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.

scholarly journals Myxoma Virus-Loaded Mesenchymal Stem Cells in Experimental Oncolytic Therapy of Murine Pulmonary Melanoma

2020 ◽  
Vol 18 ◽  
pp. 335-350
Author(s):  
Joanna Jazowiecka-Rakus ◽  
Aleksander Sochanik ◽  
Aleksandra Rusin ◽  
Agata Hadryś ◽  
Wojciech Fidyk ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Myxoma Virus ◽  
Oncolytic Therapy

scholarly journals Safety of an Oncolytic Myxoma Virus in Dogs with Soft Tissue Sarcoma

Viruses ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 398 ◽  
Author(s):  
Amy MacNeill ◽  
Kristen Weishaar ◽  
Bernard Séguin ◽  
Barbara Powers
Keyword(s):  
Soft Tissue ◽  
Human Cancer ◽  
Treatment Options ◽  
Safety Information ◽  
Soft Tissue Sarcomas ◽  
Myxoma Virus ◽  
Oncolytic Viruses ◽  
Multiple Time ◽  
Viral Dna ◽  
Multiple Time Points

Many oncolytic viruses that are efficacious in murine cancer models are ineffective in humans. The outcomes of oncolytic virus treatment in dogs with spontaneous tumors may better predict human cancer response and improve treatment options for dogs with cancer. The objectives of this study were to evaluate the safety of treatment with myxoma virus lacking the serp2 gene (MYXVΔserp2) and determine its immunogenicity in dogs. To achieve these objectives, dogs with spontaneous soft tissue sarcomas were treated with MYXVΔserp2 intratumorally (n = 5) or post-operatively (n = 5). In dogs treated intratumorally, clinical scores were recorded and tumor biopsies and swabs (from the mouth and virus injection site) were analyzed for viral DNA at multiple time-points. In all dogs, blood, urine, and feces were frequently collected to evaluate organ function, virus distribution, and immune response. No detrimental effects of MYXVΔserp2 treatment were observed in any canine cancer patients. No clinically significant changes in complete blood profiles, serum chemistry analyses, or urinalyses were measured. Viral DNA was isolated from one tumor swab, but viral dissemination was not observed. Anti-MYXV antibodies were occasionally detected. These findings provide needed safety information to advance clinical trials using MYXVΔserp2 to treat patients with cancer.

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 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 Improving Immunotherapy Efficacy in Soft-Tissue Sarcomas: A Biomarker Driven and Histotype Tailored Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Matthieu Roulleaux Dugage ◽  
Elise F. Nassif ◽  
Antoine Italiano ◽  
Rastislav Bahleda
Keyword(s):  
Soft Tissue ◽  
Immune Checkpoint ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Soft Tissue Sarcomas ◽  
Oncolytic Viruses ◽  
Cellular Therapies ◽  
M1 Macrophage ◽  
Synovial Sarcomas

Anti-PD-(L)1 therapies yield a disappointing response rate of 15% across soft-tissue sarcomas, even if some subtypes benefit more than others. The proportions of TAMs and TILs in their tumor microenvironment are variable, and this heterogeneity correlates to histotype. Tumors with a richer CD8+ T cell, M1 macrophage, and CD20+ cells infiltrate have a better prognosis than those infiltrated by M0/M2 macrophages and a high immune checkpoint protein expression. PD-L1 and CD8+ infiltrate seem correlated to response to immune checkpoint inhibitors (ICI), but tertiary lymphoid structures have the best predictive value and have been validated prospectively. Trials for combination therapies are ongoing and focus on the association of ICI with chemotherapy, achieving encouraging results especially with pembrolizumab and doxorubicin at an early stage, or ICI with antiangiogenics. A synergy with oncolytic viruses is seen and intratumoral talimogene laherpavec yields an impressive 35% ORR when associated to pembrolizumab. Adoptive cellular therapies are also of great interest in tumors with a high expression of cancer-testis antigens (CTA), such as synovial sarcomas or myxoid round cell liposarcomas with an ORR ranging from 20 to 50%. It seems crucial to adapt the design of clinical trials to histology. Leiomyosarcomas are characterized by complex genomics but are poorly infiltrated by immune cells and do not benefit from ICI. They should be tested with PIK3CA/AKT inhibition, IDO blockade, or treatments aiming at increasing antigenicity (radiotherapy, PARP inhibitors). DDLPS are more infiltrated and have higher PD-L1 expression, but responses to ICI remain variable across clinical studies. Combinations with MDM2 antagonists or CDK4/6 inhibitors may improve responses for DDLPS. UPS harbor the highest copy number alterations (CNA) and mutation rates, with a rich immune infiltrate containing TLS. They have a promising 15-40% ORR to ICI. Trials for ICB should focus on immune-high UPS. Association of ICI with FGFR inhibitors warrants further exploration in the immune-low group of UPS. Finally translocation-related sarcomas are heterogeneous, and although synovial sarcomas a poorly infiltrated and have a poor response rate to ICI, ASPS largely benefit from ICB monotherapy or its association with antiangiogenics agents. Targeting specific neoantigens through vaccine or adoptive cellular therapies is probably the most promising approach in synovial sarcomas.

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.

Mesenchymal Stem Cell Derived-Exosomes as Effective Factors in Reducing Cytokine Storm Symptoms of COVID-19

2021 ◽  
Vol 28 ◽  
Author(s):  
Amir Hossein Kheirkhah ◽  
Seyed Hossein Shahcheraghi ◽  
Malihe lotfi ◽  
Marzieh lotfi ◽  
Sanaz Raeisi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Immune System ◽  
Host Immune System ◽  
Cytokine Storm ◽  
Infection Transmission ◽  
Effective Factors ◽  
Different Types ◽  
Immune System Modulation

: Given that conventional therapies are ineffective for COVID-19, obtained exosomes from stem cells have been proposed as a sustainable and effective treatment. Exosomes are subsets with lengths between 30 and 100 nanometers, and they can be secreted by different cells. Exosomes are containing different types of miRNAs, mRNAs, and different proteins. The role of immune system modulation of exosomes of mesenchymal stem cells has been studied and confirmed in more than one study. Exosome miRNAs detect and reduce cytokines that cause cytokine storms such as IL-7, IL-2, IL-6, etc. These miRNAs include miR-21, miR-24, miR-124, miR-145, etc. The risks associated with treatment with exosomes from different cells are relatively small compared to other treatments because transplanted cells do not stimulate the host immune system and also has reduced infection transmission. Due to the ineffectiveness of existing drugs in reducing inflammation and preventing cytokine storms, the use of immune-boosting systems may be suggested as another way to control cytokine storm.

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.

Mesenchymal Stem Cell Differentiation Markers Shared with Soft Tissue Sarcomas

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4755-4755
Author(s):  
Stefan Wirths ◽  
Hans-Joerg Buehring ◽  
Lothar Kanz ◽  
Joerg T Hartmann ◽  
Hans-Georg Kopp
Keyword(s):  
Stem Cells ◽  
Soft Tissue ◽  
Expression Pattern ◽  
Cell Lines ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Soft Tissue Sarcomas ◽  
Stem Cell Differentiation ◽  
Antibody Panel

Abstract Malignant tumors are hypothesized to harbor small populations of self-renewing cancer stem cells. Targeting these cells may be the decisive step to overcome treatment resistance and achieve tumor eradication in cancer patients. Advanced soft tissue sarcomas (STS) are rare tumors with a dismal prognosis and a small number of systemic treatment options. STS may originate from mesenchymal stem cells (MSC); the latter have mainly been isolated from adult bone marrow (BM) as non-hematopoietic, self-renewing cells whose in vitro progeny comprises osteoblasts, chondroblasts, myocytes, and adipocytes. While in vitro expression profiles of MSC have been investigated extensively, the in vivo counterparts of MSC are still hypothetical. To target rare human cell BM populations including MSC, an exclusive antibody panel was developed. The target antigens include platelet-derived growth factor receptor-β (CD140b), HER-2/erbB2 (CD340), the recently described W8B2 antigen as well as several surface antigens identified by novel antibodies. To define the expression pattern of MSC-markers in STS, three STS cell lines were tested for expression of these antigens. In addition, snap-frozen primary STS sections were analyzed by immunohistochemistry using the same antibody panel. All cell lines revealed expression of selected markers including CD340, W8B2, and CD140b. Several MSC markers were restricted to a subpopulation of cells. In addition, leiomyosarcoma cells displayed a different expression pattern as compared to liposarcoma and Ewing’s sarcoma cells. Results of immunohistochemistry analysis of primary leiomyosarcoma tumor samples correlated strongly with expression patterns established by FACS analysis. However, important cytoarchitectural features regarding selected markers were revealed by immunohistochemistry: while primary leiomyosarcomas displayed uniform expression of W7C6, HEK3D6, CD10, and CD318, other markers such as CD34, W5C5, and 57D2 were expressed by tumor endothelia only. Moreover, a population of perivascular tumor cells was found to express the MSC-markers W4A5, W8B2, CD140b, W3D5, and W5C4. Novel MSC-markers are expressed by subpopulations in STS cell lines as well as in primary sarcoma tissue. Further studies on the functional significance of these phenotypical studies are underway and may help to identify novel specific targets recognizing the self-renewing STS-compartment.

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