scholarly journals Harnessing the Immune System to Fight Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4546
Author(s):  
Jakub Krejcik ◽  
Mike Bogetofte Barnkob ◽  
Charlotte Guldborg Nyvold ◽  
Thomas Stauffer Larsen ◽  
Torben Barington ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Immune System ◽  
Clinical Care ◽  
Immune Surveillance ◽  
Treatment Strategies ◽  
Genetic Alterations ◽  
Response To Treatment ◽  
Immunosuppressive Tumor Microenvironment ◽  
And Function ◽  
New Strategies

Multiple myeloma (MM) is a heterogeneous plasma cell malignancy differing substantially in clinical behavior, prognosis, and response to treatment. With the advent of novel therapies, many patients achieve long-lasting remissions, but some experience aggressive and treatment refractory relapses. So far, MM is considered incurable. Myeloma pathogenesis can broadly be explained by two interacting mechanisms, intraclonal evolution of cancer cells and development of an immunosuppressive tumor microenvironment. Failures in isotype class switching and somatic hypermutations result in the neoplastic transformation typical of MM and other B cell malignancies. Interestingly, although genetic alterations occur and evolve over time, they are also present in premalignant stages, which never progress to MM, suggesting that genetic mutations are necessary but not sufficient for myeloma transformation. Changes in composition and function of the immune cells are associated with loss of effective immune surveillance, which might represent another mechanism driving malignant transformation. During the last decade, the traditional view on myeloma treatment has changed dramatically. It is increasingly evident that treatment strategies solely based on targeting intrinsic properties of myeloma cells are insufficient. Lately, approaches that redirect the cells of the otherwise suppressed immune system to take control over myeloma have emerged. Evidence of utility of this principle was initially established by the observation of the graft-versus-myeloma effect in allogeneic stem cell-transplanted patients. A variety of new strategies to harness both innate and antigen-specific immunity against MM have recently been developed and intensively tested in clinical trials. This review aims to give readers a basic understanding of how the immune system can be engaged to treat MM, to summarize the main immunotherapeutic modalities, their current role in clinical care, and future prospects.

scholarly journals Immunometabolism at the Nexus of Cancer Therapeutic Efficacy and Resistance

2021 ◽  
Vol 12 ◽  
Author(s):  
Javier Traba ◽  
Michael N. Sack ◽  
Thomas A. Waldmann ◽  
Olga M. Anton
Keyword(s):  
Immune System ◽  
Immune Cells ◽  
Immune Cell ◽  
Cell Metabolism ◽  
Immune Surveillance ◽  
Antitumor Effects ◽  
Cancer Management ◽  
Immunosuppressive Tumor Microenvironment ◽  
And Function ◽  
Main Effects

Constitutive activity of the immune surveillance system detects and kills cancerous cells, although many cancers have developed strategies to avoid detection and to resist their destruction. Cancer immunotherapy entails the manipulation of components of the endogenous immune system as targeted approaches to control and destroy cancer cells. Since one of the major limitations for the antitumor activity of immune cells is the immunosuppressive tumor microenvironment (TME), boosting the immune system to overcome the inhibition provided by the TME is a critical component of oncotherapeutics. In this article, we discuss the main effects of the TME on the metabolism and function of immune cells, and review emerging strategies to potentiate immune cell metabolism to promote antitumor effects either as monotherapeutics or in combination with conventional chemotherapy to optimize cancer management.

scholarly journals Immunotherapy for Multiple Myeloma

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 2009 ◽  
Author(s):  
Hideto Tamura ◽  
Mariko Ishibashi ◽  
Mika Sunakawa ◽  
Koiti Inokuchi
Keyword(s):  
Multiple Myeloma ◽  
T Cell ◽  
Checkpoint Inhibitors ◽  
Immune Surveillance ◽  
Treatment Strategies ◽  
Survival Times ◽  
Tumor Vaccines ◽  
Antibody Drug Conjugate ◽  
T Cell Therapy ◽  
Anergic T Cells

Despite therapeutic advances over the past decades, multiple myeloma (MM) remains a largely incurable disease with poor prognosis in high-risk patients, and thus new treatment strategies are needed to achieve treatment breakthroughs. MM represents various forms of impaired immune surveillance characterized by not only disrupted antibody production but also immune dysfunction of T, natural killer cells, and dendritic cells, although immunotherapeutic interventions such as allogeneic stem-cell transplantation and dendritic cell-based tumor vaccines were reported to prolong survival in limited populations of MM patients. Recently, epoch-making immunotherapies, i.e., immunomodulatory drug-intensified monoclonal antibodies, such as daratumumab combined with lenalidomide and chimeric antigen receptor T-cell therapy targeting B-cell maturation antigen, have been developed, and was shown to improve prognosis even in advanced-stage MM patients. Clinical trials using other antibody-based treatments, such as antibody drug-conjugate and bispecific antigen-directed CD3 T-cell engager targeting, are ongoing. The manipulation of anergic T-cells by checkpoint inhibitors, including an anti-T-cell immunoglobulin and ITIM domains (TIGIT) antibody, also has the potential to prolong survival times. Those new treatments or their combination will improve prognosis and possibly point toward a cure for MM.

Comprehensive genomic sequencing of urothelial tumors to identify rare driver genomic alterations in SMARCB1 in a subset of patients.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 385-385
Author(s):  
Sumati Gupta ◽  
Daniel Joseph Albertson ◽  
David Gaston ◽  
Marta Elise Heilbrun ◽  
Neeraj Agarwal ◽  
...  
Keyword(s):  
Clinical Care ◽  
Epithelioid Sarcoma ◽  
Treatment Strategies ◽  
Genetic Alterations ◽  
Allelic Loss ◽  
Loss Of Function ◽  
Conventional Chemotherapy ◽  
Genomic Alterations ◽  
Nucleosome Remodeling ◽  
Urothelial Tumors

385 Background: Multiple genomic alterations leading to overlapping dysregulation of cell cycle, kinase and phosphotidyl \inositol-3-OHkinase signaling and chromatin remodeling are the hallmark of urothelial carcinoma (UC). ARID1A and SMARCA2 loss are frequently altered leading to SWI/SNF nucleosome-remodeling complex dysregulation in urothelial cancers. Mutations affecting components of the SWI/SNF complex lead to aggressive de-differentiated neoplasms. SMARCB1 loss has been implicated in malignant rhabdoid tumors, epithelioid sarcoma and renal medullary carcinoma. Upper tract UC patients with SMARCB1 loss may represent a novel, rare subset. Methods: Tissue from UC patients (n=1099) was assayed by hybrid-capture based comprehensive genomic profiling (CGP) in the course of clinical care to evaluate genomic alterations (GA: base substitutions, indels, amplifications, copy number alterations, fusions/rearrangements) and targeted therapy opportunities; 315 genes frequently altered in cancer were assayed. One patient had an advanced poorly differentiated neoplasm and received conventional chemotherapy. Results: CGP identified 10 (1%) patients with SMARCB1 alterations and different patterns overall in GAs. Three patients (1 kidney, 1 ureter, and 1 bladder) had bi-allelic loss of SMARCB1, and 7 others had a loss of function alteration with loss of heterozygosity. These patients with SMARCB1 bi-allelic loss had few or no additional alterations, notably no alterations in TP53, CDKN2A/B, or TERT, which are observed in greater than 50% of urothelial tumors, or RB1 alterations observed in ~22% of UC. The patient treated with cisplatin based chemotherapy achieved a pathologic CR. Conclusions: Genomic profiles of tumors from patients with UC revealed a rare population of patients with alterations impacting chromatin regulation and tumor suppression, specifically through loss of SMARCB1. Tumors with SMARCB1 loss have a very low burden of genetic alterations and SMARCB1 loss or deletion may be the sole driving mutation. Conventional chemotherapy may be effective. Inhibitors of EZH2, HDAC and CDK4 may be potential treatment strategies to target this subset of tumors.

scholarly journals MDM2 Protein Overexpression Promotes Proliferation and Survival of Multiple Myeloma Cells

Blood ◽  
1997 ◽  
Vol 90 (5) ◽  
pp. 1982-1992 ◽  
Author(s):  
Gerrard Teoh ◽  
Mitsuyoshi Urashima ◽  
Atsushi Ogata ◽  
Dharminder Chauhan ◽  
James A. DeCaprio ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Cell Cycle Progression ◽  
Mononuclear Cells ◽  
Treatment Strategies ◽  
Mdm2 Protein ◽  
Growth And Survival ◽  
Mdm2 Expression ◽  
Ethidium Bromide Staining ◽  
And Function

Abstract The murine double minute 2 (MDM2) protein facilitates G1 to S phase transition by activation of E2F-1 and can enhance cell survival by suppressing wild-type p53 (wtp53) function. In this study, we examined MDM2 expression and function in multiple myeloma (MM) cells. MDM2 is strongly and constitutively expressed in MM cell lines (ARH-77, RPMI 8226, and OCI-My5) and in the cells of plasma cell leukemia (PCL) patients, but is not expressed in normal bone marrow mononuclear cells (BM MNCs). Treatment of MM cells with MDM2 antisense, but not sense, nonsense, or scrambled, oligodeoxyribonucleotides (ODNs) decreased DNA synthesis and cell viability; it also induced G1 growth arrest, as evidenced by propidium iodide (PI) staining and induction of retinoblastoma protein (pRB) to E2F-1 binding. Moreover, inhibition of MDM2 using antisense ODNs also triggered MM cell apoptosis as evidenced by acridine orange–ethidium bromide staining. We next studied the association of MDM2 with wtp53 and/or mutant p53 (mtp53), E2F-1, CDK4, and p21. MDM2 constitutively binds to E2F-1 in all MM cells, to both wtp53 and mtp53, and to p21 in tumor cells lacking p53. These data suggest that MDM2 may enhance cell-cycle progression in MM cells both by activating E2F-1 and by downregulating cell-cycle inhibitory proteins (wtp53 and p21). Overexpression of MDM2 may therefore contribute to both growth and survival of MM cells, suggesting the potential utility of treatment strategies targeting MDM2 in MM.

scholarly journals Critical View of Novel Treatment Strategies for Glioblastoma: Failure and Success of Resistance Mechanisms by Glioblastoma Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Timo Burster ◽  
Rebecca Traut ◽  
Zhanerke Yermekkyzy ◽  
Katja Mayer ◽  
Mike-Andrew Westhoff ◽  
...  
Keyword(s):  
Immune System ◽  
Treatment Strategies ◽  
Resistance Mechanisms ◽  
Host Immune System ◽  
Therapeutic Approaches ◽  
Glioblastoma Cells ◽  
Major Drawback ◽  
Novel Treatment ◽  
Novel Treatment Strategies ◽  
New Strategies

According to the invasive nature of glioblastoma, which is the most common form of malignant brain tumor, the standard care by surgery, chemo- and radiotherapy is particularly challenging. The presence of glioblastoma stem cells (GSCs) and the surrounding tumor microenvironment protects glioblastoma from recognition by the immune system. Conventional therapy concepts have failed to completely remove glioblastoma cells, which is one major drawback in clinical management of the disease. The use of small molecule inhibitors, immunomodulators, immunotherapy, including peptide and mRNA vaccines, and virotherapy came into focus for the treatment of glioblastoma. Although novel strategies underline the benefit for anti-tumor effectiveness, serious challenges need to be overcome to successfully manage tumorigenesis, indicating the significance of developing new strategies. Therefore, we provide insights into the application of different medications in combination to boost the host immune system to interfere with immune evasion of glioblastoma cells which are promising prerequisites for therapeutic approaches to treat glioblastoma patients.

scholarly journals Mathematical modelling of COVID-19 disease dynamics: Interaction between immune system and SARS-CoV-2 within host

2021 ◽  
Vol 7 (2) ◽  
pp. 2618-2633
Author(s):  
S. M. E. K. Chowdhury ◽  
◽  
J. T. Chowdhury ◽  
Shams Forruque Ahmed ◽  
Praveen Agarwal ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Immune System ◽  
Natural Killer ◽  
Disease Severity ◽  
Immune Surveillance ◽  
Treatment Strategies ◽  
Vital Role ◽  
Sufficient Information ◽  
Disease Dynamics ◽  
Viral Therapy

<abstract><p>SARS-COV-2 (Coronavirus) viral growth kinetics within-host become a key fact to understand the COVID-19 disease progression and disease severity since the year 2020. Quantitative analysis of the viral dynamics has not yet been able to provide sufficient information on the disease severity in the host. The SARS-CoV-2 dynamics are therefore important to study in the context of immune surveillance by developing a mathematical model. This paper aims to develop such a mathematical model to analyse the interaction between the immune system and SARS-CoV-2 within the host. The model is developed to explore the viral load dynamics within the host by considering the role of natural killer cells and T-cell. Through analytical simplifications, the model is found well-posed and asymptotically stable at disease-free equilibrium. The numerical results demonstrate that the influx of external natural killer (NK) cells alone or integrating with anti-viral therapy plays a vital role in suppressing the SARS-CoV-2 growth within-host. Also, within the host, the virus can not grow if the virus replication rate is below a threshold limit. The developed model will contribute to understanding the disease dynamics and help to establish various potential treatment strategies against COVID-19.</p></abstract>

CD38 as an immunomodulator in cancer

2020 ◽  
Vol 16 (34) ◽  
pp. 2853-2861
Author(s):  
Yanli Li ◽  
Rui Yang ◽  
Limo Chen ◽  
Sufang Wu
Keyword(s):  
Multiple Myeloma ◽  
Cell Activation ◽  
Human Tissues ◽  
Transmembrane Glycoprotein ◽  
Cell Activation Marker ◽  
Research Findings ◽  
A Cell ◽  
And Function ◽  
Human Molecule

CD38 is a transmembrane glycoprotein that is widely expressed in a variety of human tissues and cells, especially those in the immune system. CD38 protein was previously considered as a cell activation marker, and today monoclonal antibodies targeting CD38 have witnessed great achievements in multiple myeloma and promoted researchers to conduct research on other tumors. In this review, we provide a wide-ranging review of the biology and function of the human molecule outside the field of myeloma. We focus mainly on current research findings to summarize and update the findings gathered from diverse areas of study. Based on these findings, we attempt to extend the role of CD38 in the context of therapy of solid tumors and expand the role of the molecule from a simple marker to an immunomodulator.

scholarly journals The Role of Monoclonal Antibodies in Smoldering and Newly Diagnosed Transplant-Eligible Multiple Myeloma

2020 ◽  
Vol 13 (12) ◽  
pp. 451
Author(s):  
Elena Zamagni ◽  
Paola Tacchetti ◽  
Paola Deias ◽  
Francesca Patriarca
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
Immune System ◽  
Survival Outcomes ◽  
Newly Diagnosed ◽  
Cellular Targets ◽  
Recent Introduction

The recent introduction of monoclonal antibodies (MoAbs), with several cellular targets, such as CD-38 (daratumumab and isatuximab) and SLAM F7 (elotuzumab), differently combined with other classes of agents, has significantly extended the outcomes of patients with multiple myeloma (MM) in different phases of the disease. Initially used in advanced/refractory patients, different MoAbs combination have been introduced in the treatment of newly diagnosed transplant eligible patients (NDTEMM), showing a significant improvement in the depth of the response and in survival outcomes, without a significant price in terms of toxicity. In smoldering MM, MoAbs have been applied, either alone or in combination with other drugs, with the goal of delaying the progression to active MM and restoring the immune system. In this review, we will focus on the main results achieved so far and on the main on-going trials using MoAbs in SMM and NDTEMM.

scholarly journals Molecular Subtypes and Precision Oncology in Intrahepatic Cholangiocarcinoma

2021 ◽  
Vol 10 (13) ◽  
pp. 2803
Author(s):  
Carolin Czauderna ◽  
Martha M. Kirstein ◽  
Hauke C. Tews ◽  
Arndt Vogel ◽  
Jens U. Marquardt
Keyword(s):  
Clinical Care ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Specific Treatment ◽  
Growth Factor Receptor ◽  
Treatment Modalities ◽  
Precision Oncology ◽  
Recurrence Rates ◽  
Isocitrate Dehydrogenase 1 ◽  
Liver Cancers

Cholangiocarcinomas (CCAs) are the second-most common primary liver cancers. CCAs represent a group of highly heterogeneous tumors classified based on anatomical localization into intra- (iCCA) and extrahepatic CCA (eCCA). In contrast to eCCA, the incidence of iCCA is increasing worldwide. Curative treatment strategies for all CCAs involve oncological resection followed by adjuvant chemotherapy in early stages, whereas chemotherapy is administered at advanced stages of disease. Due to late diagnosis, high recurrence rates, and limited treatment options, the prognosis of patients remains poor. Comprehensive molecular characterization has further revealed considerable heterogeneity and distinct prognostic and therapeutic traits for iCCA and eCCA, indicating that specific treatment modalities are required for different subclasses. Several druggable alterations and oncogenic drivers such as fibroblast growth factor receptor 2 gene fusions and hotspot mutations in isocitrate dehydrogenase 1 and 2 mutations have been identified. Specific inhibitors have demonstrated striking antitumor activity in affected subgroups of patients in phase II and III clinical trials. Thus, improved understanding of the molecular complexity has paved the way for precision oncological approaches. Here, we outline current advances in targeted treatments and immunotherapeutic approaches. In addition, we delineate future perspectives for different molecular subclasses that will improve the clinical care of iCCA patients.

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