scholarly journals Oncolytic Virotherapy with Myxoma Virus

2020 ◽  
Vol 9 (1) ◽  
pp. 171 ◽  
Author(s):  
Masmudur M. Rahman ◽  
Grant McFadden
Keyword(s):  
Cancer Cells ◽  
Myxoma Virus ◽  
Oncolytic Viruses ◽  
Oncolytic Virotherapy ◽  
Host Immune System ◽  
Cancer Therapies ◽  
Cancer Models ◽  
Cancer Types ◽  
Specific Antigens ◽  
The Many

Oncolytic viruses are one of the most promising novel therapeutics for malignant cancers. They selectively infect and kill cancer cells while sparing the normal counterparts, expose cancer- specific antigens and activate the host immune system against both viral and tumor determinants. Oncolytic viruses can be used as monotherapy or combined with existing cancer therapies to become more potent. Among the many types of oncolytic viruses that have been developed thus far, members of poxviruses are the most promising candidates against diverse cancer types. This review summarizes recent advances that are made with oncolytic myxoma virus (MYXV), a member of the Leporipoxvirus genus. Unlike other oncolytic viruses, MYXV infects only rabbits in nature and causes no harm to humans or any other non-leporid animals. However, MYXV can selectively infect and kill cancer cells originating from human, mouse and other host species. This selective cancer tropism and safety profile have led to the testing of MYXV in various types of preclinical cancer models. The next stage will be successful GMP manufacturing and clinical trials that will bring MYXV from bench to bedside for the treatment of currently intractable malignancies.

scholarly journals 716 Cell-based virotherapy for targeting cancers

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A758-A758
Author(s):  
Duong Nguyen ◽  
Alberto Gomez ◽  
Forrest Neuharth ◽  
Ashley Alamillo ◽  
Thomas Herrmann ◽  
...  
Keyword(s):  
Stem Cells ◽  
Vaccinia Virus ◽  
Cancer Cells ◽  
Neutralizing Antibodies ◽  
Immune Cell ◽  
Human Cancer ◽  
Oncolytic Viruses ◽  
Oncolytic Virotherapy ◽  
Adaptive Immune ◽  
Immune Barriers

BackgroundOncolytic virotherapy has been recognized as a promising new therapy for cancer for decades but only few viruses have been approved worldwide. The therapeutic potential of oncolytic viruses can be severely restricted by innate and adaptive immune barriers making oncolytic virus clinically inefficient. To overcome this obstacle, we utilized adipose-derived stem cells (AD-MSC) loaded with tumor selective CAL1 oncolytic vaccinia virus to generate a new therapeutic agent called SNV1 (SuperNova-1).MethodsCAL1 vaccinia virus was tested for its ability to replicate and selectively kill various human cancer cell lines in vitro and in vivo. Additionally, CAL1 was loaded into adipose-derived mesenchymal stem cells to generate SuperNova1 (SNV1). Both CAL1 and SNV1 were tested for their ability to kill cancer cells in the presence of active complement and neutralizing antibodies in cell culture as well as in mice. Immune cell infiltration of the treated and untreated tumors was analyzed by flow cytometry.ResultsCAL1 showed preferential amplification and killed various tested human (PC3, FaDu, MDA-MB-231, RPMI) and mouse cancer cells (CT26, EMT6, TRAMP-C2, RM1). In animals, CAL1 caused tumor regression in PC3 and CT26 mouse models without signs of toxicity. SNV1 significantly enhanced protection of CAL1 virus from clearance by the immune system as compared to naked CAL1 virus, leading to higher therapeutic efficacy in animals. Five days after SNV1 administration, tumor infiltrating lymphocytes (TILs) from both treated and untreated tumors showed increased CD4 and CD8 T-cell infiltrations. Importantly, we documented a decreased frequency of Tregs, and improved effector to Treg ratios, which was associated with inhibition of tumor growth at the treated tumor site and also at distant untreated sites.ConclusionsCAL1 is potentially used as an oncolytic agent. In addition, SNV1 cell-based platform protects and potentiates oncolytic vaccinia virus by circumventing humoral innate and adaptive immune barriers, resulting in enhanced oncolytic virotherapy. Particularly, SNV1 provided instantly active viral particles for immediate infection and simultaneous release of therapeutic proteins in the injected tumors.

scholarly journals Reeling in the Zebrafish Cancer Models

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Alicia M. McConnell ◽  
Haley R. Noonan ◽  
Leonard I. Zon
Keyword(s):  
Cancer Biology ◽  
Model Organism ◽  
Transgenic Animals ◽  
Annual Review ◽  
Transgenic Zebrafish ◽  
Publication Date ◽  
Cancer Therapies ◽  
Cancer Models ◽  
Cancer Types ◽  
New Cancer Therapies

Zebrafish are rapidly becoming a leading model organism for cancer research. The genetic pathways driving cancer are highly conserved between zebrafish and humans, and the ability to easily manipulate the zebrafish genome to rapidly generate transgenic animals makes zebrafish an excellent model organism. Transgenic zebrafish containing complex, patient-relevant genotypes have been used to model many cancer types. Here we present a comprehensive review of transgenic zebrafish cancer models as a resource to the field and highlight important areas of cancer biology that have yet to be studied in the fish. The ability to image cancer cells and niche biology in an endogenous tumor make zebrafish an indispensable model organism in which we can further understand the mechanisms that drive tumorigenesis and screen for potential new cancer therapies. Expected final online publication date for the Annual Review of Cancer Biology, Volume 5 is March 4, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Mathematical model of oncolytic virotherapy with Myxoma virus infection in cancer cells

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Sofia Ortegon ◽  
Lina S. Franco ◽  
Grant McFadden ◽  
Juan Cordovez
Keyword(s):  
Mathematical Model ◽  
Virus Infection ◽  
Cancer Cells ◽  
Myxoma Virus ◽  
Oncolytic Virotherapy

scholarly journals Oncolytic Viruses: Newest Frontier for Cancer Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5452
Author(s):  
Masmudur M. Rahman ◽  
Grant McFadden
Keyword(s):  
Clinical Trials ◽  
Immune Responses ◽  
Cancer Patient ◽  
Cancer Cells ◽  
Treatment Modality ◽  
Oncolytic Viruses ◽  
Oncolytic Virotherapy ◽  
Therapeutic Approaches ◽  
Cancer Treatments ◽  
The Past

Cancer remains a leading cause of death worldwide. Despite many signs of progress, currently available cancer treatments often do not provide desired outcomes for too many cancers. Therefore, newer and more effective therapeutic approaches are needed. Oncolytic viruses (OVs) have emerged as a novel cancer treatment modality, which selectively targets and kills cancer cells while sparing normal ones. In the past several decades, many different OV candidates have been developed and tested in both laboratory settings as well as in cancer patient clinical trials. Many approaches have been taken to overcome the limitations of OVs, including engineering OVs to selectively activate anti-tumor immune responses. However, newer approaches like the combination of OVs with current immunotherapies to convert “immune-cold” tumors to “immune-hot” will almost certainly improve the potency of OVs. Here, we discuss strategies that are explored to further improve oncolytic virotherapy.

scholarly journals Canine Adipose-Derived Mesenchymal Stem Cells (cAdMSCs) as a “Trojan Horse” in Vaccinia Virus Mediated Oncolytic Therapy against Canine Soft Tissue Sarcomas

Viruses ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 750
Author(s):  
Ivan Petrov ◽  
Ivaylo Gentschev ◽  
Anna Vyalkova ◽  
Mohamed I. Elashry ◽  
Michele C. Klymiuk ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Soft Tissue ◽  
Vaccinia Virus ◽  
Soft Tissue Sarcomas ◽  
Trojan Horse ◽  
Myxoma Virus ◽  
Oncolytic Viruses ◽  
Host Immune System ◽  
Oncolytic Therapy

Several oncolytic viruses (OVs) including various human and canine adenoviruses, canine distemper virus, herpes-simplex virus, reovirus, and members of the poxvirus family, such as vaccinia virus and myxoma virus, have been successfully tested for canine cancer therapy in preclinical and clinical settings. The success of the cancer virotherapy is dependent on the ability of oncolytic viruses to overcome the attacks of the host immune system, to preferentially infect and lyse cancer cells, and to initiate tumor-specific immunity. To date, several different strategies have been developed to overcome the antiviral host defense barriers. In our study, we used canine adipose-derived mesenchymal stem cells (cAdMSCs) as a “Trojan horse” for the delivery of oncolytic vaccinia virus Copenhagen strain to achieve maximum oncolysis against canine soft tissue sarcoma (CSTS) tumors. A single systemic administration of vaccinia virus-loaded cAdMSCs was found to be safe and led to the significant reduction and substantial inhibition of tumor growth in a CSTS xenograft mouse model. This is the first example that vaccinia virus-loaded cAdMSCs could serve as a therapeutic agent against CSTS tumors.

595 Armed myxoma virus demonstrates efficacy in syngeneic tumor models alone and in combination with immune checkpoint inhibitors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A630-A630
Author(s):  
Lina Franco ◽  
Lino Torres-Dominguez ◽  
Joseph Mamola ◽  
Ana de Matos ◽  
Mario Abrantes ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Therapeutic Option ◽  
Myxoma Virus ◽  
Oncolytic Viruses ◽  
In Vivo Models ◽  
Cancer Models ◽  
Oncolytic Activity

BackgroundOncolytic Viruses (OV) selectively replicate in and lyse tumor cells and provide stimulation to the immune system. This represents a promising therapeutic option for cancer patients that do not respond well to treatment with immune checkpoint inhibitors. Myxoma virus (MYXV) is a member of the Poxv family of double stranded DNA viruses. The natural host of MYXV is a subset of rabbits and hares, but MYXV can infect cancer cell lines of humans and other species. The genome of MYXV is relatively large and is amenable to engineering for expression of transgenes making it an excellent oncolytic virus for introduction of immunomodulatory proteins.MethodsArmed MYXV were tested for oncolytic activity and transgene production in syngeneic mouse cancer models in vitro and in vivo. In vivo models were further assessed for activity when in combination with immune checkpoint inhibitors and for immune mechanisms of action contributing to the efficacy of armed MYXV.ResultsArmed MYXV demonstrated oncolytic activity, transgene production capability and in vivo activity following intratumoral and intravenous administration of armed myxoma viruses in murine cancer models. Additional combination therapy with clinically relevant immune checkpoint inhibitors is demonstrated.ConclusionsArmed Myxoma viruses present an efficacious novel oncolytic viral therapy with the ability to modulate immune responses in murine cancer models.Ethics ApprovalAnimal studies we approved by OncoMyx and the TD2 IACUC.

scholarly journals Oncolytic Virotherapy for Hematological Malignancies

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Swarna Bais ◽  
Eric Bartee ◽  
Masmudur M. Rahman ◽  
Grant McFadden ◽  
Christopher R. Cogle
Keyword(s):  
Cancer Cells ◽  
Progenitor Cells ◽  
Measles Virus ◽  
Hematological Malignancies ◽  
Ex Vivo ◽  
Myxoma Virus ◽  
Oncolytic Viruses ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells

Hematological malignancies such as leukemias, lymphomas, multiple myeloma (MM), and the myelodysplastic syndromes (MDSs) primarily affect adults and are difficult to treat. For high-risk disease, hematopoietic stem cell transplant (HCT) can be used. However, in the setting of autologous HCT, relapse due to contamination of the autograft with cancer cells remains a major challenge.Ex vivomanipulations of the autograft to purge cancer cells using chemotherapies and toxins have been attempted. Because these past strategies lack specificity for malignant cells and often impair the normal hematopoietic stem and progenitor cells, prior efforts toex vivopurge autografts have resulted in prolonged cytopenias and graft failure. The idealex vivopurging agent would selectively target the contaminating cancer cells while spare normal stem and progenitor cells and would be applied quickly without toxicities to the recipient. One agent which meets these criteria is oncolytic viruses. This paper details experimental progress with reovirus, myxoma virus, measles virus, vesicular stomatitis virus, coxsackievirus, and vaccinia virus as well as requirements for translation of these results to the clinic.

Cancer Treatment with Liposomes Based Drugs and Genes Co-delivery Systems

2018 ◽  
Vol 25 (28) ◽  
pp. 3319-3332 ◽  
Author(s):  
Chuanmin Zhang ◽  
Shubiao Zhang ◽  
Defu Zhi ◽  
Jingnan Cui
Keyword(s):  
Cell Cycle ◽  
Cancer Cells ◽  
Synergistic Effects ◽  
Resistance Mechanisms ◽  
Delivery Systems ◽  
Cell Cycle Checkpoints ◽  
Drug Efflux ◽  
Cancer Resistance ◽  
Cancer Models ◽  
Anti Cancer

There are several mechanisms by which cancer cells develop resistance to treatments, including increasing anti-apoptosis, increasing drug efflux, inducing angiogenesis, enhancing DNA repair and altering cell cycle checkpoints. The drugs are hard to reach curative effects due to these resistance mechanisms. It has been suggested that liposomes based co-delivery systems, which can deliver drugs and genes to the same tumor cells and exhibit synergistic anti-cancer effects, could be used to overcome the resistance of cancer cells. As the co-delivery systems could simultaneously block two or more pathways, this might promote the death of cancer cells by sensitizing cells to death stimuli. This article provides a brief review on the liposomes based co-delivery systems to overcome cancer resistance by the synergistic effects of drugs and genes. Particularly, the synergistic effects of combinatorial anticancer drugs and genes in various cancer models employing multifunctional liposomes based co-delivery systems have been discussed. This review also gives new insights into the challenges of liposomes based co-delivery systems in the field of cancer therapy, by which we hope to provide some suggestions on the development of liposomes based co-delivery systems.

Potential of Mesenchymal Stem Cells in Anti-Cancer Therapies

2020 ◽  
Vol 15 (6) ◽  
pp. 482-491 ◽  
Author(s):  
Milena Kostadinova ◽  
Milena Mourdjeva
Keyword(s):  
Cancer Cells ◽  
Small Population ◽  
Tumor Formation ◽  
Bioactive Molecules ◽  
Cancer Therapies ◽  
New Methods ◽  
Cycle Arrest ◽  
Anti Cancer ◽  
Blocking Mechanisms

Mesenchymal stem/stromal cells (MSCs) are localized throughout the adult body as a small population in the stroma of the tissue concerned. In injury, tissue damage, or tumor formation, they are activated and leave their niche to migrate to the site of injury, where they release a plethora of growth factors, cytokines, and other bioactive molecules. With the accumulation of data about the interaction between MSCs and tumor cells, the dualistic role of MSCs remains unclear. However, a large number of studies have demonstrated the natural anti-tumor properties inherent in MSCs, so this is the basis for intensive research for new methods using MSCs as a tool to suppress cancer cell development. This review focuses specifically on advanced approaches in modifying MSCs to become a powerful, precision- targeted tool for killing cancer cells, but not normal healthy cells. Suppression of tumor growth by MSCs can be accomplished by inducing apoptosis or cell cycle arrest, suppressing tumor angiogenesis, or blocking mechanisms mediating metastasis. In addition, the chemosensitivity of cancer cells may be increased so that the dose of the chemotherapeutic agent used could be significantly reduced.

scholarly journals Generation of a Novel Mesothelin-Targeted Oncolytic Herpes Virus and Implemented Strategies for Manufacturing

2021 ◽  
Vol 22 (2) ◽  
pp. 477
Author(s):  
Guendalina Froechlich ◽  
Chiara Gentile ◽  
Luigia Infante ◽  
Carmen Caiazza ◽  
Pasqualina Pagano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Reproductive System ◽  
Tumor Cell Line ◽  
Breast Tumors ◽  
Oncolytic Viruses ◽  
Female Reproductive System ◽  
Viral Glycoprotein ◽  
Preclinical Development ◽  
Biological Drugs

Background: HER2-based retargeted viruses are in advanced phases of preclinical development of breast cancer models. Mesothelin (MSLN) is a cell-surface tumor antigen expressed in different subtypes of breast and non-breast cancer. Its recent identification as a marker of some triple-negative breast tumors renders it an attractive target, presently investigated in clinical trials employing antibody drug conjugates and CAR-T cells. The availability of MSLN-retargeted oncolytic viruses may complement the current immunotherapeutic panel of biological drugs against HER2-negative breast and non-breast tumors. Methods: A fully virulent, tumor-targeted oncolytic Herpes simplex virus-1 (MSLN-THV) with a selectivity for mesothelin-expressing cancer cells was generated. Recombineering technology was used to replace an essential moiety of the viral glycoprotein D with antibody fragments derived from clinically validated MSLN monoclonal antibodies, and to allow IL12 cargo expression in infected cells. Panels of breast and female reproductive system cell lines were used to verify the oncolytic potential of the viral constructs. A platform for production of the retargeted viruses was developed in HEK 293 cells, providing stable expression of a suitable chimeric receptor. Results: We demonstrated the selectivity of viral infection and cytotoxicity by MSLN-retargeted viruses in a panel of mesothelin-positive cancer cells, originating from breast and female reproductive system tumors. We also developed a second-generation oncolytic MSLN-THV, encoding IL12, to enhance the immunotherapeutic potential of the viral backbone. A non-tumor cell line expressing a chimeric MSLN/Nectin-1 receptor, de-sensitized from antiviral responses by genetic inactivation of the Stimulator of Interferon Genes (STING)-dependent pathway was engineered, to optimize viral yields. Conclusions: Our proof-of-concept study proposes MSLN-retargeted herpesviruses as potential cancer immunotherapeutics for assessments in preclinical models of MSLN-positive tumors, complementing the available panel of oncolytic viruses to HER2-negative breast tumors.

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