scholarly journals Loss of nr4a1 abrogates Fitness of asxl1-mutant Hematopoietic Clones

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3272-3272
Author(s):  
Serine Avagyan ◽  
Jonathan E Henninger ◽  
William P. Mannherz ◽  
Meeta Mistry ◽  
Song Yang ◽  
...  
Keyword(s):  
Chronic Inflammation ◽  
Myeloid Cells ◽  
Sequencing Analysis ◽  
Publicly Traded ◽  
Clone Size ◽  
Hematopoietic Stem ◽  
Frameshift Mutations ◽  
Increased Risk ◽  
Anti Inflammatory ◽  
Privately Held

Abstract Clonal fitness of mutant hematopoietic stem and progenitor cells (HSPCs) underlies clonal hematopoiesis (CH), a state of clonal expansion associated with increased risk of blood malignancies and cardiovascular disease. Mechanisms by which acquired mutations lead to clonal fitness are not known. We used a zebrafish model to study the effect of acquired asxl1 mutations on HSPC clonality with TWISTR (Tissue editing With Inducible Stem cell Tagging via Recombination) that combined mosaic CRISPR-Cas9 mutagenesis with color labeling of HSPC clones. TWISTR asxl1 mutants showed clonal dominant states with the expansion of single-colored clones contributing to over 30% of myelopoiesis. These zebrafish had normal hematopoietic output and no major lineage skewing. Single-cell RNA sequencing analysis of TWISTR mutant marrow cells harboring asxl1 mutations showed >10-fold upregulation of inflammatory cytokines in mutant mature myeloid cells and >30-fold upregulation of anti-inflammatory modulators in immature progenitors. Increased inflammation has been widely documented in persons with CH with acquired mutations in DNMT3A, TET2, ASXL1 and other genes. Moreover, chronic inflammation due to infection was shown to promote relative clonal fitness in Dnmt3a mutant mice. Based on our results, we proposed the hypothesis that upregulation of the anti-inflammatory genes, including nr4a1, served as a mechanism of resistance to chronic inflammation created by the mutant HSPC progeny, resulting in a self-perpetuating cycle of clonal fitness in that environment. To test this, we used TWISTR to generate mosaic mutants of asxl1 and nr4a1 by injecting zebrafish with guide RNAs targeting exon 12 of asxl1 and exon 3 of nr4a1 together. Our model would predict that abrogation of nr4a1 expression in asxl1-mutant clones would weaken their fitness relative to clones that maintained nr4a1 expression. We sorted over 300 clones of various sizes from this cohort of zebrafish and sequenced the two targeted genes. We found that clones with frameshift mutations in asxl1 with either no nr4a1 mutations or heterozygous nr4a1 mutations had a clone size of 20%±14% or 19.7%±15% in myeloid cells, respectively. Asxl1-mutant clones with biallelic frameshift mutations in nr4a1 were significantly smaller with a clone size of 13.8±11.5% (p < 0.015). Clones with intact asxl1 did not differ in their clone size independent of nr4a1 genetic status (11.9% wildtype nr4a1 vs 11.5% homozygous nr4a1 mutant). Chemical inhibition of nr4a1 over 3 months resulted in reduced change of edited clones in asxl1-mutant zebrafish compared to vehicle-treated zebrafish, with median change in allelic fraction of 3%±4.8% vs 5.3%±7.5%, respectively. This suggested that upregulation of nr4a1 in asxl1-mutant clones maintains their fitness in inflammatory conditions, potentially by limiting HSPC exhaustion. We successfully used TWISTR to study asxl1 induced CH in zebrafish and identified nr4a1 upregulation as a critical pathway engaged for establishing clonal fitness. Disclosures Zon: Fate Therapeutics: Current equity holder in publicly-traded company, Other: Founder; CAMP4 Therapeutics: Current holder of individual stocks in a privately-held company, Other: Founder; Amagma Therapeutics: Current holder of individual stocks in a privately-held company, Other: Founder; Scholar Rock: Current equity holder in publicly-traded company, Other: Founder; Branch Biosciences: Current holder of individual stocks in a privately-held company, Other: Founder; Celularity: Consultancy; Cellarity: Consultancy.

scholarly journals Rheumatoid arthritis: influence of inflammation and anti-inflammatory therapy on cardiovascular risk factors

2020 ◽  
pp. 32-44
Author(s):  
D. I. Trukhan ◽  
D. S. Ivanova ◽  
K. D. Belus
Keyword(s):  
Rheumatoid Arthritis ◽  
Risk Factors ◽  
Cardiovascular Risk ◽  
Cardiovascular Diseases ◽  
Cardiovascular Risk Factors ◽  
Chronic Inflammation ◽  
Pharmacological Intervention ◽  
Increased Risk ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

Rheumatoid arthritis is a frequent and one of the most severe immuno-inflammatory diseases in humans, which determines the great medical and socio-economic importance of this pathology. One of the priority problems of modern cardiac rheumatology is an increased risk of cardiovascular complications in rheumatoid arthritis. In patients with rheumatoid arthritis, traditional cardiovascular risk factors for cardiovascular diseases (metabolic syndrome, obesity, dyslipidemia, arterial hypertension, insulin resistance, diabetes mellitus, smoking and hypodynamia) and a genetic predisposition are expressed. Their specific features also have a certain effect: the “lipid paradox” and the “obesity paradox”. However, chronic inflammation as a key factor in the development of progression of atherosclerosis and endothelial dysfunction plays a leading role in morbidity and mortality from cardiovascular diseases in rheumatoid arthritis. This review discusses the effect of chronic inflammation and its mediators on traditional cardiovascular risk factors and its independent significance in the development of CVD. Drug therapy (non-steroidal anti-inflammatory drugs, glucocorticosteroids, basic anti-inflammatory drugs, genetically engineered biological drugs) of the underlying disease also has a definite effect on cardiovascular risk factors in patients with rheumatoid arthritis. A review of studies on this problem suggests a positive effect of pharmacological intervention in rheumatoid arthritis on cardiovascular risk factors, their reduction to a level comparable to the populations of patients not suffering from rheumatoid arthritis. The interaction of rheumatologists, cardiologists and first-contact doctors (therapist and general practitioner) in studying the mechanisms of the development of atherosclerosis in patients with rheumatoid arthritis will allow in real clinical practice to develop adequate methods for the timely diagnosis and prevention of cardiovascular diseases in patients with rheumatoid arthritis.

scholarly journals Outcomes of COVID-19 in Hematopoietic Stem-Cell Transplant Recipients: A Single Institution Observational Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4896-4896
Author(s):  
Sami Dwabe ◽  
Lakshmi Savitala-Damerla ◽  
Jack Rodman ◽  
Abdullah Ladha ◽  
Eric Tam ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Cell Transplant ◽  
Publicly Traded ◽  
Single Institution ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Privately Held

Abstract Intro: Hematopoietic stem-cell transplant (HSCT) recipients are considered to be at high risk for poor outcomes following COVID-19 infection given their co-morbidities and immunosuppression. Sharma et al published the CIBMTR observational report data that showed that recipients of allogeneic HSCT who contract COVID-19 have poor overall survival with a 30-day mortality of 32%. That being said, there have been relatively few studies that look into the effect of COVID-19 on HSCT recipients in the setting of in vivo T cell depletion protocols. With the increased use of post-transplant cyclophosphamide (PTCy) based GVHD prophylaxis regimens for our match related and match unrelated HSCT recipients since 2018 at our institution, we are interested to see if our COVID-19 outcomes differ from those published in the CIBMTR report. Methods: This is a single institution retrospective analysis evaluating outcomes of HSCT recipients who were diagnosed with COVID-19 between March 2020 and April 2021. Patients 18 years or older who underwent HSCT and subsequently contracted COVID-19 were included in the data collection. Demographic data including age, type of hematologic malignancy, conditioning regimen, GVHD prophylaxis, date of COVID-19 infection, with pre- and post-COVID-19 infection labs were obtained. Our primary endpoint in this retrospective analysis was non-relapse mortality within 30 days of COVID-19 diagnosis. Results: There were 21 patients at our institution who had undergone HSCT and subsequently contracted COVID-19. The most common primary disease types were acute lymphoblastic leukemia (33.3%), acute myeloid leukemia (23.8%), and myelodysplastic syndrome (19.0%). The median age of our patient population was 53 years (range, 24-66). 6 of the patients received match related allografts. 7 received cells from match unrelated donors. 7 received cells from haploidentical donors. 1 patient had received an autologous stem cell transplant. Of the remaining 20 allo-HSCT recipients, 14 of them (70.0%) received myeloablative conditioning regimens, whereas 6 (30.0%) received reduced intensity or non-myeloablative regimens. Our GVHD prophylaxis regimens were PTCy/Tacro/MMF (12 pts, 60.0%) and Tacro/MTX (8 pts, 40.0%). Patient demographics and outcomes are found on Tables 1 and 2. Our patients were diagnosed with COVID-19 a median 469 days post-transplant, with 8 patients (38.1%) diagnosed with COVID-19 within 1 year of transplant. 11 of the patients (52.4%) received steroids following their diagnosis with COVID-19. Of the 20 allo-HSCT recipients with confirmed COVID-19 infection, 1 passed away 20 days after the diagnosis was made. This gives us a 5.0% case fatality rate attributable to COVID-19 in our population in our allo-HSCT population. 16 of the 20 patients were symptomatic at the time of diagnosis (80.0%). 7 of the 20 patients (35.0%) were hospitalized for a median of 7 days (range, 5-17 days), with 2 requiring ICU level of care. The one patient who passed away tested positive for COVID-19 177 days post-transplant and was hospitalized approximately 7 days after diagnosis, where he was intubated on hospital day 4 and ultimately passed away on hospital day 13. The patient had received Tacro/MTX for GVHD prophylaxis. Discussion: Although this is a small sample size, our data suggests that our allo-HSCT recipients who contracted COVID-19 have had generally good short-term outcomes. Our study is limited by the small number of patients who got infected with COVID-19, particularly those within 1-year post-transplant. Furthermore, we acknowledge it is difficult to claim that the PTCy based GVHD prophylaxis regimens for our HSCT recipients were solely responsible for their improved outcomes since 40% of allo-HSCT recipients did not get PTCy for GVHD prophylaxis. However, we believe it would be valuable to evaluate in a prospective analysis. We are currently evaluating if a COVID-19 diagnosis has any effect on long term transplant related complications and outcomes in this population. Figure 1 Figure 1. Disclosures Chaudhary: Angeles Therapeutics: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Founder, Patents & Royalties: Cell therapy ; Celldex: Current equity holder in publicly-traded company; Moderna: Current equity holder in publicly-traded company; Pancella: Consultancy; Oncotartis: Consultancy; Athelas: Consultancy, Current holder of stock options in a privately-held company; TCR2: Current equity holder in publicly-traded company; Allogene: Current equity holder in publicly-traded company. Yaghmour: Novartis: Consultancy, Speakers Bureau; BMS: Speakers Bureau; Alexion: Speakers Bureau; Astellas: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Jazz: Speakers Bureau; Agios: Consultancy, Speakers Bureau.

scholarly journals Rigidity of Cell Fate and Function Among Monocytes

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2057-2057
Author(s):  
Catherine Rhee ◽  
Elizabeth W Scadden ◽  
Lai Ping Wong ◽  
Giulia Schiroli ◽  
Michael Mazzola ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Board Of Directors ◽  
Myeloid Cells ◽  
Innate Immune ◽  
Immune Memory ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Adaptive Immune ◽  
Classical Monocytes ◽  
Privately Held

Abstract Myeloid cells are the most evolutionarily ancient aspect of a specialized immune system and the cornerstone of innate immunity in vertebrates. Innate immunity serves at the front line of host defense playing essential roles in directly clearing infection while also activating adaptive immune cell populations. Even with the importance in its roles, the myeloid system has often been regarded as the 'dumb brute' side of cell-based immunity with limited specificity and variability of responses. Heterogeneity in innate immune cells is increasingly recognized but still modest compared to other cell types and constrained by limited investigative tools. Monocytes have traditionally been categorized into two subsets: classical and non-classical. Classical monocytes are thought to readily convert to non-classical monocytes with exogenous cues. Studies on bulk monocyte populations have shown that monocytes acquire functional features dependent on physiological needs supporting a prevailing model that monocytes are highly plastic. We adapted a system for inducible clonal expansion of mouse granulocyte-monocyte progenitor (GMP) capable of differentiating into mature myeloid cells to address at a clonal level the issues of monocyte heterogeneity, plasticity, and whether changes in monocyte functional groups are due to induction or selection, Using inducible HoxB8-ER, large numbers of primary self-renewing GMP can undergo progressive maturation to fully functional granulocytes or monocytes upon removal of estrogen. The resulting GMP clones could then be characterized molecularly and immunophenotypically in correlation with the specialized functions of their descendent monocytes (Figure 1A). Four GMP differentiation trajectories that yield functionally distinct monocytes were defined (Figures 1B and 1C). Notably the functional monocyte groups were evident at the GMP level based on unsupervised clustering of chromatin configuration data (Figure 1D). GMP bore epigenetic scripting of the potential of their descendent monocytes and this fate had little flexibility once differentiation had begun. Testing cells under in vitro and in vivo homeostasis and stress conditions revealed that the cells maintain their differentiation path and do not transition from one state to another (Figures 1E and 1F). These data imply a model whereby monocyte stimulus-specific selection may occur and may contribute to an innate immune memory that resembles adaptive immune memory. Figure 1 Figure 1. Disclosures Sykes: Keros Therapeutics: Consultancy; SAFI Biosolutions: Consultancy, Current equity holder in publicly-traded company; Clear Creek Bio: Current equity holder in publicly-traded company. Scadden: Magenta Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Clear Creek Bio: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; LifeVaultBio: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Editas Medicines: Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Current holder of individual stocks in a privately-held company; Clear Creek Bio: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Dainippon Sumitomo Pharma: Other: Sponsored research; FOG Pharma:: Consultancy; Garuda Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; VCanBio: Consultancy; Inzen Therapeutics: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Knock out of CD123 or CLL-1 By CRISPR-Cas9 Editing from Human Hematopoietic Stem Cell Transplants Provide New Possibilities for Increasing Therapeutic Index and Safety for AML Treatment

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3818-3818
Author(s):  
Chong Luo ◽  
Gabriella Angelini ◽  
Sushma Krishnamurthy ◽  
Jessica Lisle ◽  
Meltem Isik ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Gene Editing ◽  
Gene Knockout ◽  
Myeloid Cells ◽  
In Vivo Model ◽  
Cell Transplant ◽  
Publicly Traded ◽  
Hematopoietic Stem ◽  
Equal Distribution ◽  
Counter Selection

Abstract Acute myeloid leukemia (AML) is a clonal disorder of hematopoiesis and the most common form of acute leukemia in adults. Most patients with AML relapse despite intensive chemotherapy. Allogeneic hematopoietic cell transplant (HCT) has become the standard of care for patients with intermediate or adverse genetics, with >3,500 transplants performed annually in the US. However, leukemia relapse post-HCT occurs in ~40% of these patients with a 2-year survival rate at <20%, necessitating new approaches to reduce relapse and improve overall outcomes. Antigen-specific immunotherapies require cell surface antigens to be uniquely expressed on cancer cells to minimize "on-target, off-tumor" toxicity. CD123 and CLL-1 are highly expressed on normal myeloid cells, thus impeding the use of therapies targeting these antigens due to myelotoxicity. To circumvent such toxicity, we aim to create CD123 or CLL-1 negative human hematopoietic stem and progenitor cells (hHSPCs) for HCT such that this can be combined with subsequent use of targeted therapy against these antigens to prevent post-HCT relapse. Here, we present the pre-clinical evaluation of engineered hHSPCs, derived from mobilized peripheral blood of healthy donors, where CD123 or CLL-1 proteins were ablated by CRISPR/Cas9 gene editing. We have identified highly efficient guide RNAs that result in >80% on-target editing and can achieve greater than 90% biallelic gene knockout (KO). Deep sequencing followed by hybrid capture of up to 1000 potential off-target sites predicted to contain a maximum of 5 mismatches revealed minimal to no detectable off-target editing events. CD123 or CLL-1 KO hHSPCs showed >85% cell viability post-editing. Loss of CD123 or CLL-1 protein did not impact the differentiation of hHSPCs into granulocytic, monocytic, or erythroid lineages in vitro. Additionally, myeloid cells derived from CD123 or CLL-1 KO hHSPCs also retained their function, demonstrating similar phagocytotic capacity and the production of inflammatory cytokines in response to TLR agonists compared to unedited control cells. Importantly, CD123 or CLL-1 KO hHSPCs xenotransplanted into NSG or NBSGW mice showed no defect in long-term engraftment (human chimerism in NBSGW mice 16 weeks post transplant: 92.3±5.1% for CD123 KO, 91.2±4.1% for CLL-1 KO, and 93.4±3.1% unedited hHSPC engrafted mice, n=15 each). This in vivo model confirmed no observable impact on multilineage differentiation after CD123 or CLL-1 deletion either, supported by equal distribution of 10 hematopoietic lineages between groups. Bone marrow analyses revealed persistence of high gene editing frequency after 16 weeks (71±10% from CD123 KO and 86±6% from CLL-1 KO engrafted mice, n=15 each, compared to original 83% input CD123 KO and 86% input CLL-1 hHSPCs). Sorted subpopulations, including granulocytes, monocytes, dendritic cells, and mast cells, from the bone marrow similarly retained high levels of editing. Together these data suggest that there was no counter-selection against CD123 or CLL-1 KO cells, no outgrowth of any cells with particular edits or hematopoietic lineages to warrant tumorigenic concerns. Most notably, proof-of-concept experiments showed that cells depleted of CD123 or CLL-1 protein are indeed protected from the cytotoxicity of CD123 or CLL-1 targeted CAR-T cells. In conclusion, we demonstrate that CD123 or CLL-1 negative human HSPCs can successfully carry out functional hematopoiesis that is resistant to CD123 or CLL-1 targeted therapies. Our findings provide a next-generation HCT strategy that supports the safe and effective use of antigen-directed immunotherapy treatments for patients with AML. Disclosures Luo: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company. Angelini: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company. Krishnamurthy: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company. Lisle: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company. Isik: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company. Ghdossi: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company. Cummins: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company. Pettiglio: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company. Hazelbaker: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company. Ge: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company. Tavares: Vor Biopharma: Ended employment in the past 24 months. Nikam: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company. Paik: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company. Lydeard: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company. Lin: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company. Chakraborty: Vor Biopharma: Current Employment, Current equity holder in publicly-traded company.

scholarly journals Cxcl8/PKC Signaling in the Endothelial Cell Niche Regulates Long-Term Hematopoietic Stem Cell Fate

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 38-38
Author(s):  
Jami L Shaffer ◽  
Donn L Calkins ◽  
Emily M Teets ◽  
Muhammad Faisal ◽  
William Deruelle ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Phylogenetic Diversity ◽  
Myeloid Cells ◽  
Clonal Diversity ◽  
Publicly Traded ◽  
Private Company ◽  
Hematopoietic Stem ◽  
Empty Vector ◽  
Cell Niche

The sinusoidal endothelial cell niche is a component of the hematopoietic microenvironment with an important role in regulating hematopoietic stem cell (HSC) fate. Mechanisms by which the niche control the long-term functional and phylogenetic diversity of the hematopoietic system are poorly understood. We performed gene expression profiling on FACS-purified endothelial cells from the zebrafish caudal hematopoietic territory (CHT), the sinusoidal endothelial niche equivalent to the mammalian fetal liver. Kdrl:GFP+lyve1b:DsRed+ CHT endothelial cells were compared to kdrl:GFP+lyve1b:DsRed- non-CHT endothelial cells by bulk RNA-seq and 106 genes were downregulated in the CHT with q<0.05. Enforced expression of candidate genes in the CHT was achieved using a zebrafish E-selectin (sele) enhancer/promoter element. Microinjection of a sele:prkcda-2A-mCherry (protein kinase C (PKC), delta a) construct into Runx1+23:GFP HSPC reporter zebrafish embryos resulted in a significant increase in the number of HSPCs compared to empty vector control (5.4 ± 1.0 vs 2.5 ± 0.4, p = 0.007). The same construct was microinjected into hemizygous GESTALT zebrafish with barcoding sgRNAs and Cas9. Barcoded embryos were grown to adulthood, peripheral blood was sampled at 3, 6, 9 and 12 months post-fertilization (mpf), and phylogenetic diversity of the hematopoietic system was measured in a longitudinal manner by enumerating unique GESTALT clones. Transgenic animals microinjected with the sele:prkcda-2A-mCherry construct consistently showed greater HSC clonal diversity compared to empty vector control (9.5 ± 0.9 vs 6.4 ± 0.7 clones at 12 mpf, p = 0.024). Single cell RNA sequencing (scRNA-seq) of the marrow of these animals revealed expanded populations of macrophages and erythrocyte precursors in those with dysregulated expression of prkcda. PKC family members are signaling intermediates for cxcr1, the receptor for the chemokine cxcl8, and a factor we have previously shown to positively regulate CHT colonization. Treatment of human umbilical vein endothelial cells in vitro with recombinant cxcl8 showed no change in prkcd transcript levels by bulk RNAseq or quantitative RT-PCR, but did show enhanced accumulation of PKC-d protein after 2 hours consistent with induction of this pathway at the post-transcriptional level. To understand how cxcl8/PKC signaling might alter the niche in vivo, transgenic zebrafish with enforced expression of cxcl8 were generated by microinjecting embryos with a Runx1+23:cxcl8 expression construct. These were raised to 12 mpf and kidney marrow was harvested and subjected to scRNA-seq, demonstrating over 2-fold expansion of stromal and endothelial elements in Runx1:cxcl8 animals compared to controls. Hematopoietic cells were identified, a developmental trajectory was plotted using pseudotime analysis, and this was anchored using expression of genes characteristic of early (meis1b, tal1) and late (lyz, mpx) myeloid development. Runx1:cxcl8 mosaic transgenics had a relative expansion of early myeloid cells compared to control animals (61% vs 38% early myeloid cells, p = 0.0002). Our data support the following model: HSPCs or other myeloid cells may actively remodel the niche via cxcl8 expression, signaling through cxcr1 and PKC, increasing niche capacity and thereby expanding the number of HSCs that can contribute to hematopoiesis. The presence of reserve capacity within the niche may be relevant to conditions where loss of HSC clonal diversity carries a risk of myeloid neoplasia. Disclosures Zon: Amagma Therapeutics: Current equity holder in private company, Other: Founder; CAMP4 Therapeutics: Current equity holder in private company, Other: Founder; Celularity: Consultancy; Scholar Rock: Current equity holder in publicly-traded company, Other: Founder; Cellarity: Consultancy; Fate Therapeutics: Current equity holder in publicly-traded company, Other: Founder.

scholarly journals Evaluating Outcomes Using Post-Transplant Cyclophosphamide/Tacrolimus/Mycophenolate Mofetil As Gvhd Prophylaxis Compared with Methotrexate/Tacrolimus in Matched-Related and Matched-Unrelated Hematopoietic Stem Cell Transplant in Relation to the Haploidentical Setting in Acute Lymphoblastic Leukemia: A Single Center Experience

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4874-4874
Author(s):  
Sami Dwabe ◽  
Hugo Martinez ◽  
Jack Rodman ◽  
Eric Tam ◽  
Abdullah Ladha ◽  
...  
Keyword(s):  
Stem Cell ◽  
Lymphoblastic Leukemia ◽  
Cell Transplant ◽  
Publicly Traded ◽  
End Points ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Kaplan Meier ◽  
Gvhd Prophylaxis ◽  
Privately Held

Abstract Intro: Acute and chronic graft versus host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplant (allo-HSCT). Post-transplant cyclophosphamide (PTCy), alongside mycophenolate mofetil (MMF) and tacrolimus (TAC), is known to be effective in reducing cGVHD in haploidentical (HI) transplant recipients. Results of the prospective randomized HOVON-96 trial in recipients of matched related (MRD) and unrelated donors (MUD) showed that PTCy leads to a reduction in risk of severe cGVHD. However, the role of PTCy in HSCT with acute lymphoblastic leukemia (ALL) remains controversial. The purpose of this study is to evaluate outcomes using PTCy, TAC, and MMF for GVHD prophylaxis in MRD and MUD stem cell recipients who have ALL. Methods: This study is a retrospective analysis of adult patients (aged 19 and up) with ALL who received MRD, MUD, and HI HSCT at USC Norris Cancer Hospital from 2018 to 2020. The primary end-points were to compare incidence of aGVHD and cGVHD within the first year post-transplant after receiving MRD, MUD, and HI donor transplants. Secondary end-points were day +100 mortality, 1-year overall survival (OS), relapse free survival (RFS), transplant-related mortality (TRM), and GRFS within the same subgroups. Kaplan-Meier curves and Log Rank tests were used to evaluate a difference in outcomes. Results: A total of 46 patients with ALL who received HSCTs were identified and separated based on type of GVHD prophylaxis received: 7 (15.1%), 16 (34.8%), and 23 (50.0%) in the PT-Cy, HI and standard groups respectively. Demographic data can be found on Table 1 attached. Baseline characteristics among all groups were similar with the exception of the more Human Leukocyte Antigen (HLA) mismatch (p<0.01), higher number of patients receiving stem cells from bone marrow (p=0.02) and the increased proportion of patients receiving less than 5.0 x 10^6 CD34+ cells/kg (p=0.02) in the PTCy group. With regards to the primary end-points as seen on Table 2, there was a non-significant trend toward less frequent severe aGVHD and severe cGVHD in the PTCy group compared to the standard and HI cohorts (p=0.13). The rates of severe aGVHD were 0%, 6.2%, and 8.7% in the PT-Cy, HI and standard groups respectively. The rates of severe cGVHD were 0%, 6.2%, and 21.8% in the PT-Cy, HI and standard groups respectively. With regards to the secondary end-points in our study, as seen on Tables 2 and 3, patients receiving standard GVHD prophylaxis had a 95.7% 1-year OS, a 91.1% 1-year RFS, and 87.0% 1-year GRFS. Moreover, MRD/MUD recipients receiving PTCy for GVHD prophylaxis had worse outcomes with an 40.0% 1-year OS, a 62.5% 1-year RFS, and 62.5% 1-year GRFS. Comparatively, patients receiving HI transplants exhibited a 100% 1-year OS, a 100% 1-year RFS, and 91.7% 1-year GRFS. This was statistically significant across all outcome measures: OS (p=<0.01), RFS (p=0.0038), and GRFS (p=0.048). Kaplan-Meier curves for OS, GRFS, and RFS are attached. Discussion: In this single institution analysis, we observed that patients with ALL who underwent HI transplant had the best outcomes. Moreover, patients receiving MUD/MRD HSCT with use of PTCy had a non-significant reduced incidence of aGVHD and cGVHD, though had significantly worse 1-year OS, RFS, and GRFS when compared to standard GVHD prophylaxis or patients receiving HI transplants. We believe this is likely a multifactorial process. However, the increased percentage of mismatched antigens in the MUD transplants (p=0.19) and higher proportion of patients receiving less than 5.0 x 10^6 CD34+ cells/kg (p=0.02) in the PTCy group is important to acknowledge and can also be contributing to their poorer outcomes. We pose the idea that the use of PTCy may also lead to a reduced graft vs. leukemia effect in this population and thus a higher incidence of relapse and worse outcomes overall. A larger, prospective study should be considered to take into account these factors to better determine if patients with ALL could benefit from PTCy for GVHD prophylaxis. Figure 1 Figure 1. Disclosures Chaudhary: Celldex: Current equity holder in publicly-traded company; Moderna: Current equity holder in publicly-traded company; Pancella: Consultancy; Oncotartis: Consultancy; Athelas: Consultancy, Current holder of stock options in a privately-held company; TCR2: Current equity holder in publicly-traded company; Allogene: Current equity holder in publicly-traded company; Angeles Therapeutics: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Founder, Patents & Royalties: Cell therapy . Yaghmour: Takeda: Consultancy, Speakers Bureau; Astellas: Speakers Bureau; Alexion: Speakers Bureau; BMS: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Jazz: Speakers Bureau.

Consideration of a Pharmacological Combinatorial Approach to Inhibit Chronic Inflammation in Alzheimer’s Disease

2019 ◽  
Vol 16 (11) ◽  
pp. 1007-1017 ◽  
Author(s):  
James G. McLarnon
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Chronic Inflammation ◽  
Preventive Strategy ◽  
Subsequent Work ◽  
Activated Microglia ◽  
Starting Point ◽  
Anti Inflammatory ◽  
Cocktail Approach

A combinatorial cocktail approach is suggested as a rationale intervention to attenuate chronic inflammation and confer neuroprotection in Alzheimer’s disease (AD). The requirement for an assemblage of pharmacological compounds follows from the host of pro-inflammatory pathways and mechanisms present in activated microglia in the disease process. This article suggests a starting point using four compounds which present some differential in anti-inflammatory targets and actions but a commonality in showing a finite permeability through Blood-brain Barrier (BBB). A basis for firstchoice compounds demonstrated neuroprotection in animal models (thalidomide and minocycline), clinical trial data showing some slowing in the progression of pathology in AD brain (ibuprofen) and indirect evidence for putative efficacy in blocking oxidative damage and chemotactic response mediated by activated microglia (dapsone). It is emphasized that a number of candidate compounds, other than ones suggested here, could be considered as components of the cocktail approach and would be expected to be examined in subsequent work. In this case, systematic testing in AD animal models is required to rigorously examine the efficacy of first-choice compounds and replace ones showing weaker effects. This protocol represents a practical approach to optimize the reduction of microglial-mediated chronic inflammation in AD pathology. Subsequent work would incorporate the anti-inflammatory cocktail delivery as an adjunctive treatment with ones independent of inflammation as an overall preventive strategy to slow the progression of AD.

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