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In 2020 en mei 2024 verschenen er nieuwe overzichtstudies (meta-analyses) die de waarde van vaccins gemaakt van het Newcastle Disease virus aantonen bij kankerpatiënten met verschillende vormen van vooral solide tumoren.
Het werkingsmechanisme van het Newcastle Disease virus is in feite redelijk eenvoudig. Het Newcastle Disease virus infecteert alleen kankercellen, dupliceert zichzelf daarna binnenin de kankercellen tot deze openbreken, zich in het lichaam verspreiden en de hoop is dan dat deze kankercellen aangepakt worden door het immuunsysteem.
Zie deze twee afbeeldingen hoe dit vaccin te werk gaat:
Newcastle disease virus (NDV) is een RNA-virus dat behoort tot de familie Paramyxoviridae. In de natuur infecteert NDV voornamelijk vogels, maar vormt het geen bedreiging voor de gezondheid van de mens. Meerdere onderzoeken hebben aangetoond dat NDV oncolytisch potentieel heeft vanwege zijn voorkeur voor infectie en replicatie in menselijke kankercellen, terwijl normale cellen worden gespaard. Naast zijn directe lytische effecten, triggert het virus zowel aangeboren als adaptieve immuunreacties. In diermodellen is aangetoond dat injectie van NDV in een tumor resulteert in een lokale ontsteking en de rekrutering van tumorspecifieke T-cellen, een effect dat verder kan worden versterkt door het gebruik van virussen die coderen voor immuunmodulerende liganden en door combinaties met anti-PD medicijnen. Eerste klinische onderzoeken met natuurlijk voorkomend NDV dat intraveneus wordt toegediend, toonden duurzame reacties aan bij een aantal soorten kanker. Voor abstract zie verderop in dit artikel.
The Application of Newcastle Disease Virus (NDV): Vaccine Vectors and Tumor Therapy.
is nog specifieker over het Newcastle Disease virus en de mogelijkheden van een vaccin binnen immuuntherapie. Zij schrijven over de v oordelen van het NDV virus het volgende o.a.:
Vergeleken met andere oncolytische virussen heeft NDV de volgende kenmerken:
(1) NDV bestaat uit een enkele negatieve streng die repliceert in het cytoplasma, en er is geen DNA-stadium in het replicatieproces. Cytoplasmatische replicatie betekent dat het virus onafhankelijk is van het DNA-replicatiemechanisme van de gastheercel, niet kan integreren met het gastheergenoom en niet recombineert met menselijke virussen.
(2) NDV heeft lage productiekosten, kan via verschillende routes worden toegediend en heeft weinig bijwerkingen.
(3) NDV kan worden geselecteerd om efficiënt te repliceren in tumoren en repliceert niet efficiënt in normale cellen van niet-aviaire gastheren. NDV-replicatie in tumorstamcellen en slapende tumorcellen wordt mogelijk niet beïnvloed door radiotherapie of chemotherapie omdat NDV-replicatie onafhankelijk is van celproliferatie .
(4) Naast het spelen van een directe oncolytische rol, kan NDV ook de activering van het immuunsysteem bevorderen en antitumoractiviteit uitoefenen.
In de publicaties van de verschillende genoemde studies staat nog heel veel meer maar is teveel om dat allemaal te vertalen.
Hier achtereenvolgens de abstracten van genoemde studies:
Newcastle Disease Virus at the Forefront of Cancer Immunotherapy
Newcastle disease virus (NDV) is an RNA virus belonging to the Paramyxoviridae family. In nature, NDV primarily infects birds, but poses no threat to human health. Multiple studies have demonstrated that NDV caries oncolytic potential due to its predilection for infection and replication in human cancer cells while sparing normal cells. In addition to its direct lytic effects, the virus triggers both innate and adaptive immune responses. In animal models, NDV injection into a tumor has been demonstrated to result in local inflammation and the recruitment of tumor-specific T cells, an effect that can be further potentiated through the use of viruses encoding immunomodulatory ligands and through combinations with immune checkpoint blockade. Initial clinical trials with naturally occurring NDV administered intravenously demonstrated durable responses across a number of cancer types. Clinical studies utilizing recombinant NDV in combination with immune checkpoint inhibitors are ongoing.
Abstract
Preclinical and clinical studies dating back to the 1950s have demonstrated that Newcastle disease virus (NDV) has oncolytic properties and can potently stimulate antitumor immune responses. NDV selectively infects, replicates within, and lyses cancer cells by exploiting defective antiviral defenses in cancer cells. Inflammation within the tumor microenvironment in response to NDV leads to the recruitment of innate and adaptive immune effector cells, presentation of tumor antigens, and induction of immune checkpoints. In animal models, intratumoral injection of NDV results in T cell infiltration of both local and distant non-injected tumors, demonstrating the potential of NDV to activate systemic adaptive antitumor immunity. The combination of intratumoral NDV with systemic immune checkpoint blockade leads to regression of both injected and distant tumors, an effect further potentiated by introduction of immunomodulatory transgenes into the viral genome. Clinical trials with naturally occurring NDV administered intravenously demonstrated durable responses across numerous cancer types. Based on these studies, further exploration of NDV is warranted, and clinical studies using recombinant NDV in combination with immune checkpoint blockade have been initiated.
Engineering Newcastle Disease Virus as an Oncolytic Vector for Intratumoral Delivery of Immune Checkpoint Inhibitors and Immunocytokines
Newcastle disease virus (NDV) is an attractive candidate for oncolytic immunotherapy due to its ability to replicate in tumor cells and potentially to overcome the inherently immunosuppressive nature of the tumor microenvironment. The advent of checkpoint blockade immunotherapy over the past few years represents a paradigm shift in cancer therapy. However, the prevalence of severe immune-related adverse events with CTLA4 and PD1 pathway blockade in clinical studies, especially in combination therapy groups, is a cause for concern. Immunotherapies with cytokines have also been extensively explored, but they have been associated with adverse events in clinical trials. Oncolytic vectors engineered to express checkpoint blockade antibodies and cytokines could provide an avenue for reducing the clinical toxicity associated with systemic therapy by concentrating the immunomodulatory payload at the site of disease. In this study, we engineered six different recombinant viruses: NDVs expressing checkpoint inhibitors (rNDV–anti-PD1 and rNDV–anti-PDL1); superagonists (rNDV–anti-CD28); and immunocytokines, where the antibodies are fused to an immunostimulatory cytokine, such as interleukin 12 (IL-12) (rNDV–anti-CD28–murine IL-12 [mIL-12], rNDV–anti-PD1–mIL-12, and rNDV–anti-PDL1–mIL-12). These six engineered viruses induced tumor control and survival benefits in both highly aggressive unilateral and bilateral B16-F10 murine melanoma models, indicative of an abscopal effect. The data represent a strong proof of concept on which further clinical evaluation could build.
IMPORTANCE Checkpoint inhibitor therapy has shown tremendous efficacy, but also frequent and often severe side effects—especially when multiple drugs of the class are used simultaneously. Similarly, many investigational immunotherapy agents, which have shown promise in animal models, have failed in clinical trials due to dose-limiting toxicity when administered systemically. This study utilized a murine melanoma model to evaluate the efficacy of intratumoral injections of recombinant NDVs engineered to express multiple immunotherapeutic proteins with well-documented side effects in humans. Our results indicate that intratumoral administration of these recombinant NDVs, particularly when combined with systemic CTLA4 checkpoint inhibition, exerts a robust effect in treated and nontreated tumors, indicative of a systemic antitumoral response. The intratumoral delivery of rNDVs expressing immunotherapeutic proteins may be an effective method of targeting the immune cell populations most relevant for antitumoral immunity and allowing us to restrict the use of systemic immunotherapy agents.
The Application of Newcastle Disease Virus (NDV): Vaccine Vectors and Tumor Therapy
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Abstract
Newcastle disease virus (NDV) is an avian pathogen with an unsegmented negative-strand RNA genome that belongs to the Paramyxoviridae family. While primarily pathogenic in birds, NDV presents no threat to human health, rendering it a safe candidate for various biomedical applications. Extensive research has highlighted the potential of NDV as a vector for vaccine development and gene therapy, owing to its transcriptional modularity, low recombination rate, and lack of a DNA phase during replication. Furthermore, NDV exhibits oncolytic capabilities, efficiently eliciting antitumor immune responses, thereby positioning it as a promising therapeutic agent for cancer treatment. This article comprehensively reviews the biological characteristics of NDV, elucidates the molecular mechanisms underlying its oncolytic properties, and discusses its applications in the fields of vaccine vector development and tumor therapy.
This work was supported by the 2115 Talent Development Program of China Agricultural University.
Author Contributions
Conceptualization, H.Y. and G.Z.; methodology, H.Y.; software, J.T.; validation, H.Y., J.Z. and G.Z.; formal analysis, H.Y. and J.T.; resources, G.Z.; writing—original draft preparation, H.Y., J.Z. and Y.Z.; writing—review and editing, H.Y., Y.Z. and G.Z.; funding acquisition, G.Z. All authors have read and agreed to the published version of the manuscript.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
Not applicable.
Conflicts of Interest
The authors declare no conflicts of interest.
Footnotes
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