Targeting CXCR4 in AML and ALL

The interaction of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) blasts with the bone marrow microenvironment regulates self-renewal, growth signaling, as well as chemotherapy resistance. The chemokine receptor, CXC receptor 4 (CXCR4), with its ligand chemokine ligand 12 (CXCL12), plays a key role in the survival and migration of normal and malignant stem cells to the bone marrow. High expression of CXCR4 on AML and ALL blasts has been shown to be a predictor of poor prognosis for these diseases. Several small molecule inhibitors, short peptides, antibodies, and antibody drug conjugates have been developed for the purposes of more effective targeting and killing of malignant cells expressing CXCR4. In this review we will discuss recent results and strategies in targeting CXCR4 with these agents in patients with AML or ALL

Mobilized peripheral blood: An updated perspective

Enforced egress of hematopoietic stem cells (HSCs) out of the bone marrow (BM) into the peripheral circulation, termed mobilization, has come a long way since its discovery over four decades ago. Mobilization research continues to be driven by the need to optimize the regimen currently available in the clinic with regard to pharmacokinetic and pharmacodynamic profile, costs, and donor convenience. In this review, we describe the most recent findings in the field and how we anticipate them to affect the development of mobilization strategies in the future. Furthermore, the significance of mobilization beyond HSC collection, i.e. for chemosensitization, conditioning, and gene therapy as well as a means to study the interactions between HSCs and their BM microenvironment, is reviewed. Open questions, controversies, and the potential impact of recent technical progress on mobilization research are also highlighted

Innovations in hematopoietic stem-cell mobilization: A review of the novel CXCR4 inhibitor motixafortide

Hematopoietic stem-cell transplantation (HCT) and stem-cell-based gene therapies rely on the ability to collect sufficient CD34+ hematopoietic stem and progenitor cells (HSPCs), typicall

68Ga-Galmydar: A PET imaging tracer for noninvasive detection of doxorubicin-induced cardiotoxicity

BackgroundCancer patients undergoing Doxorubicin (DOX) treatment are susceptible to acute and chronic cardiac anomalies, including aberrant arrhythmias, ventricular dysfunction, and heart failure. To stratify patients at high risk for DOX -related heart failure (CHF), diagnostic techniques have been sought. While echocardiography is used for monitoring LVEF and LV volumes due to its wide-availability and cost-efficiency, it may not identify early stages of the initiation of DOX-induced systolic heart failure. To address these limitations, PET tracers could also provide noninvasive assessment of early and reversible metabolic changes of the myocardium.ObjectiveHerein, we report a preliminary investigation of 68Ga-Galmydar potential to monitor Dox-induced cardiomyopathy in vivo, ex vivo, and in cellulo employing both nuclear- and optical imaging.Methods and resultsTo assess 68Ga-Galmydar ability for monitoring DOX-induced cardiomyopathy, microPET imaging was performed 5 d post treatment of rats either with a single dose of DOX (15 mg/kg) or vehicle as a control (saline) and images were co-registered for anatomical reference using CT. Following tail-vein injection of the radiotracer in rats at 60 min, micro-PET/CT static scan (10 min acquisition), 68Ga-Galmydar demonstrated 1.91-fold lower uptake in hearts of DOX-treated (standard uptake value; SUV: 0.92, n = 3) rats compared with their vehicle treated (SUV: 1.76, n = 3) control counterparts. For correlation of PET imaging data, post-imaging quantitative biodistribution studies were also performed, wherein excised organs were counted for γ activity, and normalized to injected dose. The post imaging pharmacokinetic data also demonstrated heart uptake values of 2.0 fold lower for DOX treated rats(%ID/g; DOX: 0.44 ± 0.1, n = 3) compared to their vehicle-treated controls (%ID/g; Control: 0.89 ± 0.03, n = 3, p = 0.04). Employing the fluorescent traits of Galmydar, live cell fluorescence imaging indicated a gradual decrease in uptake and retention of Galmydar within mitochondria of H9c2 cells following DOX-treatment, while indicating dose-dependent and time-dependent uptake profiles. Following depolarization of electronegative transmembrane gradients at the mitochondrial membrane, the uptake of the probe was decreased in H9c2 cells, and the uptake profiles were found to be identical, using both fluorescence and radiotracer bioassays. Finally, the decreased uptake of the metalloprobe in H9c2 cells also correlated with caspase-3 expression resulting from DOX-induced cardiotoxicity and cell death.Conclusions68Ga-Galmydar could provide a noninvasive assessment of DOX-related and likely reversible metabolic changes at earliest stages. Further studies with other chemotherapeutics (potentially capable of inducing cardiomyopathy) are underway

Bloch Wavefunction Reconstruction using Multidimensional Photoemission Spectroscopy

Angle-resolved spectroscopy is the most powerful technique to investigate the electronic band structure of crystalline solids. To completely characterize the electronic structure of topological materials, one needs to go beyond band structure mapping and probe the texture of the Bloch wavefunction in momentum-space, associated with Berry curvature and topological invariants. Because phase information is lost in the process of measuring photoemission intensities, retrieving the complex-valued Bloch wavefunction from photoemission data has yet remained elusive. In this Article, we introduce a novel measurement methodology and observable in extreme ultraviolet angle-resolved photoemission spectroscopy, based on continuous modulation of the ionizing radiation polarization axis. By tracking the energy- and momentum-resolved amplitude and phase of the photoemission modulation upon polarization variation, we reconstruct the Bloch wavefunction of prototypical semiconducting transition metal dichalcogenide 2H-WSe$_2$ with minimal theory input. This novel experimental scheme, which is articulated around the manipulation of the photoionization transition dipole matrix element, in combination with a simple tight-binding theory, is general and can be extended to provide insights into the Bloch wavefunction of many relevant crystalline solids.Comment: 11 pages, 5 figure

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. However, to treat acute leukemias or induce tolerance for solid organ transplantation, this approach must be expanded to allogeneic HSCT (allo-HSCT). Using murine allo-HSCT models, we show that pharmacologic Janus kinase 1/2 (JAK1/2) inhibition combined with CD45- or cKit-targeted ADCs enables robust multilineage alloengraftment. Strikingly, myeloid lineage donor chimerism exceeding 99% was achievable in fully MHC-mismatched HSCT using this approach. Mechanistic studies using the JAK1/2 inhibitor baricitinib revealed marked impairment of T and NK cell survival, proliferation, and effector function. NK cells were exquisitely sensitive to JAK1/2 inhibition due to interference with IL-15 signaling. Unlike irradiated mice, ADC-conditioned mice did not develop pathogenic graft-versus-host alloreactivity when challenged with mismatched T cells. Finally, the combination of ADCs and baricitinib balanced graft-versus-host disease and graft-versus-leukemia responses in delayed donor lymphocyte infusion models. Our allo-HSCT conditioning strategy exemplifies the promise of immunotherapy to improve the safety of HSCT for treating hematologic diseases

Motixafortide and G-CSF to mobilize hematopoietic stem cells for autologous transplantation in multiple myeloma: A randomized phase 3 trial

Autologous hematopoietic stem cell transplantation (ASCT) improves survival in multiple myeloma (MM). However, many individuals are unable to collect optimal CD3