scholarly journals Systemic Delivery of Oncolytic Viruses: Hopes and Hurdles

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Mark S. Ferguson ◽  
Nicholas R. Lemoine ◽  
Yaohe Wang
Keyword(s):  
Clinical Trials ◽  
Primary Tumour ◽  
Oncolytic Viruses ◽  
Viral Escape ◽  
Systemic Delivery ◽  
Stage Of Development ◽  
Viral Therapy ◽  
Rapid Clearance ◽  
Novel Therapeutic Strategies ◽  
Vascular Compartment

Despite recent advances in both surgery and chemoradiotherapy, mortality rates for advanced cancer remain high. There is a pressing need for novel therapeutic strategies; one option is systemic oncolytic viral therapy. Intravenous administration affords the opportunity to treat both the primary tumour and any metastatic deposits simultaneously. Data from clinical trials have shown that oncolytic viruses can be systemically delivered safely with limited toxicity but the results are equivocal in terms of efficacy, particularly when delivered with adjuvant chemotherapy. A key reason for this is the rapid clearance of the viruses from the circulation before they reach their targets. This phenomenon is mainly mediated through neutralising antibodies, complement activation, antiviral cytokines, and tissue-resident macrophages, as well as nonspecific uptake by other tissues such as the lung, liver and spleen, and suboptimal viral escape from the vascular compartment. A range of methods have been reported in the literature, which are designed to overcome these hurdles in preclinical models. In this paper, the potential advantages of, and obstacles to, successful systemic delivery of oncolytic viruses are discussed. The next stage of development will be the commencement of clinical trials combining these novel approaches for overcoming the barriers with systemically delivered oncolytic viruses.

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.

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.

scholarly journals Strategies to Optimise Oncolytic Viral Therapies: The Role of Natural Killer Cells

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1450
Author(s):  
Elaine Y. L. Leung ◽  
Iain A. McNeish
Keyword(s):  
Clinical Trials ◽  
Nk Cells ◽  
Viral Infections ◽  
The United States ◽  
Oncolytic Viruses ◽  
Malignant Cells ◽  
Therapeutic Benefits ◽  
Viral Therapy ◽  
Potential Efficacy ◽  
Early Phase Clinical Trials

Oncolytic viruses (OVs) are an emerging class of anti-cancer agents that replicate selectively within malignant cells and generate potent immune responses. Their potential efficacy has been shown in clinical trials, with talimogene laherparepvec (T-VEC or IMLYGIC®) now approved both in the United States and Europe. In healthy individuals, NK cells provide effective surveillance against cancer and viral infections. In oncolytic viral therapy, NK cells may render OV ineffective by rapid elimination of the propagating virus but could also improve therapeutic efficacy by preferential killing of OV-infected malignant cells. Existing evidence suggests that the overall effect of NK cells against OV is context dependent. In the past decade, the understanding of cancer and OV biology has improved significantly, which helped refine this class of treatments in early-phase clinical trials. In this review, we summarised different strategies that have been evaluated to modulate NK activities for improving OV therapeutic benefits. Further development of OVs will require a systematic approach to overcome the challenges of the production and delivery of complex gene and cell-based therapies in clinical settings.

scholarly journals Mesenchymal stem cells and oncolytic viruses: joining forces against cancer

2021 ◽  
Vol 9 (2) ◽  
pp. e001684
Author(s):  
Rafael Moreno
Keyword(s):  
Stem Cells ◽  
Clinical Trials ◽  
Mesenchymal Stem Cells ◽  
Immune System ◽  
Oncolytic Viruses ◽  
Immunogenic Cell Death ◽  
The Past ◽  
Physical Barriers ◽  
Immunogenic Properties ◽  
New Strategies

The development of oncolytic viruses (OVs) has increased significantly in the past 20 years, with many candidates entering clinical trials and three of them receiving approval for some indications. Recently, OVs have also gathered interest as candidates to use in combination with immunotherapies for cancer due to their immunogenic properties, which include immunogenic cell death and the possibility to carry therapeutic transgenes in their genomes. OVs transform non-immunogenic ‘cold’ tumors into inflamed immunogenic ‘hot’ tumors, where immunotherapies show the highest efficacy. However, in monotherapy or in combination with immunotherapy, OVs face numerous challenges that limit their successful application, in particular upon systemic administration, such as liver sequestration, neutralizing interactions in blood, physical barriers to infection, and fast clearance by the immune system. In this regard, the use of mesenchymal stem cells (MSCs) as cells carrier for OV delivery addresses many of these obstacles acting as virus carriers and factories, expressing additional transgenes, and modulating the immune system. Here, I review the current progress of OVs-loaded MSCs in cancer, focusing on their interaction with the immune system, and discuss new strategies to improve their therapeutic efficacy.

scholarly journals Repurposing of Antimicrobial Agents for Cancer Therapy: What Do We Know?

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3193
Author(s):  
Christina Pfab ◽  
Luisa Schnobrich ◽  
Samir Eldnasoury ◽  
André Gessner ◽  
Nahed El-Najjar
Keyword(s):  
Clinical Trials ◽  
Antimicrobial Agents ◽  
Large Body ◽  
Drug Repurposing ◽  
Extensive Discussion ◽  
Attrition Rates ◽  
Beneficial Effects ◽  
Stage Of Development ◽  
Development Costs ◽  
Approved Drugs

The substantial costs of clinical trials, the lengthy timelines of new drug discovery and development, along the high attrition rates underscore the need for alternative strategies for finding quickly suitable therapeutics agents. Given that most approved drugs possess more than one target tightly linked to other diseases, it encourages promptly testing these drugs in patients. Over the past decades, this has led to considerable attention for drug repurposing, which relies on identifying new uses for approved or investigational drugs outside the scope of the original medical indication. The known safety of approved drugs minimizes the possibility of failure for adverse toxicology, making them attractive de-risked compounds for new applications with potentially lower overall development costs and shorter development timelines. This latter case is an exciting opportunity, specifically in oncology, due to increased resistance towards the current therapies. Indeed, a large body of evidence shows that a wealth of non-cancer drugs has beneficial effects against cancer. Interestingly, 335 drugs are currently being evaluated in different clinical trials for their potential activities against various cancers (Redo database). This review aims to provide an extensive discussion about the anti-cancer activities exerted by antimicrobial agents and presents information about their mechanism(s) of action and stage of development/evaluation.

Future Interventional Oncology Catheter-Based Therapies

2017 ◽  
Vol 01 (03) ◽  
pp. 225-232
Author(s):  
Christopher Noda ◽  
Mihail Roubhaka ◽  
Resmi Charalel ◽  
Abdulrahman Masrani ◽  
Olaguoke Akinwande
Keyword(s):  
Minimally Invasive ◽  
Interventional Oncology ◽  
Complete Removal ◽  
Systemic Delivery ◽  
Delivery Method ◽  
Viral Therapy ◽  
Attractive Option ◽  
Rapid Pace ◽  
Invasive Techniques ◽  
All Diseases

AbstractMinimally invasive techniques in the treatment of cancer continue to develop at a rapid pace. Although surgical resection currently remains the only option for a complete cure, not all diseases are amenable to complete removal. This leaves opportunities to develop effective downstaging techniques as well as palliative care. In the realm of minimally invasive oncologic techniques, catheter-based therapies are an attractive option because malignancies require a blood supply to remain active. The intra-arterial (IA) delivery of specific tumoricidal drugs has been shown to be a successful delivery method in a variety of different cancers, and it is currently a progressive area of research. There is work both to increase the delivery specificity of oncologic drugs, including SW43 sigma receptor ligand and nanoparticle research. In addition, oncolytic viral therapy and 3-bromopyruvate have become increasingly more attractive tumoricidal drug prospects. In the future, the success of these therapies will ultimately determine the degree to which IA delivery will compete with the systemic delivery of drugs in the treatment of cancer.

scholarly journals Convection-enhanced delivery to the central nervous system

2015 ◽  
Vol 122 (3) ◽  
pp. 697-706 ◽  
Author(s):  
Russell R. Lonser ◽  
Malisa Sarntinoranont ◽  
Paul F. Morrison ◽  
Edward H. Oldfield
Keyword(s):  
Drug Delivery ◽  
Central Nervous System ◽  
Clinical Trials ◽  
Nervous System ◽  
Convective Flow ◽  
Clinical Applications ◽  
Systemic Delivery ◽  
Convection Enhanced Delivery ◽  
The Central Nervous System ◽  
Real Time Tracking

Convection-enhanced delivery (CED) is a bulk flow–driven process. Its properties permit direct, homogeneous, targeted perfusion of CNS regions with putative therapeutics while bypassing the blood-brain barrier. Development of surrogate imaging tracers that are co-infused during drug delivery now permit accurate, noninvasive real-time tracking of convective infusate flow in nervous system tissues. The potential advantages of CED in the CNS over other currently available drug delivery techniques, including systemic delivery, intrathecal and/or intraventricular distribution, and polymer implantation, have led to its application in research studies and clinical trials. The authors review the biophysical principles of convective flow and the technology, properties, and clinical applications of convective delivery in the CNS.

scholarly journals Systemic Delivery of mLIGHT-Armed Myxoma Virus Is Therapeutic for Later-Stage Syngeneic Murine Lung Metastatic Osteosarcoma

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 337
Author(s):  
John D. Christie ◽  
Nicole Appel ◽  
Liqiang Zhang ◽  
Kenneth Lowe ◽  
Jacquelyn Kilbourne ◽  
...  
Keyword(s):  
Lung Metastases ◽  
Ex Vivo ◽  
Tumor Burden ◽  
Myxoma Virus ◽  
Oncolytic Viruses ◽  
Systemic Delivery ◽  
Clinical Cancer Research ◽  
Critical Issues

Cancers that metastasize to the lungs represent a major challenge in both basic and clinical cancer research. Oncolytic viruses are newly emerging options but successful delivery and choice of appropriate therapeutic armings are two critical issues. Using an immunocompetent murine K7M2-luc lung metastases model, the efficacy of MYXV armed with murine LIGHT (TNFSF14/CD258) expressed under virus-specific early/late promoter was tested in an advanced later-stage disease K7M2-luc model. Results in this model show that mLIGHT-armed MYXV, delivered systemically using ex vivo pre-loaded PBMCs as carrier cells, reduced tumor burden and increased median survival time. In vitro, when comparing direct infection of K7M2-luc cancer cells with free MYXV vs. PBMC-loaded virus, vMyx-mLIGHT/PBMCs also demonstrated greater cytotoxic capacity against the K7M2 cancer cell targets. In vivo, systemically delivered vMyx-mLIGHT/PBMCs increased viral reporter transgene expression levels both in the periphery and in lung tumors compared to unarmed MYXV, in a tumor- and transgene-dependent fashion. We conclude that vMyx-mLIGHT, especially when delivered using PBMC carrier cells, represents a new potential therapeutic strategy for solid cancers that metastasize to the lung.

Characterization of patient-derived bone marrow human mesenchymal stem cells as oncolytic virus carriers for the treatment of glioblastoma

2021 ◽  
pp. 1-11
Author(s):  
Yuzaburo Shimizu ◽  
Joy Gumin ◽  
Feng Gao ◽  
Anwar Hossain ◽  
Elizabeth J. Shpall ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Human Mesenchymal Stem Cells ◽  
Oncolytic Viruses ◽  
In Vivo Studies ◽  
Systemic Delivery ◽  
Previously Treated

OBJECTIVE Delta-24-RGD is an oncolytic adenovirus that is capable of replicating in and killing human glioma cells. Although intratumoral delivery of Delta-24-RGD can be effective, systemic delivery would improve its clinical application. Bone marrow–derived human mesenchymal stem cells (BM-hMSCs) obtained from healthy donors have been investigated as virus carriers. However, it is unclear whether BM-hMSCs can be derived from glioma patients previously treated with marrow-toxic chemotherapy or whether such BM-hMSCs can deliver oncolytic viruses effectively. Herein, the authors undertook a prospective clinical trial to determine the feasibility of obtaining BM-hMSCs from patients with recurrent malignant glioma who were previously exposed to marrow-toxic chemotherapy. METHODS The authors enrolled 5 consecutive patients who had been treated with radiation therapy and chemotherapy. BM aspirates were obtained from the iliac crest and were cultured to obtain BM-hMSCs. RESULTS The patient-derived BM-hMSCs (PD-BM-hMSCs) had a morphology similar to that of healthy donor–derived BM-hMSCs (HD-BM-hMSCs). Flow cytometry revealed that all 5 cell lines expressed canonical MSC surface markers. Importantly, these cultures could be made to differentiate into osteocytes, adipocytes, and chondrocytes. In all cases, the PD-BM-hMSCs homed to intracranial glioma xenografts in mice after intracarotid delivery as effectively as HD-BM-hMSCs. The PD-BM-hMSCs loaded with Delta-24-RGD (PD-BM-MSC-D24) effectively eradicated human gliomas in vitro. In in vivo studies, intravascular administration of PD-BM-MSC-D24 increased the survival of mice harboring U87MG gliomas. CONCLUSIONS The authors conclude that BM-hMSCs can be acquired from patients previously treated with marrow-toxic chemotherapy and that these PD-BM-hMSCs are effective carriers for oncolytic viruses.

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