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Cells
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CD38 and Disease: A Bi-Directional Cross-Talk between Pathology and Physiology
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CD38 and Disease: A Bi-Directional Cross-Talk between Pathology and Physiology

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (31 October 2019) | Viewed by 119661

Special Issue Editors

Prof. Dr. Fabio Malavasi

E-Mail Website
Guest Editor
Department of Medical Science, University of Turin and Fondazione Ricerca Molinette, 10123 Turin, Italy
Interests: antibody therapy; human myeloma; leukemia; IgG receptors; immune modulation
Special Issues, Collections and Topics in MDPI journals
Dr. Aneel Paulus

E-Mail Website
Guest Editor
1. Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA
2. Division of Hematology & Oncology, Mayo Clinic, Jacksonville, FL 32224, USA
Interests: multiple myeloma; MGUS; chronic lymphocytic leukemia; waldenstrom macroglobulinemia; immunotherapy; cancer vaccines; antibody therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The products of the CD38/CD157 gene family are attracting attention from the scientific and medical community. Over three decades of research on CD38 and CD157 and their role in human diseases has recently culminated in the development of agents that target CD38 for therapeutic exploit. The use of anti-CD38 therapeutic antibodies has emerged as an important treatment modality for the clinical management of patients with multiple myeloma. On the heels of this success, the efficacy of CD38-targeting agents is also being actively investigated for patients with other hematologic or solid tumor cancers.

Although CD38 and CD157 are expressed on the cell surface, both molecules are endowed with pleiotropic functions and, therefore, it is reasonable to expect that they may exert functions beyond that of a mere marker. An experimental approach based on analysis of the distribution of the molecules in the context of different diseases (from autoimmunity to more complex clinical entities, such as aging, metabolism, or social behaviour) may enrich our knowledge on the functions of these ancient cell-surface receptors beyond their current recognition as activation markers, adhesion molecules, and ectoenzymes.

The results may be expected to provide a comprehensive (and perhaps unified) view of the real in vivo function of these molecules, whose high conservation in phylogeny bears testament to their significant role in life.

The Special Issue of Cells “CD38 and Disease: A Bi-Directional Cross-Talk between Pathology and Physiology" welcomes contributions from basic and clinical scientists working in the field. The scientific contribution may be in the form of an original research paper or reviews. We encourage papers starting from experimental observations and ending with a perspective related to the focus. The basic idea of the issue is to dissect the roles of CD38/CD157 in the pathogenesis or progression of diseases and their potential application in therapy. Concurrently, these observations may become a contribution to the improvement of the therapeutic model in use today.

Relevant topics include:

  • CD38/CD157 and NAD+ Metabolism
  • CD38/CD157 and Aging
  • CD38/CD157 and Multiple Myeloma
  • CD38/CD157 and Leukemias
  • CD38/CD157 and Mesotheliomas
  • CD38/CD157 and Systemic Sclerosis
  • CD38/CD157 and T-cell Lymphomas
  • CD38/CD157 and Behaviors
  • CD38/CD157 and Immune Response
  • CD38/CD157 and Check-Point Inhibitors
  • CD38/CD157 and Solid Tumors
  • CD38/CD157 and Cells with Suppressive Functions
  • CD38/CD157 and Alternative Therapeutic Approaches
  • CD38/CD157 and Central Nervous System Function

Prof. Fabio Malavasi
Dr. Aneel Paulus
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Ectoenzymes and NAD and ATP metabolisms
  • Immune activation and immune suppression
  • Multiple Myeloma therapy
  • CLL therapy
  • Cancer therapy
  • Aging
  • Behavior
  • Central nervous system

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Related Special Issue

Published Papers (15 papers)

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Research

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14 pages, 3884 KiB  
Article
Targeting CD38-Expressing Multiple Myeloma and Burkitt Lymphoma Cells In Vitro with Nanobody-Based Chimeric Antigen Receptors (Nb-CARs)
by Julia Hambach, Kristoffer Riecken, Sophia Cichutek, Kerstin Schütze, Birte Albrecht, Katharina Petry, Jana Larissa Röckendorf, Natalie Baum, Nicolaus Kröger, Timon Hansen, Gunter Schuch, Friedrich Haag, Gerhard Adam, Boris Fehse, Peter Bannas and Friedrich Koch-Nolte
Cells 2020, 9(2), 321; https://doi.org/10.3390/cells9020321 - 29 Jan 2020
Cited by 48 | Viewed by 6166
Abstract
The NAD-hydrolyzing ecto-enzyme CD38 is overexpressed by multiple myeloma and other hematological malignancies. We recently generated CD38-specific nanobodies, single immunoglobulin variable domains derived from heavy-chain antibodies naturally occurring in llamas. Nanobodies exhibit high solubility and stability, allowing easy reformatting into recombinant fusion proteins. [...] Read more.
The NAD-hydrolyzing ecto-enzyme CD38 is overexpressed by multiple myeloma and other hematological malignancies. We recently generated CD38-specific nanobodies, single immunoglobulin variable domains derived from heavy-chain antibodies naturally occurring in llamas. Nanobodies exhibit high solubility and stability, allowing easy reformatting into recombinant fusion proteins. Here we explore the utility of CD38-specific nanobodies as ligands for nanobody-based chimeric antigen receptors (Nb-CARs). We cloned retroviral expression vectors for CD38-specific Nb-CARs. The human natural killer cell line NK-92 was transduced to stably express these Nb-CARs. As target cells we used CD38-expressing as well as CRISPR/Cas9-generated CD38-deficient tumor cell lines (CA-46, LP-1, and Daudi) transduced with firefly luciferase. With these effector and target cells we established luminescence and flow-cytometry CAR-dependent cellular cytotoxicity assays (CARDCCs). Finally, the cytotoxic efficacy of Nb-CAR NK-92 cells was tested on primary patient-derived CD38-expressing multiple myeloma cells. NK-92 cells expressing CD38-specific Nb-CARs specifically lysed CD38-expressing but not CD38-deficient tumor cell lines. Moreover, the Nb-CAR-NK cells effectively depleted CD38-expressing multiple myeloma cells in primary human bone marrow samples. Our results demonstrate efficacy of Nb-CARs in vitro. The potential clinical efficacy of Nb-CARs in vivo remains to be evaluated. Full article
(This article belongs to the Special Issue CD38 and Disease: A Bi-Directional Cross-Talk between Pathology and Physiology)
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Review

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16 pages, 1230 KiB  
Review
The Many Facets of CD38 in Lymphoma: From Tumor–Microenvironment Cell Interactions to Acquired Resistance to Immunotherapy
by Eleonora Calabretta and Carmelo Carlo-Stella
Cells 2020, 9(4), 802; https://doi.org/10.3390/cells9040802 - 26 Mar 2020
Cited by 27 | Viewed by 8669
Abstract
The CD38 antigen is expressed in several hematological malignancies, and the anti-CD38 monoclonal antibodies Daratumumab and Isatuximab have an established role in the therapy of multiple myeloma. However, data on the therapeutic utility of CD38 targeting in other lymphoid malignancies are limited. In [...] Read more.
The CD38 antigen is expressed in several hematological malignancies, and the anti-CD38 monoclonal antibodies Daratumumab and Isatuximab have an established role in the therapy of multiple myeloma. However, data on the therapeutic utility of CD38 targeting in other lymphoid malignancies are limited. In chronic lymphocytic leukemia, the prognostic significance of CD38 expression is well accepted, and preclinical studies on the use of Daratumumab in monotherapy or combination therapy have demonstrated considerable efficacy. In other lymphoproliferative disorders, preclinical and clinical data have not been as compelling; however, CD38 overexpression likely contributes to resistance to checkpoint inhibitors, prompting numerous clinical trials in Hodgkin and non-Hodgkin lymphoma to investigate whether blocking CD38 enhances the efficacy of checkpoint inhibitors. Furthermore, due to its widespread expression in hematological tumors, CD38 represents an attractive target for cellular therapies such as CAR-T cells. The present review discusses current knowledge of CD38 expression and its implications in various lymphoid malignancies. Furthermore, it addresses current and future therapeutic perspectives, with a particular emphasis on the significance of CD38 interaction with immune cells of the tumor microenvironment. Lastly, results of ongoing studies using anti-CD38 antibodies will be reviewed. Full article
(This article belongs to the Special Issue CD38 and Disease: A Bi-Directional Cross-Talk between Pathology and Physiology)
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12 pages, 3894 KiB  
Review
NK cells and CD38: Implication for (Immuno)Therapy in Plasma Cell Dyscrasias
by Renato Zambello, Gregorio Barilà, Sabrina Manni, Francesco Piazza and Gianpietro Semenzato
Cells 2020, 9(3), 768; https://doi.org/10.3390/cells9030768 - 21 Mar 2020
Cited by 30 | Viewed by 7919
Abstract
Immunotherapy represents a promising new avenue for the treatment of multiple myeloma (MM) patients, particularly with the availability of Monoclonal Antibodies (mAbs) as anti-CD38 Daratumumab and Isatuximab and anti-SLAM-F7 Elotuzumab. Although a clear NK activation has been demonstrated for Elotuzumab, the effect of [...] Read more.
Immunotherapy represents a promising new avenue for the treatment of multiple myeloma (MM) patients, particularly with the availability of Monoclonal Antibodies (mAbs) as anti-CD38 Daratumumab and Isatuximab and anti-SLAM-F7 Elotuzumab. Although a clear NK activation has been demonstrated for Elotuzumab, the effect of anti-CD38 mAbs on NK system is controversial. As a matter of fact, an initial reduction of NK cells number characterizes Daratumumab therapy, limiting the potential role of this subset on myeloma immunotherapy. In this paper we discuss the role of NK cells along with anti-CD38 therapy and their implication in plasma cell dyscrasias, showing that mechanisms triggered by anti-CD38 mAbs ultimately lead to the activation of the immune system against myeloma cell growth. Full article
(This article belongs to the Special Issue CD38 and Disease: A Bi-Directional Cross-Talk between Pathology and Physiology)
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15 pages, 2077 KiB  
Review
Roles of CD38 in the Immune Response to Infection
by Estibaliz Glaría and Annabel F. Valledor
Cells 2020, 9(1), 228; https://doi.org/10.3390/cells9010228 - 16 Jan 2020
Cited by 93 | Viewed by 13604
Abstract
CD38 is a multifunctional protein widely expressed in cells from the immune system and as a soluble form in biological fluids. CD38 expression is up-regulated by an array of inflammatory mediators, and it is frequently used as a cell activation marker. Studies in [...] Read more.
CD38 is a multifunctional protein widely expressed in cells from the immune system and as a soluble form in biological fluids. CD38 expression is up-regulated by an array of inflammatory mediators, and it is frequently used as a cell activation marker. Studies in animal models indicate that CD38 functional expression confers protection against infection by several bacterial and parasitic pathogens. In addition, infectious complications are associated with anti-CD38 immunotherapy. Although CD38 displays receptor and enzymatic activities that contribute to the establishment of an effective immune response, recent work raises the possibility that CD38 might also enhance the immunosuppressive potential of regulatory leukocytes. This review integrates the current knowledge on the diversity of functions mediated by CD38 in the host defense to infection. Full article
(This article belongs to the Special Issue CD38 and Disease: A Bi-Directional Cross-Talk between Pathology and Physiology)
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14 pages, 755 KiB  
Review
Mechanisms of Resistance to Anti-CD38 Daratumumab in Multiple Myeloma
by Ilaria Saltarella, Vanessa Desantis, Assunta Melaccio, Antonio Giovanni Solimando, Aurelia Lamanuzzi, Roberto Ria, Clelia Tiziana Storlazzi, Maria Addolorata Mariggiò, Angelo Vacca and Maria Antonia Frassanito
Cells 2020, 9(1), 167; https://doi.org/10.3390/cells9010167 - 9 Jan 2020
Cited by 77 | Viewed by 13508
Abstract
Daratumumab (Dara) is the first-in-class human-specific anti-CD38 mAb approved for the treatment of multiple myeloma (MM). Although recent data have demonstrated very promising results in clinical practice and trials, some patients do not achieve a partial response, and ultimately all patients undergo progression. [...] Read more.
Daratumumab (Dara) is the first-in-class human-specific anti-CD38 mAb approved for the treatment of multiple myeloma (MM). Although recent data have demonstrated very promising results in clinical practice and trials, some patients do not achieve a partial response, and ultimately all patients undergo progression. Dara exerts anti-MM activity via antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), and immunomodulatory effects. Deregulation of these pleiotropic mechanisms may cause development of Dara resistance. Knowledge of this resistance may improve the therapeutic management of MM patients. Full article
(This article belongs to the Special Issue CD38 and Disease: A Bi-Directional Cross-Talk between Pathology and Physiology)
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16 pages, 2300 KiB  
Review
CD38, CD157, and RAGE as Molecular Determinants for Social Behavior
by Haruhiro Higashida, Minako Hashii, Yukie Tanaka, Shigeru Matsukawa, Yoshihiro Higuchi, Ryosuke Gabata, Makoto Tsubomoto, Noriko Seishima, Mitsuyo Teramachi, Taiki Kamijima, Tsuyoshi Hattori, Osamu Hori, Chiharu Tsuji, Stanislav M. Cherepanov, Anna A. Shabalova, Maria Gerasimenko, Kana Minami, Shigeru Yokoyama, Sei-ichi Munesue, Ai Harashima, Yasuhiko Yamamoto, Alla B. Salmina and Olga Lopatinaadd Show full author list remove Hide full author list
Cells 2020, 9(1), 62; https://doi.org/10.3390/cells9010062 - 25 Dec 2019
Cited by 43 | Viewed by 7573
Abstract
Recent studies provide evidence to support that cluster of differentiation 38 (CD38) and CD157 meaningfully act in the brain as neuroregulators. They primarily affect social behaviors. Social behaviors are impaired in Cd38 and Cd157 knockout mice. Single-nucleotide polymorphisms of the CD38 and CD157/BST1 [...] Read more.
Recent studies provide evidence to support that cluster of differentiation 38 (CD38) and CD157 meaningfully act in the brain as neuroregulators. They primarily affect social behaviors. Social behaviors are impaired in Cd38 and Cd157 knockout mice. Single-nucleotide polymorphisms of the CD38 and CD157/BST1 genes are associated with multiple neurological and psychiatric conditions, including autism spectrum disorder, Parkinson’s disease, and schizophrenia. In addition, both antigens are related to infectious and immunoregulational processes. The most important clues to demonstrate how these molecules play a role in the brain are oxytocin (OT) and the OT system. OT is axo-dendritically secreted into the brain from OT-containing neurons and causes activation of OT receptors mainly on hypothalamic neurons. Here, we overview the CD38/CD157-dependent OT release mechanism as the initiation step for social behavior. The receptor for advanced glycation end-products (RAGE) is a newly identified molecule as an OT binding protein and serves as a transporter of OT to the brain, crossing over the blood–brain barrier, resulting in the regulation of brain OT levels. We point out new roles of CD38 and CD157 during neuronal development and aging in relation to nicotinamide adenine dinucleotide+ levels in embryonic and adult nervous systems. Finally, we discuss how CD38, CD157, and RAGE are crucial for social recognition and behavior in daily life. Full article
(This article belongs to the Special Issue CD38 and Disease: A Bi-Directional Cross-Talk between Pathology and Physiology)
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20 pages, 1050 KiB  
Review
The Good, the Bad and the Unknown of CD38 in the Metabolic Microenvironment and Immune Cell Functionality of Solid Tumors
by Jessica M. Konen, Jared J. Fradette and Don L. Gibbons
Cells 2020, 9(1), 52; https://doi.org/10.3390/cells9010052 - 24 Dec 2019
Cited by 54 | Viewed by 7782
Abstract
The regulation of the immune microenvironment within solid tumors has received increasing attention with the development and clinical success of immune checkpoint blockade therapies, such as those that target the PD-1/PD-L1 axis. The metabolic microenvironment within solid tumors has proven to be an [...] Read more.
The regulation of the immune microenvironment within solid tumors has received increasing attention with the development and clinical success of immune checkpoint blockade therapies, such as those that target the PD-1/PD-L1 axis. The metabolic microenvironment within solid tumors has proven to be an important regulator of both the natural suppression of immune cell functionality and the de novo or acquired resistance to immunotherapy. Enzymatic proteins that generate immunosuppressive metabolites like adenosine are thus attractive targets to couple with immunotherapies to improve clinical efficacy. CD38 is one such enzyme. While the role of CD38 in hematological malignancies has been extensively studied, the impact of CD38 expression within solid tumors is largely unknown, though most current data indicate an immunosuppressive role for CD38. However, CD38 is far from a simple enzyme, and there are several remaining questions that require further study. To effectively treat solid tumors, we must learn as much about this multifaceted protein as possible—i.e., which infiltrating immune cell types express CD38 for functional activities, the most effective CD38 inhibitor(s) to employ, and the influence of other similarly functioning enzymes that may also contribute towards an immunosuppressive microenvironment. Gathering knowledge such as this will allow for intelligent targeting of CD38, the reinvigoration of immune functionality and, ultimately, tumor elimination. Full article
(This article belongs to the Special Issue CD38 and Disease: A Bi-Directional Cross-Talk between Pathology and Physiology)
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18 pages, 4950 KiB  
Review
The Roles of CD38 and CD157 in the Solid Tumor Microenvironment and Cancer Immunotherapy
by Yu Jun Wo, Adelia Shin Ping Gan, Xinru Lim, Isabel Shu Ying Tay, Sherlly Lim, Jeffrey Chun Tatt Lim and Joe Poh Sheng Yeong
Cells 2020, 9(1), 26; https://doi.org/10.3390/cells9010026 - 20 Dec 2019
Cited by 31 | Viewed by 6081
Abstract
The tumor microenvironment (TME) consists of extracellular matrix proteins, immune cells, vascular cells, lymphatics and fibroblasts. Under normal physiological conditions, tissue homeostasis protects against tumor development. However, under pathological conditions, interplay between the tumor and its microenvironment can promote tumor initiation, growth and [...] Read more.
The tumor microenvironment (TME) consists of extracellular matrix proteins, immune cells, vascular cells, lymphatics and fibroblasts. Under normal physiological conditions, tissue homeostasis protects against tumor development. However, under pathological conditions, interplay between the tumor and its microenvironment can promote tumor initiation, growth and metastasis. Immune cells within the TME have an important role in the formation, growth and metastasis of tumors, and in the responsiveness of these tumors to immunotherapy. Recent breakthroughs in the field of cancer immunotherapy have further highlighted the potential of targeting TME elements, including these immune cells, to improve the efficacy of cancer prognostics and immunotherapy. CD38 and CD157 are glycoproteins that contribute to the tumorigenic properties of the TME. For example, in the hypoxic TME, the enzymatic functions of CD38 result in an immunosuppressive environment. This leads to increased immune resistance in tumor cells and allows faster growth and proliferation rates. CD157 may also aid the production of an immunosuppressive TME, and confers increased malignancy to tumor cells through the promotion of tumor invasion and metastasis. An improved understanding of CD38 and CD157 in the TME, and how these glycoproteins affect cancer progression, will be useful to develop both cancer prognosis and treatment methods. This review aims to discuss the roles of CD38 and CD157 in the TME and cancer immunotherapy of a range of solid tumor types. Full article
(This article belongs to the Special Issue CD38 and Disease: A Bi-Directional Cross-Talk between Pathology and Physiology)
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12 pages, 902 KiB  
Review
CD38 Expression by Myeloma Cells and Its Role in the Context of Bone Marrow Microenvironment: Modulation by Therapeutic Agents
by Federica Costa, Benedetta Dalla Palma and Nicola Giuliani
Cells 2019, 8(12), 1632; https://doi.org/10.3390/cells8121632 - 13 Dec 2019
Cited by 32 | Viewed by 7462
Abstract
In the last decades CD38 has emerged as an attractive target for multiple myeloma (MM). CD38 is a novel multifunctional glycoprotein that acts as a receptor, adhesion molecule interacting with CD31 and as an ectoenzyme. As an ectoenzyme, CD38 functions as a metabolic [...] Read more.
In the last decades CD38 has emerged as an attractive target for multiple myeloma (MM). CD38 is a novel multifunctional glycoprotein that acts as a receptor, adhesion molecule interacting with CD31 and as an ectoenzyme. As an ectoenzyme, CD38 functions as a metabolic sensor catalyzing the extracellular conversion of NAD+ to the immunosuppressive factor adenosine (ADO). Other ectoenzymes, CD73 and CD203a, together with CD38, are also involved in the alternative axis of extracellular production of ADO, bypassing the canonical pathway mediated by CD39. CD38 is ubiquitously expressed in the bone marrow microenvironment; however, only MM cells display a very high surface density, which lead to the development of several anti-CD38 monoclonal antibodies (mAbs). The efficacy of anti-CD38 mAbs depends from the presence of CD38 on the surface of MM and immune-microenvironment cells. Interestingly, it has been reported that several drugs like lenalidomide, panobinostat, the all-trans retinoic acid and the DNA methyltransferase inhibitors may increase the expression of CD38. Hence, the possibility to modulate CD38 by increasing its expression on MM cells is the pre-requisite to potentiate the clinical efficacy of the anti-CD38 mAbs and to design clinical trials with the combination of anti-CD38 mAbs and these drugs. Full article
(This article belongs to the Special Issue CD38 and Disease: A Bi-Directional Cross-Talk between Pathology and Physiology)
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9 pages, 212 KiB  
Review
The Anti-CD38 Antibody Therapy in Multiple Myeloma
by Maria Teresa Petrucci and Federico Vozella
Cells 2019, 8(12), 1629; https://doi.org/10.3390/cells8121629 - 12 Dec 2019
Cited by 30 | Viewed by 5455
Abstract
Multiple myeloma (MM) is the second-most common hematologic malignancy after diffuse large B-cell lymphoma. Despite the improvement in response and survival rates following the introduction of novel therapies, only a few patients are cured, and the majority of MM patients experience several relapses [...] Read more.
Multiple myeloma (MM) is the second-most common hematologic malignancy after diffuse large B-cell lymphoma. Despite the improvement in response and survival rates following the introduction of novel therapies, only a few patients are cured, and the majority of MM patients experience several relapses and receive multiple lines of treatment. Currently, bortezomib and lenalidomide are the core component of treatment both at the time of diagnosis and at the relapse as well as the new proteasome inhibitors (PIs), such as carfilzomib and ixazomib, and the next-generation immunomodulatory drug, pomalidomide, are now available for patients in relapse. In addition, drugs with a different mechanism of action, such as the histone deacetylase inhibitor and the monoclonal antibodies (MoAb) targeting SLAMF7 or CD38, are a part of the anti-myeloma armamentarium and are very important for heavily pretreated or double refractory to a PI and IMiD patients. In this paper, we focus on the efficacy as well as toxicities of CD38 antibodies used both as a single agent and in combination as multiple myeloma treatment. Full article
(This article belongs to the Special Issue CD38 and Disease: A Bi-Directional Cross-Talk between Pathology and Physiology)
16 pages, 6650 KiB  
Review
CD157: From Myeloid Cell Differentiation Marker to Therapeutic Target in Acute Myeloid Leukemia
by Yuliya Yakymiv, Stefania Augeri, Giulia Fissolo, Silvia Peola, Cristiano Bracci, Monica Binaschi, Daniela Bellarosa, Andrea Pellacani, Enza Ferrero, Erika Ortolan and Ada Funaro
Cells 2019, 8(12), 1580; https://doi.org/10.3390/cells8121580 - 5 Dec 2019
Cited by 12 | Viewed by 5083
Abstract
Human CD157/BST-1 and CD38 are dual receptor-enzymes derived by gene duplication that belong to the ADP ribosyl cyclase gene family. First identified over 30 years ago as Mo5 myeloid differentiation antigen and 10 years later as Bone Marrow Stromal Cell Antigen 1 (BST-1), [...] Read more.
Human CD157/BST-1 and CD38 are dual receptor-enzymes derived by gene duplication that belong to the ADP ribosyl cyclase gene family. First identified over 30 years ago as Mo5 myeloid differentiation antigen and 10 years later as Bone Marrow Stromal Cell Antigen 1 (BST-1), CD157 proved not to be restricted to the myeloid compartment and to have a diversified functional repertoire ranging from immunity to cancer and metabolism. Despite being a NAD+-metabolizing ectoenzyme anchored to the cell surface through a glycosylphosphatidylinositol moiety, the functional significance of human CD157 as an enzyme remains unclear, while its receptor role emerged from its discovery and has been clearly delineated with the identification of its high affinity binding to fibronectin. The aim of this review is to provide an overview of the immunoregulatory functions of human CD157/BST-1 in physiological and pathological conditions. We then focus on CD157 expression in hematological tumors highlighting its emerging role in the interaction between acute myeloid leukemia and extracellular matrix proteins and its potential utility for monoclonal antibody targeted therapy in this disease. Full article
(This article belongs to the Special Issue CD38 and Disease: A Bi-Directional Cross-Talk between Pathology and Physiology)
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17 pages, 1000 KiB  
Review
CD38, a Receptor with Multifunctional Activities: From Modulatory Functions on Regulatory Cell Subsets and Extracellular Vesicles, to a Target for Therapeutic Strategies
by Fabio Morandi, Irma Airoldi, Danilo Marimpietri, Cristiano Bracci, Angelo Corso Faini and Roberto Gramignoli
Cells 2019, 8(12), 1527; https://doi.org/10.3390/cells8121527 - 27 Nov 2019
Cited by 55 | Viewed by 7511
Abstract
CD38 is a multifunctional cell surface protein endowed with receptor/enzymatic functions. The protein is generally expressed at low/intermediate levels on hematological tissues and some solid tumors, scoring the highest levels on plasma cells (PC) and PC-derived neoplasia. CD38 was originally described as a [...] Read more.
CD38 is a multifunctional cell surface protein endowed with receptor/enzymatic functions. The protein is generally expressed at low/intermediate levels on hematological tissues and some solid tumors, scoring the highest levels on plasma cells (PC) and PC-derived neoplasia. CD38 was originally described as a receptor expressed by activated cells, mainly T lymphocytes, wherein it also regulates cell adhesion and cooperates in signal transduction mediated by major receptor complexes. Furthermore, CD38 metabolizes extracellular NAD+, generating ADPR and cyclic ADPR. This ecto-enzyme controls extra-cellular nucleotide homeostasis and intra-cellular calcium fluxes, stressing its relevance in multiple physiopathological conditions (infection, tumorigenesis and aging). In clinics, CD38 was adopted as a cell activation marker and in the diagnostic/staging of leukemias. Quantitative surface CD38 expression by multiple myeloma (MM) cells was the basic criterion used for therapeutic application of anti-CD38 monoclonal antibodies (mAbs). Anti-CD38 mAbs-mediated PC depletion in autoimmunity and organ transplants is currently under investigation. This review analyzes different aspects of CD38’s role in regulatory cell populations and how these effects are obtained. Characterizing CD38 functional properties may widen the extension of therapeutic applications for anti-CD38 mAbs. The availability of therapeutic mAbs with different effects on CD38 enzymatic functions may be rapidly translated to immunotherapeutic strategies of cell immune defense. Full article
(This article belongs to the Special Issue CD38 and Disease: A Bi-Directional Cross-Talk between Pathology and Physiology)
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26 pages, 1693 KiB  
Review
Therapeutic Opportunities with Pharmacological Inhibition of CD38 with Isatuximab
by Thomas G. Martin, Kathryn Corzo, Marielle Chiron, Helgi van de Velde, Giovanni Abbadessa, Frank Campana, Malini Solanki, Robin Meng, Helen Lee, Dmitri Wiederschain, Chen Zhu, Alexey Rak and Kenneth C. Anderson
Cells 2019, 8(12), 1522; https://doi.org/10.3390/cells8121522 - 26 Nov 2019
Cited by 111 | Viewed by 12762
Abstract
CD38 is a transmembrane glycoprotein with ectoenzymatic activity involved in regulation of migration, signal transduction, and receptor-mediated adhesion. CD38 is highly expressed on various malignant cells, including multiple myeloma (MM), and at relatively low levels in other tissues, making it a suitable target [...] Read more.
CD38 is a transmembrane glycoprotein with ectoenzymatic activity involved in regulation of migration, signal transduction, and receptor-mediated adhesion. CD38 is highly expressed on various malignant cells, including multiple myeloma (MM), and at relatively low levels in other tissues, making it a suitable target for therapeutic antibodies. Several anti-CD38 therapies have been, or are being, developed for the treatment of MM, including daratumumab and isatuximab (SAR650984), respectively. Studies have shown that anti-CD38 therapies are effective in the treatment of relapsed/refractory MM and are well tolerated, with infusion reactions being the most common side effects. They can be used as monotherapy or in combination with immunomodulatory agents, such as pomalidomide, or proteasome inhibitors to potentiate their activity. Here we examine isatuximab and several anti-CD38 agents in development that were generated using new antibody engineering techniques and that may lead to more effective CD38 targeting. We also summarize trials assessing these antibodies in MM, other malignancies, and solid organ transplantation. Finally, we propose that further research on the mechanisms of resistance to anti-CD38 therapy and the development of biomarkers and new backbone regimens with CD38 antibodies will be important steps in building more personalized treatment for patients with MM. Full article
(This article belongs to the Special Issue CD38 and Disease: A Bi-Directional Cross-Talk between Pathology and Physiology)
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Other

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5 pages, 212 KiB  
Viewpoint
Controversy in the Use of CD38 Antibody for Treatment of Myeloma: Is High CD38 Expression Good or Bad?
by Torben Plesner, Niels W. C. J. van de Donk and Paul G. Richardson
Cells 2020, 9(2), 378; https://doi.org/10.3390/cells9020378 - 6 Feb 2020
Cited by 15 | Viewed by 4196
Abstract
During a time span of just a few years, the CD38 antibody, daratumumab, has been established as one of the most important new drugs for the treatment of multiple myeloma, both in the relapsed/refractory setting and, more recently, as a first-line treatment. Although [...] Read more.
During a time span of just a few years, the CD38 antibody, daratumumab, has been established as one of the most important new drugs for the treatment of multiple myeloma, both in the relapsed/refractory setting and, more recently, as a first-line treatment. Although much is known about the pleiotropic modes of action of daratumumab, we are still not sure how to use it in an optimal manner. Daratumumab targets CD38 on myeloma cells and a high level of CD38 expression facilitates complement-mediated cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Since the expression of CD38 by myeloma cells is downregulated during treatment with daratumumab, it may seem reasonable to introduce a wash-out period and retreat with daratumumab at a later time point when CD38 expression has recovered in order to gain the maximum benefit of daratumumab’s capacity to kill myeloma cells by CDC, ADCC and ADCP. In other aspects, CD38 seems to serve as a survival factor for myeloma cells by facilitating protective myeloma cell–stromal-cell interactions, contributing to the formation of nanotubes that transfer mitochondria from the stromal cells to myeloma cells, boosting myeloma cell proliferation and survival and by generation of immunosuppressive adenosine in the bone marrow microenvironment. In addition, continuous exposure to daratumumab may keep immune suppressor cells at a low level, which boosts the anti-tumor activity of T-cells. In fact, one may speculate if in the early phase of treatment of a myeloma patient, the debulking effects of daratumumab achieved by CDC, ADCC and ADCP are more important while at a later stage, reprogramming of the patient’s own immune system and certain metabolic effects may take over and become more essential. This duality may be reflected by what we often observe when we watch the slope of the M-protein from myeloma patients responding to daratumumab: A rapid initial drop followed by a slow decline of the M-protein during several months or even years. Ongoing and future clinical trials will teach us how to use daratumumab in an optimal way. Full article
(This article belongs to the Special Issue CD38 and Disease: A Bi-Directional Cross-Talk between Pathology and Physiology)
9 pages, 274 KiB  
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Is There a Future for Anti-CD38 Antibody Therapy in Systemic Autoimmune Diseases?
by Devis Benfaremo and Armando Gabrielli
Cells 2020, 9(1), 77; https://doi.org/10.3390/cells9010077 - 27 Dec 2019
Cited by 17 | Viewed by 4674
Abstract
CD38 is a type II glycoprotein highly expressed on plasmablasts, short-lived and long-lived plasma cells, but weakly expressed on other lymphoid cells, myeloid cells and non-hematopoietic cells. This expression pattern makes CD38 an interesting target for a targeted therapy aiming to deplete antibody-producing [...] Read more.
CD38 is a type II glycoprotein highly expressed on plasmablasts, short-lived and long-lived plasma cells, but weakly expressed on other lymphoid cells, myeloid cells and non-hematopoietic cells. This expression pattern makes CD38 an interesting target for a targeted therapy aiming to deplete antibody-producing plasma cells. We present data suggesting that anti-CD38 therapy may be effective for the prevention at the preclinical stage and for the treatment of established autoimmune diseases, such as systemic lupus erythematosus, systemic sclerosis, Sjögren’s syndrome and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Given the high unmet need for efficacious disease-modifying treatment in these diseases, studies are warranted to determine if anti-CD38 antibody-based therapies may delay or prevent the disease progression of systemic autoimmune diseases. Full article
(This article belongs to the Special Issue CD38 and Disease: A Bi-Directional Cross-Talk between Pathology and Physiology)
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