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 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 Distinct cellular immune signatures in acute Zika virus infection are associated with high or low persisting neutralizing antibody titers

2021 ◽  
Author(s):  
Elizabeth E. McCarthy ◽  
Pamela M. Odorizzi ◽  
Emma Lutz ◽  
Carolyn P. Smullin ◽  
Iliana Tenvooren ◽  
...  
Keyword(s):  
Zika Virus ◽  
Neutralizing Antibodies ◽  
Viral Infections ◽  
Immune Cell ◽  
Acute Infection ◽  
Neutralizing Antibody ◽  
Natural Immunity ◽  
Zikv Infection ◽  
Antibody Titers ◽  
Cellular Immune

Although the formation of a durable neutralizing antibody response after an acute viral infection is a key component of protective immunity, little is known about why some individuals generate high versus low neutralizing antibody titers to infection or vaccination. Infection with Zika virus (ZIKV) during pregnancy can cause devastating fetal outcomes, and efforts to understand natural immunity to this infection are essential for optimizing vaccine design. In this study, we leveraged the high-dimensional single-cell profiling capacity of mass cytometry (CyTOF) to deeply characterize the cellular immune response to acute and convalescent ZIKV infection in a cohort of blood donors in Puerto Rico incidentally found to be viremic during the 2015-2016 epidemic in the Americas. During acute ZIKV infection, we identified widely coordinated responses across innate and adaptive immune cell lineages. High frequencies of multiple activated innate immune subsets, as well as activated follicular helper CD4+ T cells and proliferating CD27-IgD- B cells, during acute infection were associated with high titers of ZIKV neutralizing antibodies at 6 months post-infection. On the other hand, low titers of ZIKV neutralizing antibodies were associated with immune features that suggested a cytotoxic-skewed immune "set-point." Our study offers insight into the cellular coordination of immune responses and identifies candidate cellular biomarkers that may offer predictive value in vaccine efficacy trials for ZIKV and other acute viral infections aimed at inducing high titers of neutralizing antibodies.

Dose escalation and pharmacodynamic study of intravenous adminstration of Reolysin, a live replication competent RNA virus in patients with advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3583-3583
Author(s):  
M. H. Ghalib ◽  
K. K. Desai ◽  
R. Gollamudi ◽  
I. Chaudhary ◽  
M. Einstein ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Rna Virus ◽  
Single Agent ◽  
Neutralizing Antibody ◽  
Viral Shedding ◽  
Activating Mutations ◽  
Anti Cancer ◽  
Activating Mutation ◽  
Anti Tumor Activity ◽  
Wall Mass

3583 Background: Reolysin is reovirus serotype 3 - Dearing strain, a double-stranded replication- competent RNA non-enveloped icosahedral virus. It induces cytopathic and anti-cancer effects in cells with an activating mutation in the ras proto-oncogene. Methods: This was a single center dose escalation trial of Reolysin administered intravenously every four weeks in doses ranging from 1X108 to 3X1010 tissue culture infective dose (TCID)50. Serum for neutralizing antibody, and serum, stool, saliva, and urine for viral shedding were collected. Tumor samples were analyzed for activating mutations in the ras and braf oncogenes. Results: Eighteen patients received 27 doses of Reolysin in 6 dose cohorts accomplishing a 300 fold dose escalation without a protocol-defined dose limiting toxicity. Drug related grade 2 toxicities included fatigue and fever (1 patient each). All patients developed neutralizing antibody during the course of the study. Viral shedding was observed in 6 patients [urine (5), serum (4), saliva (3), and stool (2)]. One patient with anthracycline and taxane refractory breast cancer experienced a partial response (PR) and her tumor had a mutation in the ras oncogene. Biopsy from a chest wall mass showed evidence of necrosis and viral replication by electron microscopy. The overall clinical benefit rate was 45% and appeared higher in patients with viral shedding (67%) than those without (33%). Conclusions: Reolysin administered as a one hour infusion on a monthly schedule is safe and well-tolerated even in multiple doses. Reolysin has anti-tumor activity as a single agent warranting further evaluation, including in combination with chemotherapy. Viral shedding may suggest intrapatient replication yielding a benefit and should be studied carefully in future studies. [Table: see text]

scholarly journals Antiviral antibody responses to systemic administration of an oncolytic RNA virus: the impact of standard concomitant anticancer chemotherapies

2021 ◽  
Vol 9 (7) ◽  
pp. e002673
Author(s):  
Victoria Roulstone ◽  
David Mansfield ◽  
Robert J Harris ◽  
Katie Twigger ◽  
Christine White ◽  
...  
Keyword(s):  
Antibody Response ◽  
Neutralizing Antibodies ◽  
Rna Virus ◽  
Single Agent ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Concomitant Treatment ◽  
Phase I Clinical Trials ◽  
Antiviral Antibody ◽  
The Impact

BackgroundOncolytic reovirus therapy for cancer induces a typical antiviral response to this RNA virus, including neutralizing antibodies. Concomitant treatment with cytotoxic chemotherapies has been hypothesized to improve the therapeutic potential of the virus. Chemotherapy side effects can include immunosuppression, which may slow the rate of the antiviral antibody response, as well as potentially make the patient more vulnerable to viral infection.MethodReovirus neutralizing antibody data were aggregated from separate phase I clinical trials of reovirus administered as a single agent or in combination with gemcitabine, docetaxel, carboplatin and paclitaxel doublet or cyclophosphamide. In addition, the kinetics of individual antibody isotypes were profiled in sera collected in these trials.ResultsThese data demonstrate preserved antiviral antibody responses, with only moderately reduced kinetics with some drugs, most notably gemcitabine. All patients ultimately produced an effective neutralizing antibody response.ConclusionPatients’ responses to infection by reovirus are largely unaffected by the concomitant drug treatments tested, providing confidence that RNA viral treatment or infection is compatible with standard of care treatments.

scholarly journals Distinct immune cell dynamics mark adverse events and antibody responses of SARS-CoV-2 mRNA vaccine

2021 ◽  
Author(s):  
Tomohiro Takano ◽  
Miwa Morikawa ◽  
Yu Adachi ◽  
Kiyomi Kabasawa ◽  
Nicolas Sax ◽  
...  
Keyword(s):  
Adverse Events ◽  
Neutralizing Antibodies ◽  
Immune Cell ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Vaccine Strategy ◽  
Cell Dynamics ◽  
Immune Correlates ◽  
Antibody Titers ◽  
Immune Profiling

Abstract Pfizer/BioNTec BNT162b2 mRNA vaccine robustly elicits neutralizing antibodies against SARS-CoV-2 in clinical trials and real-world settings. However, booster vaccinations are frequently associated with self-limited adverse events. Here, by applying a high-dimensional immune profiling approach to peripheral blood, we linked early vaccine-induced immune dynamics with adverse events and neutralizing antibody responses. The dynamics of two dendritic cell subsets (DC3s and AS-DCs) were identified as the specific correlates for adverse events; the combination of these cell dynamics stratified the vaccinees with severe reactogenicity, while the stratification did not affect the neutralizing antibody titers. Furthermore, the NKT-like cell dynamics that correlated with adverse events and antibody titers were accounted for distinct magnitudes of both events by sex and age. The identified immune correlates for adverse events and antibody responses may pave the way for a rational vaccine strategy for reducing the reactogenicity of mRNA vaccines without compromising the immunogenicity.

scholarly journals Models to inform neutralizing antibody therapy strategies during pandemics: the case of SARS-CoV-2

2021 ◽  
Vol 4 (1) ◽  
pp. 60-71
Author(s):  
Donovan Guttieres ◽  
Anthony J Sinskey ◽  
Stacy L Springs
Keyword(s):  
Value Chain ◽  
Neutralizing Antibodies ◽  
Resource Constraints ◽  
Antibody Therapy ◽  
Neutralizing Antibody ◽  
Epidemiological Data ◽  
Production Costs ◽  
Production Scale ◽  
Design And Optimization ◽  
Critical Components

Abstract Background Neutralizing antibodies (nAbs) against SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) can play an important role in reducing impacts of the COVID-19 pandemic, complementing ongoing public health efforts such as diagnostics and vaccination. Rapidly designing, manufacturing and distributing nAbs requires significant planning across the product value chain and an understanding of the opportunities, challenges and risks throughout. Methods A systems framework comprised of four critical components is presented to aid in developing effective end-to-end nAbs strategies in the context of a pandemic: (1) product design and optimization, (2) epidemiology, (3) demand and (4) supply. Quantitative models are used to estimate product demand using available epidemiological data, simulate biomanufacturing operations from typical bioprocess parameters and calculate antibody production costs to meet clinical needs under various realistic scenarios. Results In a US-based case study during the 9-month period from March 15 to December 15, 2020, the projected number of SARS-CoV-2 infections was 15.73 million. The estimated product volume needed to meet therapeutic demand for the maximum number of clinically eligible patients ranged between 6.3 and 31.5 tons for 0.5 and 2.5 g dose sizes, respectively. The relative production scale and cost needed to meet demand are calculated for different centralized and distributed manufacturing scenarios. Conclusions Meeting demand for anti-SARS-CoV-2 nAbs requires significant manufacturing capacity and planning for appropriate administration in clinical settings. MIT Center for Biomedical Innovation’s data-driven tools presented can help inform time-critical decisions by providing insight into important operational and policy considerations for making nAbs broadly accessible, while considering time and resource constraints.

scholarly journals Modulation of Autophagy by SARS-CoV-2: A Potential Threat for Cardiovascular System

2020 ◽  
Vol 11 ◽  
Author(s):  
Puneet Kaur Randhawa ◽  
Kaylyn Scanlon ◽  
Jay Rappaport ◽  
Manish K. Gupta
Keyword(s):  
Host Cell ◽  
Rna Virus ◽  
Clinical Manifestations ◽  
Cardiovascular Complications ◽  
Extracellular Proteases ◽  
Potential Threat ◽  
Surface Receptors ◽  
Drug Candidates ◽  
A Genome ◽  
Number Of Patients

Recently, we have witnessed an unprecedented increase in the number of patients suffering from respiratory tract illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The COVID-19 virus is a single-stranded positive-sense RNA virus with a genome size of ~29.9 kb. It is believed that the viral spike (S) protein attaches to angiotensin converting enzyme 2 cell surface receptors and, eventually, the virus gains access into the host cell with the help of intracellular/extracellular proteases or by the endosomal pathway. Once, the virus enters the host cell, it can either be degraded via autophagy or evade autophagic degradation and replicate using the virus encoded RNA dependent RNA polymerase. The virus is highly contagious and can impair the respiratory system of the host causing dyspnea, cough, fever, and tightness in the chest. This disease is also characterized by an abrupt upsurge in the levels of proinflammatory/inflammatory cytokines and chemotactic factors in a process known as cytokine storm. Certain reports have suggested that COVID-19 infection can aggravate cardiovascular complications, in fact, the individuals with underlying co-morbidities are more prone to the disease. In this review, we shall discuss the pathogenesis, clinical manifestations, potential drug candidates, the interaction between virus and autophagy, and the role of coronavirus in exaggerating cardiovascular complications.

scholarly journals SARS-CoV-2 vaccines strategies: a comprehensive review of phase 3 candidates

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Nikolaos C. Kyriakidis ◽  
Andrés López-Cortés ◽  
Eduardo Vásconez González ◽  
Alejandra Barreto Grimaldos ◽  
Esteban Ortiz Prado
Keyword(s):  
Neutralizing Antibodies ◽  
Large Scale ◽  
Vaccine Development ◽  
Rna Virus ◽  
Protein S ◽  
Effective Vaccine ◽  
Phase 3 ◽  
Vaccine Candidates ◽  
Advantages And Disadvantages ◽  
The World

AbstractThe new SARS-CoV-2 virus is an RNA virus that belongs to the Coronaviridae family and causes COVID-19 disease. The newly sequenced virus appears to originate in China and rapidly spread throughout the world, becoming a pandemic that, until January 5th, 2021, has caused more than 1,866,000 deaths. Hence, laboratories worldwide are developing an effective vaccine against this disease, which will be essential to reduce morbidity and mortality. Currently, there more than 64 vaccine candidates, most of them aiming to induce neutralizing antibodies against the spike protein (S). These antibodies will prevent uptake through the human ACE-2 receptor, thereby limiting viral entrance. Different vaccine platforms are being used for vaccine development, each one presenting several advantages and disadvantages. Thus far, thirteen vaccine candidates are being tested in Phase 3 clinical trials; therefore, it is closer to receiving approval or authorization for large-scale immunizations.

scholarly journals Neutralizing Antibody Therapeutics for COVID-19

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 628
Author(s):  
Aeron C. Hurt ◽  
Adam K. Wheatley
Keyword(s):  
High Risk ◽  
Neutralizing Antibodies ◽  
Controlled Trial ◽  
Antiviral Treatment ◽  
Severe Disease ◽  
Neutralizing Antibody ◽  
Supplemental Oxygen ◽  
European Medicines Agency ◽  
Global Public Health ◽  
Public Health Burden

The emergence of SARS-CoV-2 and subsequent COVID-19 pandemic has resulted in a significant global public health burden, leading to an urgent need for effective therapeutic strategies. In this article, we review the role of SARS-CoV-2 neutralizing antibodies (nAbs) in the clinical management of COVID-19 and provide an overview of recent randomized controlled trial data evaluating nAbs in the ambulatory, hospitalized and prophylaxis settings. Two nAb cocktails (casirivimab/imdevimab and bamlanivimab/etesevimab) and one nAb monotherapy (bamlanivimab) have been granted Emergency Use Authorization by the US Food and Drug Administration for the treatment of ambulatory patients who have a high risk of progressing to severe disease, and the European Medicines Agency has similarly recommended both cocktails and bamlanivimab monotherapy for use in COVID-19 patients who do not require supplemental oxygen and who are at high risk of progressing to severe COVID-19. Efficacy of nAbs in hospitalized patients with COVID-19 has been varied, potentially highlighting the challenges of antiviral treatment in patients who have already progressed to severe disease. However, early data suggest a promising prophylactic role for nAbs in providing effective COVID-19 protection. We also review the risk of treatment-emergent antiviral resistant “escape” mutants and strategies to minimize their occurrence, discuss the susceptibility of newly emerging SARS-COV-2 variants to nAbs, as well as explore administration challenges and ways to improve patient access.

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