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Inhibition of Lysine-Specific Demethylase-1 in Myelodysplastic Syndrome Progenitors Restores Differentiation of CD141Hi Conventional Dendritic Cells

ABSTRACT: Immunotherapeutic approaches to treat patients with myelodysplastic syndromes (MDS) show promise but progress is hindered by our incomplete knowledge of the immunologic milieu. In a recent phase I trial, we found that vaccination of MDS patients against the tumor antigen NY-ESO-1 activated antigen-specific adaptive immune responses in patients with higher numbers of CD141Hi conventional dendritic cells (cDCs). In solid tumor models, the CD141Hi cDC is critical for initiating anti-tumor immune responses but its impact in myeloid malignancies is unknown. In a series of studies using human samples and mouse models, we tested the hypothesis that MDS patients would exhibit decreased quantity and quality of CD141Hi cDCs due to myeloid dysplasia. Overall, we found CD141Hi cDCs were decreased in MDS patients’ bone marrow and that decreased numbers of CD141Hi cDCs were associated with reduced overall survival. MDS patients had reduced numbers of DC committed progenitors and their progenitors expressed lower levels of the transcription factor interferon regulatory factor-8 (IRF8), a master regulator of CD141Hi cDC differentiation. Induction of IRF8 expression in mouse, healthy human and MDS patient progenitors using an inhibitor of lysine-specific demethylase-1 (LSD1) increased CD141Hi cDC differentiation. These data reveal a previously unrecognized factor of the immune microenvironment in MDS and suggest intriguing connections between epigenetic regulation of CD141Hi cDC differentiation in MDS and the ability to translate these mechanisms to improve immunotherapy for MDS patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE131792 | GEO | 2019/11/23

REPOSITORIES: GEO

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Project description:BACKGROUND: Pulmonary Arterial Hypertension (PAH) is a progressive condition with no cure. Even with pharmacologic advances, survival remains poor. Lung pathology on PAH therapies still shows impressive occlusive arteriolar remodeling and plexiform lesions. Cardiosphere derived cells (CDCs) are heart derived progenitor cells exhibiting anti inflammatory and immunomodulatory effects, are anti fibrotic, anti oxidative and anti apoptotic to potentially impact several aspects of PAH pathobiology. In preclinical trials CDCs reduced right ventricular (RV) systolic pressure, RV hypertrophy, pulmonary arteriolar wall thickness and inflammation. METHODS: The ALPHA study was a Phase 1a/b study in which CDCs were infused into patients with Idiopathic (I)PAH, Heritable (H) HPAH, PAH connective tissue disease (CTD ) and PAH human immunodeficiency virus (HIV). The study was IRB approved and DSMB monitored. Phase 1a, was an open label study (n=6). Phase 1b was a double blind placebo controlled study (n=20) in which half received 100 million CDCs (the maximum feasible dose from manufacturing perspective) and half placebo (PLAC) infusions. Right heart catheterization (RHC) and cardiac MR imaging (cMR) were performed at baseline and at 4 months post infusion. Patients were followed over a year. FINDINGS: No short term clinical safety adverse events (AE) were related to the IP, the primary outcome measure. There were no adverse hemodynamic, gas exchange, rhythm or other clinical events following infusion and in the 1st 23 hours monitored in hospital. There were no long term AEs over 12 months noted, including unrelated limited hospitalizations. No immunologic short or long term AEs were noted. We examined exploratory outcomes across multiple domains to determine encouraging signals to motivate future advanced phase testing. Phase 1a data showed encouraging observations for both 50 and 100 million CDC doses. Several encouraging findings favoring CDCs (n=16) compared to placebo (n=10) were noted. On cMR, the RV end diastolic volume (RVEDV) and index (RVEDVI) decreased with CDCs with a rise in the PLAC group. The 6 minute walk distance was increased 2 months post infusion in the CDC group compared with PLAC. With PLAC, diffusing capacity (DLCO) decreased at 4 months but was unchanged with CDCs. Serum creatinine decreased with CDCs at 4 months. Encouraging observations favoring CDCs were also noted for RV fractional area change on echo and RV ejection fraction (RVEF) on cMR at 4 months. No differences were observed for mean pulmonary artery pressures or pulmonary vascular resistance. Review of long term data to 12 months showed continued decline in DLCO for the PLAC cohort at 6 months with no change through 12 months. By contrast, CDC subjects showed an unchanged DLCO over 12 months. For parameters exhibiting early encouraging exploratory findings in CDC subjects, no further improvement was noted in long term follow up through 12 months. INTERPRETATION: Intravenous CDCs were safe in both the short and long term in PAH subjects and thus may be safe in larger cohorts, in line with our extensive track record of safety in clinical trials for other conditions. Further, CDCs exhibited encouraging exploratory findings across several domains. Repeat dosing (quarterly, over one year) of intravenous CDCs has been reported to yield highly significant sustained disease modifying bioactivity in subjects with advanced Duchenne muscular dystrophy. Because only single CDC doses were used here, the findings represent a lower limit estimate of CDCs potential in PAH. Upcoming phase 2 studies would logically use a repeat dosing paradigm.

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Inhibition of Lysine-Specific Demethylase-1 in Myelodysplastic Syndrome Progenitors Restores Differentiation of CD141Hi Conventional Dendritic Cells

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