scholarly journals Oncolytic Virotherapy for Multiple Myeloma: Past, Present, and Future

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Chandini M. Thirukkumaran ◽  
Don G. Morris
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Anticancer Agents ◽  
Measles Virus ◽  
Clinical Investigation ◽  
Cancer Therapeutics ◽  
Oncolytic Viruses ◽  
Treatment Modalities ◽  
Dna And Rna ◽  
Viral Therapy

Multiple myeloma (MM) is a B-cell malignancy that is currently felt to be incurable. Despite recently approved novel targeted treatments such as lenalidomide and bortezomib, most MM patients' relapse is emphasizing the need for effective and well-tolerated therapies for this deadly disease. The use of oncolytic viruses has garnered significant interest as cancer therapeutics in recent years, and are currently under intense clinical investigation. Both naturally occurring and engineered DNA and RNA viruses have been investigated preclinically as treatment modalities for several solid and hematological malignancies. Presently, only a genetically modified measles virus is in human clinical trials for MM. The information obtained from this and other future clinical trials will guide clinical application of oncolytic viruses as anticancer agents for MM. This paper provides a timely overview of the history of oncolytic viruses for the treatment of MM and future strategies for the optimization of viral therapy for this disease.

Fully Retargeted Oncolytic Measles Virus for Multiple Myeloma Therapy.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5474-5474
Author(s):  
Horst D. Hummel ◽  
Gaby Kuntz ◽  
Takafumi Nakamura ◽  
Axel Greiner ◽  
Stephen J. Russell ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibody ◽  
Cell Lines ◽  
Plasma Cell ◽  
Measles Virus ◽  
Plasma Cells ◽  
Treatment Modalities ◽  
Single Chain ◽  
Gfp Expression ◽  
Frequent Relapses

Abstract Multiple Myeloma (MM) is a disseminated plasma cell malignancy with approximately 14,600 new cases diagnosed in the USA annually. Despite recent progress in current therapeutical options the median survival is 3 to 5 years and cure is extremely rare. Therefore the evaluation of new treatment modalities for MM is highly warranted. An attractive approach to treat Myeloma with a minimum of undesired side effects is the use of a tumour antigen specific for MM cells. Wue-1, a monoclonal antibody binds very selectively normal and malignant plasma cells (50 of 51 MM samples, 14 of 15 immunocytoma and 13 of 13 MALT type lymphomas with plasma cell differentiation were Wue-1 positive, normal tissue including hematopoietic cells were negative) and offers the possibility to define MM cells as targets. The tool for selective killing of MM cells recognized by Wue-1 monoclonal antibody is in this study the measles virus vaccine strain Edmonston B in an ablated variant (MV-Wue) which no longer binds the usual measles receptors CD46 and CD150 (SLAM) expressed on almost every human cell type displaying a single-chain antibody (scFv) derived from the monoclonal Wue-1-antibody which has been tethered to the C-terminus of the H protein to restrict and retarget its interaction to malignant plasma cells especially MM cells. In addition, MV-Wue encodes EGFP facilitating the read out of infected cells. To determine if the fully retargeted MV-Wue would be able to infect MM cell lines and primary MM cells selectively an array of infection assays were performed using the MM cell lines U266 as well as primary CD138 positive MM cells expressing the Wue-1 antigen as expected targets and CD138 negative cells and normal B cells as controls negative for Wue-1. In these experiments selective infections of the MM cell line and primary MM cells were observed whereas the control cells were not infected with MV-Wue. In all cell types GFP expression indicating replicative infection correlated with the expression of the Wue-1 antigen determined by FACS. Infection experiments performed in the presence of monoclonal Wue-1 antibody showed a decreased GFP expression of about 78% in CD138 positive MM cells demonstrating specificity of the infection by MV-Wue. These results indicate that the engineered virus can be a safe and potential curative oncolytic agent to face the main problem in Multiple Myeloma which is responsible for frequent relapses, the minimal residual disease (MRD).

scholarly journals The Use of Oncolytic Viruses in the Treatment of Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5687
Author(s):  
Georgia Stewart ◽  
Andrew Chantry ◽  
Michelle Lawson
Keyword(s):  
Multiple Myeloma ◽  
Measles Virus ◽  
Plasma Cells ◽  
Residual Disease ◽  
Proteasome Inhibitors ◽  
Bovine Viral Diarrhoea Virus ◽  
Myxoma Virus ◽  
Oncolytic Viruses ◽  
Coxsackie Virus ◽  
Diarrhoea Virus

Multiple myeloma accounts for 1% of all new cancers worldwide. It is the second most common haematological malignancy and has a low five-year survival rate (53.2%). Myeloma remains an incurable disease and is caused by the growth of malignant plasma cells in the bone marrow. Current anti-myeloma therapies (conventional chemotherapies, immunomodulatory drugs i.e., thalidomide and its’ analogues, proteasome inhibitors, monoclonal antibodies, and radiotherapy) initially substantially debulk tumour burden, but after a period of remission ‘plateau phase’ disease invariably relapses due to tumour recrudescence from foci of minimal residual disease (MRD) and accumulating drug resistance. Therefore, there is a compelling clinical need for the development of novel treatment regimens to target MRD and effectively eliminate all remaining tumour cells. This review will discuss the potential use of oncolytic virus (OV) therapies in the treatment of myeloma. Specifically, it will focus on preclinical studies using DNA viruses (adenovirus (Ad), vaccinia virus (VV), myxoma virus (MYXV), and herpes simplex virus (HSV)), RNA viruses (reovirus (reo), coxsackie virus, measles virus (MV) and bovine viral diarrhoea virus (BVDV), and vesicular stomatitis virus (VSV)), and on four types of viruses (VV, reo, MV-NIS and VSV-IFNβ-NIS) that have been assessed clinically in a small number of myeloma patients.

scholarly journals Clinical landscape of oncolytic virus research in 2020

2020 ◽  
Vol 8 (2) ◽  
pp. e001486 ◽  
Author(s):  
Nicholas Macedo ◽  
David M Miller ◽  
Rizwan Haq ◽  
Howard L Kaufman
Keyword(s):  
Clinical Trials ◽  
Immune Responses ◽  
Plaque Assay ◽  
Cancer Therapeutics ◽  
Oncolytic Viruses ◽  
Low Grade ◽  
Current Profile ◽  
Tumor Biopsy ◽  
The Impact ◽  
Insight Into

Oncolytic viruses (OVs) are a new class of cancer therapeutics. This review was undertaken to provide insight into the current landscape of OV clinical trials. A PubMed search identified 119 papers from 2000 to 2020 with 97 studies reporting data on 3233 patients. The viruses used, presence of genetic modifications and/or transgene expression, cancer types targeted, inclusion of combination strategies and safety profile were reported. In addition, information on viral bioshedding across the studies, including which tissues or body fluids were evaluated and how virus was detected (eg, PCR, plaque assay or both), is also reported. Finally, the number of studies evaluating antiviral and antitumor humoral and cellular immune responses were noted. We found that adenovirus (n=30) is the most common OV in clinical trials with approximately two-thirds (n=63) using modified or recombinant viral backbones and granulocyte-macrophage colony-stimulating factor (n=24) was the most common transgene. The most common tumors targeted were melanoma (n=1000) and gastrointestinal (GI; n=577) cancers with most using monotherapy OVs given by intratumoral (n=1482) or intravenous (n=1347) delivery. The most common combination included chemotherapy (n=36). Overall, OV treatment-related adverse events were low-grade constitutional and local injection site reactions. Viral shedding was frequently measured although many studies restricted this to blood and tumor tissue and used PCR only. While most studies did report antiviral antibody titers (n=63), only a minority of studies reported viral-specific T cell responses (n=10). Tumor immunity was reported in 48 studies and largely relied on general measures of immune activation (eg, tumor biopsy immunohistochemistry (n=25) and serum cytokine measurement (n=19)) with few evaluating tumor-specific immune responses (n=7). Objective responses were reported in 292 (9%) patients and disease control was achieved in 681 (21.1%) patients, although standard reporting criteria were only used in 53% of the trials. Completed clinical trials not reported in the peer-reviewed literature were not included in this review potentially underestimating the impact of OV treatment. These data provide insight into the current profile of OV clinical trials reporting and identifies potential gaps where further studies are needed to better define the role of OVs, alone and in combination, for patients with cancer.

Recent Progress in Histone Deacetylase Inhibitors as Anticancer Agents

2020 ◽  
Vol 27 (15) ◽  
pp. 2449-2493 ◽  
Author(s):  
Loredana Cappellacci ◽  
Diego R. Perinelli ◽  
Filippo Maggi ◽  
Mario Grifantini ◽  
Riccardo Petrelli
Keyword(s):  
Clinical Trials ◽  
Histone Deacetylase ◽  
Anticancer Agents ◽  
Histone Deacetylase Inhibitors ◽  
Cyclic Peptide ◽  
Hdac Inhibitors ◽  
Cancer Therapeutics ◽  
Rational Drug Design ◽  
Modeling Tools ◽  
Anti Cancer

Histone Deacetylase (HDAC) inhibitors are a relatively new class of anti-cancer agents that play important roles in epigenetic or non-epigenetic regulation, inducing death, apoptosis, and cell cycle arrest in cancer cells. Recently, their use has been clinically validated in cancer patients resulting in the approval by the FDA of four HDAC inhibitors, vorinostat, romidepsin, belinostat and panobinostat, used for the treatment of cutaneous/peripheral T-cell lymphoma and multiple myeloma. Many more HDAC inhibitors are at different stages of clinical development for the treatment of hematological malignancies as well as solid tumors. Also, clinical trials of several HDAC inhibitors for use as anti-cancer drugs (alone or in combination with other anti-cancer therapeutics) are ongoing. In the intensifying efforts to discover new, hopefully, more therapeutically efficacious HDAC inhibitors, molecular modelingbased rational drug design has played an important role. In this review, we summarize four major structural classes of HDAC inhibitors (hydroxamic acid derivatives, aminobenzamide, cyclic peptide and short-chain fatty acids) that are in clinical trials and different computer modeling tools available for their structural modifications as a guide to discover additional HDAC inhibitors with greater therapeutic utility.

scholarly journals BCMA in Multiple Myeloma—A Promising Key to Therapy

2021 ◽  
Vol 10 (18) ◽  
pp. 4088
Author(s):  
Martina Kleber ◽  
Ioannis Ntanasis-Stathopoulos ◽  
Evangelos Terpos
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
T Cell ◽  
Cell Therapy ◽  
Targeted Treatment ◽  
Treatment Modalities ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Despite the discoveries of numerous agents including next generation proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies, multiple myeloma (MM) remains an incurable disease. The field of myeloma treatment in refractory or relapsed patients after standard therapy entered a new era due to the B-cell maturation antigen (BMCA) targeted approach. BCMA is a member of the tumor necrosis factor receptor family with high expression in mature B-lymphocytes and plasma cells. Given the understanding of BCMA mechanism of action in MM, BCMA plays a promising role as a therapeutic target. Several clinical trials are underway to evolve the current BCMA targeted treatment concept such as antibody-drug conjugates (ADCs), bispecific T cell engagers (BITEs) and chimeric antigen receptor (CAR) T cell therapy. Current results of representative BCMA trials may close the gap of the unmet clinical need to further improve the outcome of heavily pretreated MM patients with the potency to change the paradigm in newly diagnosed and refractory MM. This comprehensive review will give an update on various BMCA targeted treatment modalities (ADCs, BITEs, CAR T cell therapy) and its existing results on efficacy and safety from preclinical and clinical trials.

scholarly journals Oncolytic viruses for therapy of malignant glioma

2016 ◽  
Vol 62 (4) ◽  
pp. 376-390 ◽  
Author(s):  
A.O. Sosnovtceva ◽  
N.F. Grinenko ◽  
A.V. Lipatova ◽  
P.M. Chumakov ◽  
V.P. Chekhonin
Keyword(s):  
Clinical Trials ◽  
Tumor Cells ◽  
Disease Recurrence ◽  
Oncolytic Viruses ◽  
High Rate ◽  
Glial Tumor ◽  
Viral Therapy ◽  
The Brain ◽  
Virus Strains ◽  
Single Tumor

Effective treatment of malignant brain tumors is still an open problem. Location of tumor in vital areas of the brain significantly limits capasities of surgical treatment. The presence of tumor stem cells resistant to radiation and anticancer drugs in brain tumor complicates use of chemoradiotherapy and causes a high rate of disease recurrence. A technological improvement in bioselection and production of recombinant resulted in creation of viruses with potent oncolytic properties against glial tumors. Recent studies, including clinical trials, showed, that majority of oncolytic viruses are safe. Despite the impressive results of the viral therapy in some patients, the treatment of other patients is not effective; therefore, further improvement of the methods of oncolytic virotherapy is necessary. High genetic heterogeneity of glial tumor cells even within a single tumor determines differences in individual sensitivity of tumor cells to oncolytic viruses. This review analyses the most successful oncolytic virus strains, including those which had reached clinical trials, and discusses the prospects for new approaches to virotherapy of gliomas.

Oncolytic Virotherapy and Gene Therapy Strategies for Hepatobiliary Cancers

2018 ◽  
Vol 18 (2) ◽  
pp. 188-201 ◽  
Author(s):  
Takeshi Yamada ◽  
Yukako Hamano ◽  
Naoyuki Hasegawa ◽  
Emiko Seo ◽  
Kuniaki Fukuda ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Anticancer Agents ◽  
Preliminary Evidence ◽  
Therapeutic Agents ◽  
Oncolytic Viruses ◽  
Preclinical Models ◽  
Invasion And Metastasis ◽  
Dismal Prognosis ◽  
Liver Cancers ◽  
Therapy Strategies

Advanced liver cancers and biliary cancers represent diseases with dismal prognosis because of frequent local invasion and metastasis. Effective therapeutic agents for these cancers have not been established. Oncolytic viruses (OVs) constitute a novel class of promising, selective anticancer agents and recent studies have elucidated their unique features. Moreover, clinical trials are demonstrating promising results. Numerous OVs are being tested in preclinical models of hepatocellular carcinoma (HCC). The lead agent Pexa-Vec (pexastimogene devacirepvec, JX-594), a recombinant Wyeth strain vaccinia virus, has demonstrated preliminary evidence of safety and efficacy for HCC in clinical trials. Few other OVs have entered clinical testing. Relatively few preclinical studies and clinical trials exist for biliary cancers. In this review, we introduce various approaches using OVs to treat the intractable hepatobiliary cancers.

scholarly journals A New Role for Vitamin D: The Enhancement of Oncolytic Viral Therapy in Pancreatic Cancer

Biomedicines ◽  
2018 ◽  
Vol 6 (4) ◽  
pp. 104 ◽  
Author(s):  
Christopher LaRocca ◽  
Susanne Warner
Keyword(s):  
Pancreatic Cancer ◽  
Vitamin D ◽  
Cancer Therapeutics ◽  
Tumor Stroma ◽  
Oncolytic Viruses ◽  
Response To Treatment ◽  
Fda Approval ◽  
Viral Therapy ◽  
Anti Cancer ◽  
United States Food

Oncolytic viruses have emerged as a novel class of anti-cancer therapeutics with one virus already receiving United States Food and Drug Administration (FDA) approval (talimogene laherparepvec) and many others undergoing testing in clinical trials. These viruses have direct lytic effects on tumor cells as well as immunomodulatory functions to increase inflammatory cell infiltrates in the tumor microenvironment. Despite all of the advances in cancer care, pancreatic cancer remains a highly lethal malignancy. One of the main barriers to successful systemic treatment of the disease is the fibrotic tumor stroma, as the unique extracellular matrix creates an environment that promotes tumor growth and is resistant to chemotherapy and other anti-cancer agents. The pleiotropic effects of Vitamin D have been widely studied, but recent research has now demonstrated it to be an effective agent in modulating pancreatic cancer stroma to facilitate the enhanced delivery of cytotoxic chemotherapy and immunogenicity in response to treatment. This review will explore the combination of Vitamin D with oncolytic viruses and how this novel application of Vitamin D’s ability to modulate pancreatic tumor stroma may result in a potential mechanism for increasing the efficacy of oncolytic virotherapy in pancreatic cancer.

scholarly journals Measles Virus as an Oncolytic Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 544
Author(s):  
Christine E. Engeland ◽  
Guy Ungerechts
Keyword(s):  
Clinical Trials ◽  
Measles Virus ◽  
Viral Vectors ◽  
Reverse Genetics ◽  
Cancer Therapeutics ◽  
Immune Checkpoint Blockade ◽  
Combination Treatments ◽  
Rational Combination ◽  
Oncolytic Immunotherapy ◽  
Combination Regimens

Measles virus (MeV) preferentially replicates in malignant cells, leading to tumor lysis and priming of antitumor immunity. Live attenuated MeV vaccine strains are therefore under investigation as cancer therapeutics. The versatile MeV reverse genetics systems allows for engineering of advanced targeted, armed, and shielded oncolytic viral vectors. Therapeutic efficacy can further be enhanced by combination treatments. An emerging focus in this regard is combination immunotherapy, especially with immune checkpoint blockade. Despite challenges arising from antiviral immunity, availability of preclinical models, and GMP production, early clinical trials have demonstrated safety of oncolytic MeV and yielded promising efficacy data. Future clinical trials with engineered viruses, rational combination regimens, and comprehensive translational research programs will realize the potential of oncolytic immunotherapy.

scholarly journals Recent Advances in Repurposing Disulfiram and Disulfiram Derivatives as Copper-Dependent Anticancer Agents

2021 ◽  
Vol 8 ◽  
Author(s):  
Vinodh Kannappan ◽  
Misha Ali ◽  
Benjamin Small ◽  
Gowtham Rajendran ◽  
Salena Elzhenni ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Anticancer Agents ◽  
Molecular Targets ◽  
Cancer Therapeutics ◽  
New Drugs ◽  
Cancer Clinical Trials ◽  
Anticancer Efficacy ◽  
Wide Range

Copper (Cu) plays a pivotal role in cancer progression by acting as a co-factor that regulates the activity of many enzymes and structural proteins in cancer cells. Therefore, Cu-based complexes have been investigated as novel anticancer metallodrugs and are considered as a complementary strategy for currently used platinum agents with undesirable general toxicity. Due to the high failure rate and increased cost of new drugs, there is a global drive towards the repositioning of known drugs for cancer treatment in recent years. Disulfiram (DSF) is a first-line antialcoholism drug used in clinics for more than 65 yr. In combination with Cu, it has shown great potential as an anticancer drug by targeting a wide range of cancers. The reaction between DSF and Cu ions forms a copper diethyldithiocarbamate complex (Cu(DDC)2 also known as CuET) which is the active, potent anticancer ingredient through inhibition of NF-κB and ubiquitin-proteasome system as well as alteration of the intracellular reactive oxygen species (ROS). Importantly, DSF/Cu inhibits several molecular targets related to drug resistance, stemness, angiogenesis and metastasis and is thus considered as a novel strategy for overcoming tumour recurrence and relapse in patients. Despite its excellent anticancer efficacy, DSF has proven unsuccessful in several cancer clinical trials. This is likely due to the poor stability, rapid metabolism and/or short plasma half-life of the currently used oral version of DSF and the inability to form Cu(DDC)2 at relevant concentrations in tumour tissues. Here, we summarize the scientific rationale, molecular targets, and mechanisms of action of DSF/Cu in cancer cells and the outcomes of oral DSF ± Cu in cancer clinical trials. We will focus on the novel insights on harnessing the immune system and hypoxic microenvironment using DSF/Cu complex and discuss the emerging delivery strategies that can overcome the shortcomings of DSF-based anticancer therapies and provide opportunities for translation of DSF/Cu or its Cu(DDC)2 complex into cancer therapeutics.

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