208 research outputs found
B-Cell Therapies in Relapsing Remitting and Primary Progressive Multiple Sclerosis: A Short Clinical Review
No full textThe history of multiple sclerosis (MS) has been focused primarily on T cells. Nevertheless, T lymphocytes directed approaches miss to understand the complexity underlying the progressive disease. Novel evidences triggered both laboratory and clinical research in an attempt to pursue this possible mechanism of action and improve therapeutic options for patients with MS. For several years, there have been hints that B cells play an important role in MS pathophysiology, but only recently has interest increased in the role of B cell-directed therapies in MS. With anti-B-cell treatment, part of the immune repertoire is targeted, but not completely in the lymph nodes or tissues. This does not seem to compromise the physiologic activity of our immune system. Surprisingly, it seems possible to deplete B cells without compromising normal immune reactivity. In this short review, these novel approaches are illustrated, and the new intriguing opportunities offered by B-cell directed therapy are summarized
Immunogenic therapy: new actors in myeloma
No full textIn this issue of Blood, , Gulla et al identify GABA type A receptor-associated protein, GABARAP, as a key player in mediating resistance to immunogenic chemotherapy in multiple myeloma (MM), by halting calreticulin translocation to the external leaflet fl et of the cell membrane. By shedding light on immunogenic cell death (ICD), the authors provide a framework for potential novel combination treatments including ICD inducers to restore anti-MM immunity.(1
Mast Cells and Interleukins
No full textMast cells play a critical role in inflammatory diseases and tumor growth. The versatility of mast cells is reflected in their ability to secrete a wide range of biologically active cytokines, including interleukins, chemokines, lipid mediators, proteases, and biogenic amines. The aim of this review article is to analyze the complex involvement of mast cells in the secretion of interleukins and the role of interleukins in the regulation of biological activities of mast cells
Highlights in clinical medicine-Giant cell arteritis, polymyalgia rheumatica and Takayasu's arteritis: pathogenic links and therapeutic implications
No full textGiant cell arteritis (GCA), frequently associated with polymyalgia rheumatica (PMR), and Takayasu's arteritis (TAK) are characterized by extensive vascular remodeling that results in occlusion and stenosis. The pathophysiological mechanisms underlying the onset of GCA/PMR and TAK are still hypothetical. However, similarities and differences in the immunopathology and clinical phenotypes of these diseases point toward a possible link between them. The loss of tolerance in the periphery, a breakdown of tissue barriers, and the development of granulomatous vasculitis define a disease continuum. However, statistically powered studies are needed to confirm these correlations. In addition to glucocorticoids, inhibition of the interleukin-6 axis has been proposed as a cornerstone in the treatment of GCA/PMR and TAK. Novel biologic agents targeting the pathogenic pathway at various levels hold promise to achieve glucocorticoid-free sustained remission
Angiogenesis as Therapeutic Target in Metastatic Prostate Cancer – Narrowing the Gap Between Bench and Bedside
No full textAngiogenesis in metastatic castration-resistant prostate cancer (mCRPC) has been extensively investigated as a promising druggable biological process. Nonetheless, targeting angiogenesis has failed to impact overall survival (OS) in patients with mCRPC despite promising preclinical and early clinical data. This discrepancy prompted a literature review highlighting the tumor heterogeneity and biological context of Prostate Cancer (PCa). Narrowing the gap between the bench and bedside appears critical for developing novel therapeutic strategies. Searching clinicaltrials.gov for studies examining angiogenesis inhibition in patients with PCa resulted in n=20 trials with specific angiogenesis inhibitors currently recruiting (as of September 2021). Moreover, several other compounds with known anti-angiogenic properties – such as Metformin or Curcumin – are currently investigated. In general, angiogenesis-targeting strategies in PCa include biomarker-guided treatment stratification – as well as combinatorial approaches. Beyond established angiogenesis inhibitors, PCa therapies aiming at PSMA (Prostate Specific Membrane Antigen) hold the promise to have a substantial anti-angiogenic effect – due to PSMA ́s abundant expression in tumor vasculatur
Inborn Error of Immunity: A Journey Through Novel Genes and Clinical Presentation
No full textClinicians often face challenges due to symptoms that may result from a primary inborn error of immunity. Although the genetic root of these diseases is still largely unknown, progressively an underlying genetic determinant either due to new genes or to hypomorphic genetic errors in already described genes can be revealed. Monogenic inborn errors of immunity unreveal a broad spectrum of clinical phenotype in which autoimmune and autoinflammatory disorders, due to immune dysregulation can variably be combined with infections. Paradigmatic conditions are covered in this synopsis, which main aim is to uncover the state of the art clinical point of view within the primary immunodeficiencies pathophysiological landscape
Visualizing the Interactions Shaping the Imaging of the Microenvironment in Human Cancers
No full textThe Visium Spatial Gene Expression Solution (Visium 10) allows for the mRNA analysis using high
throughput sequencing and maps a transcriptional expression pattern in tissue sections using highresolution
microscope imaging in ex-vivo human and mice samples. The workflow surveys spatial global
gene expression in tissue sections, exploiting the whole transcriptome profiling and defining the set of
transcripts via targeted gene panels. An automated cell type annotation allows a comparison with control
tissue samples. This technique delineates cancerous or diseased tissue boundaries and details gene expression
gradients in the tissue surrounding the tumor or pathologic nests. Remarkably, the Visium 10 allows
for whole transcriptome and targeted analysis without the loss of spatial information. This approach
provides gene expression data within the context of tissue architecture, tissue microenvironments, and
cell groups. It can be used in association with therapy, anti-angiogenic therapy, and immunotherapy to
improve treatment response
Cancer-Associated Angiogenesis: The Endothelial Cell as a Checkpoint for Immunological Patrolling
No full textCancer-associated neo vessels’ formation acts as a gatekeeper that orchestrates the entrance and egress of patrolling immune cells within the tumor milieu. This is achieved, in part, via the directed chemokines’ expression and cell adhesion molecules on the endothelial cell surface that attract and retain circulating leukocytes. The crosstalk between adaptive immune cells and the cancer endothelium is thus essential for tumor immune surveillance and the success of immune-based therapies that harness immune cells to kill tumor cells. This review will focus on the biology of the endothelium and will explore the vascular-specific molecular mediators that control the recruitment, retention, and trafficking of immune cells that are essential for effective antitumor immunity. The literature revision will also explore how abnormalities in the tumor endothelium impair crosstalk with adaptive immune cells and how targeting these abnormalities can improve the success of immune-based therapies for different malignancies, with a particular focus on the paradigmatic example represented by multiple myeloma. We also generated and provide two original bio-informatic analyses, in order to sketch the physiopathology underlying the endothelial–neoplastic interactions in an easier manner, feeding into a vicious cycle propagating disease progression and highlighting novel pathways that might be exploited therapeutically
Ricerca di base nello sviluppo di isatuximab e il suo impiego per il trattamento dei pazienti con mieloma multiplo recidivato/refrattario
No full textThe CD38 molecule has become a target for antibody-mediated therapy of Multiple Myeloma (MM), providing favorable clinical results and manageable patient toxicity. There are currently two anti-CD38 antibodies available in Italy. This note is aimed at examining the characteristics of isatuximab (Isa), against the backdrop of accumulated evidence concerning the CD38 target. The results of pre-clinical studies are described and assessed in a translational perspective. Comparative analysis of these results is necessary because of the variety of functions attributed to CD38. The results obtained indicate that the molecule is an appropriate target, and that the antibody acts through the cooperation with effector leukocyte cells. The interaction with receptors for the Fc portion of the therapeutic molecule is then evaluated for increasing the half-life of Isa. CD38 is also an ectoenzyme, which metabolizes extracellular NAD+ and production of cADPR and ADPR. Isa was the only antibody inhibiting CD38 enzymatic activities. Evaluation of the antibody's mechanism of action leaves multiple unanswered questions. It is to be expected that the results from in vivo experience with Isa may shed light on some of them. Preclinical studies have shown that Isa activity is significantly enhanced when combined with immunomodulators, particularly pomalidomide (IsaPd). Indeed, the pomalidomide based combination can overcome lenalidomide (Len) resistance. Preclinical and clinical results supported the investigation of Isa as a monotherapy and in combination with IMiDs in clinical studies. Indeed, the clinical efficacy provided by the association of IsaPd hold the potential to challenge an unmet medical need represented by the Len previous exposure or refractoriness. Nowadays, if the patient is fit enough, a triplet-based approach seems more reasonable than a doublet one. Nevertheless, within the subgroup of Len exposed patients the mPFS is still unsatisfactory. Thus, given that frontline Len would represent a growing option the question regarding the relapse setting after those regimen warrants further improvements. ICARIA-MM is the first randomized phase 3 trial adding a CD38 antibody to Pd backbone. Remarkably, the patients' characteristics comprised subjects with renal insufficiency, approximately one third of the patients had three median lines of therapy, and most subjects was Len refractory. Benefit of anti-CD38 Isa addition was statistically and clinically significant, irrespectively from glomerular filtration rate, cytogenetic risk, Len refractoriness
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