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.

A cell-based platform to potentiate oncolytic virus: Potential approach for cancer therapies.

2020 ◽  
Vol 38 (5_suppl) ◽  
pp. 21-21
Author(s):  
Duong Nguyen ◽  
Alberto Gomez ◽  
Ashley Alamillo ◽  
Forrest Neuharth ◽  
Ivelina Minev ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Vaccinia Virus ◽  
Cell Lines ◽  
Cancer Cell ◽  
Therapeutic Potential ◽  
Cancer Cell Lines ◽  
Oncolytic Viruses ◽  
Oncolytic Virotherapy ◽  
Adaptive Immune ◽  
Immune Barriers

21 Background: Oncolytic virotherapy has been pursued by multiple companies and institutions with few candidates reaching the clinic and demonstrating limited efficacy. The therapeutic potential of oncolytic viruses can be severely restricted by innate and adaptive immune barriers. To overcome this obstacle, we load and protect tumor selective CAL1 oncolytic vaccinia virus into adipose-derived stem cells (AD-MSC) to generate a new therapeutic agent called SNV1(SuperNova1). Methods: SNV1s were generated by incubating AD-MSC with CAL1 virus. SNV1 was analyzed for its ability to kill cancer cell lines and protect virus in the presence of active neutralizing antibodies and complement. In animals, SNV1 was intratumorally injected in various xenograft and syngeneic models. Viral biodistribution was also evaluated by PCR. Immune infiltration were analyzed using flow cytometry. Results: Compared to the naked virus, SNV1 showed improved protection against the humoral barriers and efficient eradication of various human cancer cell lines in vitro. Intratumoral SNV1 treatment showed statistically significant and potentiated tumor growth inhibition compared to control or CAL1 naked virus treatment in all tested models (prostate, breast, melanoma, colon, and prostate cancers). Importantly, local administration of SNV1 induced systemic therapeutic effects. Five days after SNV1 administration, tumor infiltrating lymphocytes (TILs) from both treated and untreated tumors showed increased CD4 and CD8 T-cell populations. As well as 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. Ongoing and persistent virus infection could be detected in the treated tumor as late as 15 days after administration. Conclusions: This study demonstrates the ability of our cell-based platform to protect and potentiate oncolytic vaccinia virus by circumventing the innate and adaptive immune barriers, resulting in enhanced oncolytic virotherapy. These findings provide fundamental rationale for the development of cell-based platforms to maximize the therapeutic potential of various oncolytic viruses.

scholarly journals Correction to: Delivery of oncolytic vaccinia virus by matched allogeneic stem cells overcomes critical innate and adaptive immune barriers

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Dobrin D. Draganov ◽  
Antonio F. Santidrian ◽  
Ivelina Minev ◽  
Duong Nguyen ◽  
Mehmet Okyay Kilinc ◽  
...  
Keyword(s):  
Stem Cells ◽  
Vaccinia Virus ◽  
Adaptive Immune ◽  
Immune Barriers

An amendment to this paper has been published and can be accessed via the original article.

scholarly journals Delivery of oncolytic vaccinia virus by matched allogeneic stem cells overcomes critical innate and adaptive immune barriers

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Dobrin D. Draganov ◽  
Antonio F. Santidrian ◽  
Ivelina Minev ◽  
Duong Nguyen ◽  
Mehmet Okyay Kilinc ◽  
...  
Keyword(s):  
Stem Cells ◽  
Vaccinia Virus ◽  
Adaptive Immune ◽  
Immune Barriers

scholarly journals Development of intravenously administered synthetic RNA virus immunotherapy for the treatment of cancer

2021 ◽  
Author(s):  
Edward Kennedy ◽  
Agnieszka Denslow ◽  
Jacqueline Hewett ◽  
Lingxin Kong ◽  
Ana De Almeida ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Immune Cell ◽  
Rna Virus ◽  
Neutralizing Antibody ◽  
Repeated Administration ◽  
Oncolytic Viruses ◽  
Drug Candidates ◽  
Novel Approach ◽  
Coxsackievirus A21 ◽  
Anti Tumor Activity

Abstract Oncolytic viruses (OVs) are an emerging therapeutic approach for the treatment of cancer. Clinical benefit has been demonstrated for intratumoral administration, but the therapeutic effectiveness of intravenous delivery has been limited by neutralizing antibody responses against the virus. To circumvent this limitation, we developed Synthetic RNA viruses, a novel approach for intravenous and repeated administration of OVs, consisting of a viral RNA genome (vRNA) formulated within lipid nanoparticles. For two Synthetic RNA virus drug candidates, Seneca Valley virus (SVV) and Coxsackievirus A21 (CVA21), we demonstrate vRNA delivery, viral replication, spread, and lysis of tumor cells leading to potent anti-tumor efficacy, even in the presence of OV neutralizing antibodies in the bloodstream. Synthetic-SVV replication in tumors promoted immune cell infiltration and enhanced anti-tumor activity in combination with anti-PD-1 checkpoint inhibitor. Altogether, the Synthetic RNA virus platform provides an innovative approach that enables repeat intravenous administration of viral immunotherapy.

scholarly journals TMIC-57. PRO-TUMORAL EFFECTS OF INTRA-TUMORAL NEUTROPHILS IN THE GLIOBLASTOMA MICROENVIRONMENT

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi260-vi260
Author(s):  
Sumedh Shah ◽  
Garima Yagnik ◽  
Alan Nguyen ◽  
Harsh Wadhwa ◽  
Jordan Spatz ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Neutralizing Antibodies ◽  
Immune Cell ◽  
Flow Cytometric Analysis ◽  
Leukotriene B4 ◽  
Low Grade ◽  
Stem Cell Markers ◽  
Perivascular Niche ◽  
Migration Assay

Abstract While macrophage enrichment and lymphocyte depletion have been described in glioblastoma, intratumoral neutrophils and their effect on glioblastoma have been under-characterized. While tumor-associated neutrophils (TANs) were initially regarded as passive bystanders due to their short-lived nature, investigation of TANs in other cancer types revealed pro-tumoral roles. Therefore, we sought to characterize TANs in the glioblastoma microenvironment using transcriptomic analysis and define their oncologic effects. Flow cytometric analysis of patient samples for neutrophils (CD11b+/CD15+/CD66b+) revealed higher percentages of TANs in glioblastoma compared to low-grade gliomas (1.76% [n=13] vs. 0.33% [n=6], p=0.03). Using the Transwell migration assay with glioblastoma tumor conditioned-media (CM), we found that recruitment of circulating neutrophils to tumor sites is mediated by leukotriene-B4 chemoattraction and that this interaction can be blocked with the addition of LtB4 receptor antagonist, LY293111. TANs were morphologically activated, unlike circulating neutrophils from GBM patients (P< 0.05) and, while not intravascular, were close to blood vessels. We performed single-cell RNA sequencing of isolated TANs and found a distinct transcriptomic profile relative to circulating neutrophils from these patients, particularly upregulated osteopontin. Osteopontin concentration was significantly higher in TAN CM than in patient-matched peripheral blood neutrophil CM (3.2ng/mL [n=3] vs. 0.02ng/mL [n=3], p< 0.05). Because osteopontin is linked to GBM stem cell-like phenotype maintenance and TANs localized to the perivascular niche where GBM stem cells reside, we investigated TAN-GBM stem cell interactions and osteopontin as a potential mediator. We found TAN CM increased proliferation and stem cell markers (Nanog, Oct4, Sox2) of stem cell-containing GBM neurospheres (p< 0.01). These effects were blocked by osteopontin-neutralizing antibodies (p< 0.01). Our work defines neutrophil-mediated pro-tumoral effects and their mechanisms and identifies a novel approach to target GBM stem cells—by disrupting the immune cell mediators that create their supportive microenvironment in the perivascular niche.

scholarly journals Chimeric antigen receptors that trigger phagocytosis

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Meghan A Morrissey ◽  
Adam P Williamson ◽  
Adriana M Steinbach ◽  
Edward W Roberts ◽  
Nadja Kern ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Immune Cell ◽  
Human Cancer ◽  
Antibody Fragment ◽  
Cell Number ◽  
Antigen Receptors ◽  
Chimeric Antigen Receptors ◽  
Cell Therapies ◽  
Human Cancer Cells

Chimeric antigen receptors (CARs) are synthetic receptors that reprogram T cells to kill cancer. The success of CAR-T cell therapies highlights the promise of programmed immunity and suggests that applying CAR strategies to other immune cell lineages may be beneficial. Here, we engineered a family of Chimeric Antigen Receptors for Phagocytosis (CAR-Ps) that direct macrophages to engulf specific targets, including cancer cells. CAR-Ps consist of an extracellular antibody fragment, which can be modified to direct CAR-P activity towards specific antigens. By screening a panel of engulfment receptor intracellular domains, we found that the cytosolic domains from Megf10 and FcRɣ robustly triggered engulfment independently of their native extracellular domain. We show that CAR-Ps drive specific engulfment of antigen-coated synthetic particles and whole human cancer cells. Addition of a tandem PI3K recruitment domain increased cancer cell engulfment. Finally, we show that CAR-P expressing murine macrophages reduce cancer cell number in co-culture by over 40%.

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 Viability Reduction andRac1Gene Downregulation of HeterogeneousEx-VivoGlioma Acute Slice Infected by the Oncolytic Newcastle Disease Virus Strain V4UPM

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Zulkifli Mustafa ◽  
Hilda Shazana Shamsuddin ◽  
Aini Ideris ◽  
Rohaya Ibrahim ◽  
Hasnan Jaafar ◽  
...  
Keyword(s):  
Newcastle Disease Virus ◽  
Cancer Cells ◽  
Disease Virus ◽  
Newcastle Disease ◽  
Cell Cycle Progression ◽  
Ex Vivo ◽  
Human Cancer ◽  
Significant Inhibition ◽  
Oncolytic Viruses ◽  
Tissue Viability

Oncolytic viruses have been extensively evaluated for anticancer therapy because this virus preferentially infects cancer cells without interfering with normal cells. Newcastle Disease Virus (NDV) is an avian virus and one of the intensively studied oncolytic viruses affecting many types of cancer including glioma. Nevertheless, the capability of NDV infection on heterogeneous glioma tissue in a cerebrospinal fluid atmosphere has never been reported. Recently,Rac1is reported to be required for efficient NDV replication in human cancer cells and established a link between tumourigenesis and sensitivity to NDV.Rac1is a member of the Rho GTPases involved in the regulation of the cell migration and cell-cycle progression.Rac1knockdown leads to significant inhibition of viral replication. In this work, we demonstrated that NDV treatment led to significant reduction of tumour tissue viability of freshly isolated heterogeneous human brain tumour slice, known as anex vivo glioma acute slice(EGAS). Analysis of gene expression indicated that reduced tissue viability was associated with downregulation ofRac1. However, the viability reduction was not persistent. We conclude that NDV treatment induced EGAS viability suppression, but subsequent downregulation ofRac1gene may reduce the NDV replication and lead to regrowth of EGAS tissue.

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.

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