma biomarkers that associate with thrombotic risk in this population and provide potential insight into its pathophysiology . Prospective and mechanistic studies are underway to validate and further expand these findings.
- |||||||||| Disease Model of Atherosclerosis Using Werner Syndrome Patient-Derived Induced Pluripotent Stem Cells Reveals Excessive Inflammatory Response Against Ox-LDL (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_5328;
Although no differences were observed in the induction efficiency, cell proliferation and mean fluorescent intensity of Ox-LDL uptake between WS- and healthy-iPSC-derived VEC and Mφ, qRT-PCR analysis revealed that, VEC derived from WS-iPSC shows much higher mRNA expression of cell adhesion molecule gene (ICAM-1; 2.5 fold and VCAM-1; 3.6 fold), inflammatory cytokine gene (IL-6; 12.5 fold and TGF-β; 4.3 fold) and endothelial dysfunction related gene (ET-1; 5.9 fold and PAI-1; 25.2 fold) compared with healthy-iPSC-derived VEC . Consequently, our results suggest that the higher risk of atherosclerosis in WS patients might be due to excessive inflammation response against Ox-LDL in WS-iPSC-derived cells, which is independent of other risk factors frequently observed in WS, such as diabetes and hyperlipidemia, and might be implicated to understand the pathogenesis and therapeutic strategy against WS and general atherosclerosis.
- |||||||||| Evaluation of in Vitro Macrophage Characterization in Gaucher Type 1 (GD1) Patients (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_5303;
These preliminary data suggest that GD macrophages, when stimulated, display a proinflammatory potential . These activated M1 macrophages could contribute to an inflammatory-producing environment, triggering hepcidin and ferroportin expression by an autocrine/paracrine mechanism and leading to dysregulation of iron distribution.
- |||||||||| Empliciti (elotuzumab) / AbbVie, BMS, bortezomib / J&J, Generic mfg., Pomalyst (pomalidomide) / BMS
Defining the Differentiation States of Multiple Myeloma at Single Cell Resolution Reveals Opportunities for Immunotherapy (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_4284;
P2
In conclusion, we find that higher transcriptional diversity and activation of alternate gene regulatory programs facilitate the emergence of altered transcriptional states. Interestingly, these altered states are associated with up-regulation of putative immune-therapeutic targets in myeloma cells, thus providing novel therapeutic vulnerabilities.
- |||||||||| Investigation of Homing Capacity As Prognostic Marker in Human Acute Myeloid Leukemia (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_3877;
Comparative studies using AML cells of intermediate and adverse molecular risk are underway . These findings provide proof-of-principle data for a prospective clinical study analyzing correlations between AML cell homing capacity in mice and outcome of disease in patients.
- |||||||||| doxorubicin hydrochloride / Generic mfg.
Preclinical Assessment of Non-Virally Engineered CD33.CAR Cytokine-Induced Killer (CIK) Cells in Chemoresistant AML Patient-Derived Xenografts (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_3840;
Finally, when starting CD33.CAR-CIK cell treatment after disease recurrence post induction therapy, a significant disease reduction was observed in the CD33.CAR-CIK-treated group, reaching undetectable levels in half of the mice, as compared to chemotherapy-only treated mice (up to 60% of engraftment in BM)(Figure 1). Conclusions The employment of a non-viral SB-based CD33.CAR-gene transfer approach, which is overall associated to less cumbersome protocols and reduces the cost of goods, offers a unique alternative to current viral-based strategies to be explored in the setting of resistant forms of AML.
- |||||||||| Leustatin (cladribine) / J&J, Actimab-A (lintuzumab-Ac225) / Actinium
Lintuzumab Ac-225 in Combination with CLAG-M Chemotherapy in Relapsed/Refractory AML: Interim Results of a Phase I Study (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_3777;
With dose escalation, increased myelosuppression has been noted alongside, but also highly encouraging efficacy results for RR-AML. As two patients in Cohort 2 met DLT criteria due to prolonged ANC recovery, this study will be amended to mandate the addition of G-CSF two weeks after Lintuzumab Ac225 treatment.
- |||||||||| chloroquine phosphate / Generic mfg., Vanflyta (quizartinib) / Daiichi Sankyo
Role of Autophagy in Resistance of FLT3–ITD AML Stem Cells to FLT3 TKI Treatment (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_3717;
The combination of AC220 with Lys05 reduced CD45 engraftment (11% vs 37%, p=0.004) and absolute CD45+CD34+ stem cell numbers in BM compared with AC220 alone...We show that induction of autophagy in MOLM13 cells by starvation and mTOR inhibitor was associated with reduced p53 expression, whereas autophagy inhibition by chloroquine or SAR405, a PIK3C3/Vps34 inhibitor, was associated with increased p53 expression by WB...We demonstrate important roles for autophagy in regulating p53 levels and cell cycle in FL3-ITD AML cells. These studies support further development of strategies to target autophagy and related pathways to enhance efficacy of TKI in eliminating AML stem cells.
- |||||||||| Germanin (suramin) / Optimum Therapeutics
Targeted Inhibition of the NUP98-NSD1 Fusion Oncogene in AML (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_3714;
In summary, our findings demonstrate that targeted inhibition of NUP98-NSD1 either through siRNA-LNP or suramin delays leukemia development in vivo and prolongs the survival of mice carrying a NUP98-NSD1 positive AML . Our results provide the rationale for the evaluation of NSD1 methyltransferase inhibitors and siRNA-LNP formulations in NUP98-NSD1 positive AML.
- |||||||||| Growth Factor-Dependent Activation of a MYC-Induced Latent AML Program in Human Hematopoietic Cells (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_3701;
The rapidity, consistency, and high frequency of this transformation process obtained by transducing late granulopoietic as well as early types of normal human CD34+ progenitor cells makes this system highly attractive for future mechanistic and therapeutic testing experiments . The discovery that MYC deregulation alone generates a stable “latent program” that can be rapidly activated by exposure to exogenous growth factors typical of inflammatory states also raises intriguing questions about the potential role of such events in the genesis of AML populations that arise in patients.
- |||||||||| dexamethasone / Generic mfg.
Establishment of a Spontaneous Stromal Microenvironment from Cord Blood Supports Human Dynamic Erythropoietic Temporal Maturation in Long-Term Serum- and Cytokine-Free 3D Cultures and Reveals a Distinct CD44hi Population (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_3367;
We have previously reported on a 3D bone marrow (BM) biomimicry using polyurethane scaffolds to expand cord blood mononuclear cells (CBMNCs) in a serum- and cytokine-free environment, without addition of dexamethasone, for 28 days (D)...A unique CD44hi immature monocyte/macrophage population was identified, which contributes to the inductive microenvironment, and distinct stages of human erythroid maturation could be identified using CD44 and CD235a. This work presents a novel and dynamic ex vivo model that can (1) recapitulate physiologic human erythropoiesis in steady-state and stress conditions, (2) capture the fetal to adult hemoglobin transition, (3) explore the direct role of oxygen on erythropoiesis, (4) assess the microenvironment relevant to erythropoiesis in the absence of serum and exogenous factors, (5) sustain long-term erythropoiesis with terminal maturation and, (6) explore the different stromal niche environments spontaneously created for the support of erythropoiesis.
- |||||||||| Exploiting an Anti-CD3/CD33 Bispecific Antibody to Redirect Donor T Cells Against HLA Loss Leukemia Relapses (Sunburst Room (W340) (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_3345;
Conclusions Our results demonstrate that anti-CD3/CD33 BsAbs can effectively redirect donor T cells against HLA loss leukemia variants, resulting in their rapid and effective killing . Taken together, these promising findings strongly support translation of this approach to ad hoc designed early-phase clinical trials, to provide a rational therapy for this increasingly recognized but still treatment-orphan modality of post-transplantation relapse.
- |||||||||| Loss of KLF6 Recapitulates Molecular and Functional Changes Associated with Aging in Human Hematopoietic Stem and Progenitor Cells (W230, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_3251;
These observations were further validated by the reactivation of KLF6 in aged HSPCs, which resulted in an attenuation of the aging HSPC phenotype in vitro . Finally, changes in gene expression in KLF6 KO cells indicate that it may be essential for regulation of gene expression programs involved in malignant transformation, such that age-related loss of this transcription factor may contribute to predisposition to myeloid malignancies.
- |||||||||| ECT-001 / ExCellThera
Optimized Culture Medium for Enhanced Ex Vivo expansion of Human Hematopoietic Stem Cells (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_2814;
These results for 1 wk ex vivo expansion of mPB CD34+ cells in SPHSC are similar or superior to reported 12d or 15d expansions of CB CD34+ cells in cytokine-supplemented standard media containing UM171 or SR1 (Fares et al...Cell Stem Cell 18:144;2016) . Thus, SPHSC medium may by itself be impactful in clinical transplantation and gene therapy and would also be an optimized platform medium for additional approaches to further enhance ex vivo expansion of human HSCs for transplant and gene therapies.
- |||||||||| CD70-Specific CAR T Cells Have Potent Activity Against Acute Myeloid Leukemia (AML) without HSC Toxicity (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_2779;
We demonstrate here that hinge and costimulatory domain greatly influences CD70-CAR T-cell function . LFS-28z- and CD27z-CAR T-cells had potent anti-AML activity in xenograft models with a favorable safety profile, warranting future early phase clinical testing of CD70-CAR T-cells in patients with CD70-positive AML.
- |||||||||| Reblozyl (luspatercept-aamt) / Acceleron, BMS
Effect of Rap-536 on MDS PDX-Murine Models with or without SF3B1 Mutation (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_2544;
RAP-536 improves hemoglobin and WBC levels and seems to enhance the engraftment of human myeloid hematopoiesis in this PDX murine model of MDS . Molecular analyses are ongoing to clarify the relative proportions of normal and pathological human hematopoiesis before and after RAP-536.
- |||||||||| Mylotarg (gemtuzumab ozogamicin) / UCB, PDL, Pfizer
Preliminary Lasso Regression Analysis Identifies DNA-Damage Gene Expression Signature Predictive of Clinical Outcomes in Patients Using Gemtuzumab Ozogamicin (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_2227;
The model included four genes well known for their involvement in DNA-damage response: AKT1, a kinase that regulates cell growth and division; CASP9, The initiator caspase involved in apoptosis; H2AFX, a DNA-damage marker that recruits other DNA-damage response proteins to damaged loci; and XRCC4, a ligase for DNA damage repair . Our future work focuses on expanding this investigation in bigger cohorts of patients representing different risk groups of AML as well as in vitro mechanistic studies .
- |||||||||| fludarabine / Generic mfg., cytarabine / Generic mfg., Mylotarg (gemtuzumab ozogamicin) / UCB, PDL, Pfizer
Addition of the Anti-CD33 Monoclonal Antibody Mylotarg to Fludarabine/High Dose Cytarabine - Based Induction Significantly Improves Outcome in Patient Affected By FLT3-ITD Positive Cytogenetically Normal Acute Myeloid Leukemia (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_2190;
Aims: To investigate the efficacy of MY added to an intensive fludarabine, high dose cytarabine and Idarubicin-based induction regimen (FLAI) as frontline treatment for younger (<65 years), cytogenetically normal AML patients according to NPM1 and FLT3-ITD mutational status. Despite the potential bias due to the retrospective nature of the analysis, our data seem to indicate that Mylotarg, added to an intensive fludarabine/high dose cytarabine-based induction, provides a significant improvement in anti-leukemic efficacy in patients carrying FLT3-ITD mutation, especially if concomitant NPM1 mutation is not present.
- |||||||||| azacitidine / Generic mfg.
Identification of Novel Combination Therapies Active in BCL2 Inhibitor-Resistant Patient-Derived AML Models (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_2092;
Notably, 2/5 PDX models screened (DFAM-68555 and DFAM-10360) were insensitive to both venetoclax and the combination of venetoclax + 5-azacytidine (HMA) ex vivo...However, in DFAM-68555, AZD5153, AZD5991, and AZD2811 showed improved activity over venetoclax alone (67%, 54%, and 67% vs. 26% decrease in viability for venetoclax alone, respectively)...Using this platform and subsequent in vivo efficacy, we identified venetoclax combinations across multiple mechanisms (pro-apoptotic, cell cycle regulation, transcriptional regulation, DNA damage response) with activity in venetoclax-insensitive models. These results suggest potential therapeutic options to explore clinically for AML patients.
- |||||||||| AMG 330 / Amgen, Blincyto (blinatumomab) / Astellas, Amgen, 4-1BB agonist mAb / Amgen
Impact of p53 Knock-Down on T-Cell Proliferation and T-Cell Mediated Cytotoxicity Against AML Cell Lines Mediated By a CD33 Specific BiTE® Antibody Construct (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_2084;
Proof of concept was shown by Blinatumomab, a CD19xCD3 BiTE® antibody construct, for treatment of r/r B-cell precursor ALL...HD T cells and murine Ba/F3 cells (transduced with CD33 and CD86) were cocultured at an E:T ratio of 1:10 in presence of 5 ng/ml AMG 330 or control BiTE®in the lower compartment...Bulk RNA sequencing of p53 kd AML cell lines compared to p53 wt revealed downregulation of a co-stimulatory ligand 4-1BBL with log2 fold change of - 0.33, -0.30, -0.39 in Molm-13, MV4-11 and OCI-AML3, respectively...We will also characterize primary patient samples for their T-cell-inhibiting capacities, e.g . p53-mutated disease.
- |||||||||| Blincyto (blinatumomab) / Astellas, Amgen, Imbruvica (ibrutinib) / AbbVie, J&J
Ibrutinib Treatment in CLL Patients Improves T Cell Function and Blinatumomab Redirected Cytotoxicity (Hall B, Level 2 (Orange County Convention Center)) - Nov 7, 2019 - Abstract #ASH2019ASH_1853;
CLL patients’ T cells post ibrutinib treatment demonstrated superior cytotoxicity against autologous leukemia cells compared to T cells from treatment baseline . Moreover, we show that increased T cell activity is not solely due to ibrutinib-related Treg depletion .
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