Development of VLA4 and CXCR4 Antagonists for the Mobilization of Hematopoietic Stem and Progenitor Cells.

The treatment of patients diagnosed with hematologic malignancies typically includes hematopoietic stem cell transplantation (HSCT) as part of a therapeutic standard of care. The primary graft source of hematopoietic stem and progenitor cells (HSPCs) for HSCT is mobilized from the bone marrow into the peripheral blood of allogeneic donors or patients. More recently, these mobilized HSPCs have also been the source for gene editing strategies to treat diseases such as sickle-cell anemia.

A single-cell atlas characterizes dysregulation of the bone marrow immune microenvironment associated with outcomes in multiple myeloma.

Multiple Myeloma (MM) remains incurable despite advances in treatment options. Although tumor subtypes and specific DNA abnormalities are linked to worse prognosis, the impact of immune dysfunction on disease emergence and/or treatment sensitivity remains unclear. We established a harmonized consortium to generate an Immune Atlas of MM aimed at informing disease etiology, risk stratification, and potential therapeutic strategies.

Control of acute myeloid leukemia and generation of immune memory in vivo using AMV564, a bivalent bispecific CD33 x CD3 T cell engager.

Off-the-shelf immunotherapeutics that suppress tumor growth and provide durable protection against relapse could enhance cancer treatment. We report preclinical studies on a CD33 x CD3 bivalent bispecific diabody, AMV564, that not only suppresses tumor growth, but also facilitates memory responses in a mouse model of acute myelogenous leukemia (AML). Mechanistically, a single 5-day treatment with AMV564 seems to reduce tumor burden by redirection of T cells, providing a time window for allogeneic or other T cells that innately recognize tumor antigens to become activated and proliferate.

Duvelisib for Critically Ill Patients With Coronavirus Disease 2019: An Investigator-Initiated, Randomized, Placebo-Controlled, Double-Blind Pilot Trial.

Background: Despite improvements in prevention and treatment, severe coronavirus disease 2019 (COVID-19) is associated with high mortality. Phosphoinositide 3-kinase (PI3K) pathways contribute to cytokine and cell-mediated lung inflammation. We conducted a randomized, placebo-controlled, double-blind pilot trial to determine the feasibility, safety, and preliminary activity of duvelisib, a PI3Kδγ inhibitor, for the treatment of COVID-19 critical illness.

Apolipoprotein M Attenuates Anthracycline Cardiotoxicity and Lysosomal Injury.

Apolipoprotein M (ApoM) binds sphingosine-1-phosphate (S1P) and is inversely associated with mortality in human heart failure (HF). Here, we show that anthracyclines such as doxorubicin (Dox) reduce circulating ApoM in mice and humans, that ApoM is inversely associated with mortality in patients with anthracycline-induced heart failure, and ApoM heterozygosity in mice increases Dox-induced mortality. In the setting of Dox stress, our studies suggest ApoM can help sustain myocardial autophagic flux in a post-transcriptional manner, attenuate Dox cardiotoxicity, and prevent lysosomal injury.

Single-Cell Discovery and Multiomic Characterization of Therapeutic Targets in Multiple Myeloma.

Unlabelled: Multiple myeloma (MM) is a highly refractory hematologic cancer. Targeted immunotherapy has shown promise in MM but remains hindered by the challenge of identifying specific yet broadly representative tumor markers. We analyzed 53 bone marrow (BM) aspirates from 41 MM patients using an unbiased, high-throughput pipeline for therapeutic target discovery via single-cell transcriptomic profiling, yielding 38 MM marker genes encoding cell-surface proteins and 15 encoding intracellular proteins.

Flotetuzumab and other T-cell immunotherapies upregulate MHC class II expression on acute myeloid leukemia cells.

Acute myeloid leukemia (AML) relapse is one of the most common and significant adverse events following allogeneic hematopoietic cell transplantation (HCT). Downregulation of major histocompatibility class II (MHC-II) surface expression on AML blasts may represent a mechanism of escape from the graft-versus-malignancy effect and facilitate relapse. We hypothesized that T-cell immunotherapies targeting AML antigens would upregulate MHC-II surface expression via localized release of interferon gamma (IFN-γ), a protein known to upregulate MHC-II expression via JAK-STAT signaling.

CS1 CAR-T targeting the distal domain of CS1 (SLAMF7) shows efficacy in high tumor burden myeloma model despite fratricide of CD8+CS1 expressing CAR-T cells.

Despite improvement in treatment options for myeloma patients, including targeted immunotherapies, multiple myeloma remains a mostly incurable malignancy. High CS1 (SLAMF7) expression on myeloma cells and limited expression on normal cells makes it a promising target for CAR-T therapy. The CS1 protein has two extracellular domains - the distal Variable (V) domain and the proximal Constant 2 (C2) domain.

Antibody-drug conjugates plus Janus kinase inhibitors enable MHC-mismatched allogeneic hematopoietic stem cell transplantation.

Despite the curative potential of hematopoietic stem cell transplantation (HSCT), conditioning-associated toxicities preclude broader clinical application. Antibody-drug conjugates (ADCs) provide an attractive approach to HSCT conditioning that minimizes toxicity while retaining efficacy. Initial studies of ADC conditioning have largely focused on syngeneic HSCT.

Combination of dociparstat sodium (DSTAT), a CXCL12/CXCR4 inhibitor, with azacitidine for the treatment of hypomethylating agent refractory AML and MDS.

Leukemia stem cells utilize cell adhesion molecules like CXCR4/CXCL12 to home to bone marrow stromal niches where they are maintained in a dormant, protected state. Dociparstat sodium (DSTAT, CX-01) is a low anticoagulant heparin with multiple mechanisms of action, including inhibition of the CXCR4/CXCL12 axis, blocking HMGB1, and binding platelet factor 4 (PF-4). We conducted a pilot study adding DSTAT to azacitidine for patients with AML or MDS unresponsive to or relapsed after prior hypomethylating agent therapy, hypothesizing that DSTAT may improve response rates.

Machine learning-based scoring models to predict hematopoietic stem cell mobilization in allogeneic donors.

Mobilized peripheral blood has become the primary source of hematopoietic stem cells for both autologous and allogeneic stem cell transplantation. Granulocyte colony-stimulating factor (G-CSF) is currently the standard agent used in the allogeneic setting. Despite the high mobilization efficacy in most donors, G-CSF requires 4-5 days of daily administration, and a small percentage of the donors fail to mobilize an optimal number of stem cells necessary for a safe allogeneic stem cell transplant.

Functional and epigenetic phenotypes of humans and mice with DNMT3A Overgrowth Syndrome.

Germline pathogenic variants in DNMT3A were recently described in patients with overgrowth, obesity, behavioral, and learning difficulties (DNMT3A Overgrowth Syndrome/DOS). Somatic mutations in the DNMT3A gene are also the most common cause of clonal hematopoiesis, and can initiate acute myeloid leukemia (AML). Using whole genome bisulfite sequencing, we studied DNA methylation in peripheral blood cells of 11 DOS patients and found a focal, canonical hypomethylation phenotype, which is most severe with the dominant negative DNMT3A mutation.

3D tissue engineered plasma cultures support leukemic proliferation and induces drug resistance.

Chronic myeloid leukemia (CML), acute myeloid leukemia (AML), and chronic lymphocytic leukemia (CLL) are hematological malignancies that remain incurable despite novel treatments. In order to improve current treatments and clinical efficacy, there remains a need for more complex models that mimic the intricate human leukemic microenvironment. This study aimed to use 3D tissue engineered plasma cultures (3DTEPC) derived from CML, AML and CLL patients to promote proliferation of leukemic cells for use as a drug screening tool for treatment.

Co-evolution of tumor and immune cells during progression of multiple myeloma.

Multiple myeloma (MM) is characterized by the uncontrolled proliferation of plasma cells. Despite recent treatment advances, it is still incurable as disease progression is not fully understood. To investigate MM and its immune environment, we apply single cell RNA and linked-read whole genome sequencing to profile 29 longitudinal samples at different disease stages from 14 patients.