&lt;em&gt;Ex Vivo&lt;/em&gt; Infection of Live Tissue with Oncolytic Viruses

Diallo, Jean-Simon; Roy, D.; Abdelbary, Hesham; Silva, Naomi De; Bell, John

doi:10.3791/2854-v

Cited by 3 publications

(3 citation statements)

References 3 publications

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“…We next aimed to evaluate the impact of TPF in ex vivo tissues to assess its potential in a more physiologically relevant setting and to assess its tumor selectivity, a feature that has been previously established for DMF [ 15 ]. Briefly, CT26.wt murine colon cancer cells were implanted subcutaneously in mice, and once the tumors had grown to approximately 1500 mm 3 these were harvested and cored for in vitro culture using uniform slices from a biopsy punch ( Figure 3 A) [ 23 ]. Samples from normal tissues including brain, spleen, and lung, were also similarly harvested.…”

Section: Resultsmentioning

confidence: 99%

Tepilamide Fumarate as a Novel Potentiator of Virus-Based Therapy

Alwithenani,

Arulanandam,

Wong

et al. 2024

Viruses

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Oncolytic virotherapy, using viruses such as vesicular stomatitis virus (VSVΔ51) and Herpes Simplex Virus-1 (HSV-1) to selectively attack cancer cells, faces challenges such as cellular resistance mediated by the interferon (IFN) response. Dimethyl fumarate (DMF) is used in the treatment of multiple sclerosis and psoriasis and is recognized for its anti-cancer properties and has been shown to enhance both VSVΔ51 and HSV-1 oncolytic activity. Tepilamide fumarate (TPF) is a DMF analog currently undergoing clinical trials for the treatment of moderate-to-severe plaque psoriasis. The aim of this study was to evaluate the potential of TPF in enhancing the effectiveness of oncolytic viruses. In vitro, TPF treatment rendered 786-0 carcinoma cells more susceptible to VSVΔ51 infection, leading to increased viral replication. It outperformed DMF in both increasing viral infection and increasing the killing of these resistant cancer cells and other cancer cell lines tested. Ex vivo studies demonstrated TPF’s selective boosting of oncolytic virus infection in cancer cells without affecting healthy tissues. Effectiveness was notably high in pancreatic and ovarian tumor samples. Our study further indicates that TPF can downregulate the IFN pathway through a similar mechanism to DMF, making resistant cancer cells more vulnerable to viral infection. Furthermore, TPF’s impact on gene therapy was assessed, revealing its ability to enhance the transduction efficiency of vectors such as lentivirus, adenovirus type 5, and adeno-associated virus type 2 across various cell lines. This data underscore TPF’s potential role in not only oncolytic virotherapy but also in the broader application of gene therapy. Collectively, these findings position TPF as a promising agent in oncolytic virotherapy, warranting further exploration of its therapeutic potential.

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Section: Resultsmentioning

confidence: 99%

Tepilamide Fumarate as a Novel Potentiator of Virus-Based Therapy

Alwithenani,

Arulanandam,

Wong

et al. 2024

Viruses

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“…Assays (in vitro viral replication) were performed on 3 independent samples, and each experiment (i.e., assay) was repeated twice (i.e., 3 experiments in total per sample); infected cells were used as control in all experiments. 26,31…”

Section: Infection Of Tumor Cells and Gastric Explantsmentioning

confidence: 99%

“…24 Given these limitations, the use of the explant culture method has been proposed as an ex vivo model that can provide more realistic results and offer more advantages in the preclinical evaluation of OVs. 25,26 However, it remains necessary to consider the current challenges of virotherapy for solid tumors, such as insufficient selectivity toward tumor cells; inability to penetrate and disseminate in the tumor mass; premature viral clearance; low oncolytic potency; and poor stimulation of tumor-specific immunity. 27 In addition, it should be noted that the efficacy of RV Wt1-5 has not been evaluated in an ex vivo explant model of solid tumors.…”

Section: Introductionmentioning

confidence: 99%

Cultivo de explantes de adenocarcinoma gástrico humano: Modelo para la evaluación de la actividad oncolítica del rotavirus Wt1-5

Sossa-Rojas,

Franco-Maz,

Zapata-Acevedo

et al. 2023

Rev. Fac. Med.

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Introducción. A nivel mundial, el cáncer gástrico es el quinto cáncer más comúnmente diagnosticado y la cuarta mayor causa de mortalidad por cáncer. Los virus oncolíticos son un agente terapéutico potencial para el cáncer. Objetivo. Evaluar la capacidad de penetración, la selectividad y la eficiencia oncolítica del rotavirus Wt1-5 mediante un modelo de infección ex vivo en muestras tumorales obtenidas de pacientes con diagnóstico de adenocarcinoma gástrico. Materiales y métodos. Estudio experimental de laboratorio realizado en explantes de adenocarcinoma gástricos de subtipo-difuso e intestinal recolectados en el Hospital Universitario de la Samaritana (Bogotá D.C., Colombia). Estos explantes se infectaron con el rotavirus Wt1-5 y, mediante pruebas inmunohistoquímicas, se evaluó su capacidad de penetración y difusión a través del microambiente tumoral, así como su potencial como virus oncolítico. Los datos se describen usando medias y desviaciones estándar. Además, se realizó un análisis bivariado mediante la prueba de U de Mann-Whitney para determinar las diferencias entre los datos de los ensayos evaluados y el control empleado en cada uno. Se consideró un nivel de significancia estadística de p <0.05. Resultados. A las 12 horas post infección (h.p.i) se observó que el rotavirus Wt1- se había diseminado en todas las capas del tumor, lo cual favoreció la infección de las células tumorales y generó necrosis del tejido tumoral a partir de las 48 h.p.i. Por otro lado, los tejidos no-tumorales adyacentes no mostraron evidencia de infección con este rotavirus, ni lisis tisular (p<0.05). Conclusiones. El cultivo de explantes es un modelo útil para estudiar y predecir el comportamiento infeccioso ex vivo. El rotavirus Wt1-5 infecta de manera selectiva y eficiente las células tumorales en explantes de adenocarcinoma gástrico, tanto del subtipo difuso como del subtipo intestinal.

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Preclinical evaluation of oncolytic potential human rotavirus Wt 1-5 in gastric adenocarcinoma

et al. 2023

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Despite advances in biomedical research, gastric cancer remains the leading cause of morbidity and mortality worldwide due to the limited efficacy of conventional therapies. In recent decades, oncolytic viruses have emerged as a biological therapeutic alternative to cancer due to their selectivity, effectiveness, and low toxicity. However, clinical trials have shown that developing a virus with selectivity for multiple tumor receptors and the ability to penetrate and diffuse through the tumor microenvironment to reactivate the immune system remains challenging. This study aimed to examine the oncolytic potential of tumor cell-adapted rotavirus Wt1-5 in gastric adenocarcinoma samples. This study focused on determining the propagation capacity of the RV Wt1-5 through the tumor and the importance of the expression of cell surface co-receptors, including integrin β3, protein disulfide isomerase (PDI), and heat shock proteins (Hsp-90, -70, -60, -40, and Hsc 70), during infection of tumor cells. These proteins were found to be differentially expressed in tumor cells compared to adjacent non-tumor cells. Preincubation of gastric tumor cells with antibodies against these proteins decreased rotavirus infections, validating their importance in the binding and entry of RV Wt1-5 into tumor cells, as previously reported. Upon RV infection, apoptosis was one of the types of death that was observed. This was evidenced by evaluating the expression of CASP-3, -9, PARP, cytochrome C, Bax, Bid, p53, and Bcl-2, as well as observing morphological changes such as chromatin margination, nuclear condensation, and fragmentation. Finally, at 60 h.p.i, histological analysis revealed that oncolysis compromised the entire thickness of the tumor. Therefore, the results suggest that RV Wt1-5 could be a novel therapeutic agent co-adjuvant agent for conventional and targeted therapies in managing GC. Ex vivo infection of the tumor tissue model showed characteristics of an immune response that could be explored in future studies.

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<em>Ex Vivo</em> Infection of Live Tissue with Oncolytic Viruses

Cited by 3 publications

References 3 publications

Tepilamide Fumarate as a Novel Potentiator of Virus-Based Therapy

Tepilamide Fumarate as a Novel Potentiator of Virus-Based Therapy

Cultivo de explantes de adenocarcinoma gástrico humano: Modelo para la evaluación de la actividad oncolítica del rotavirus Wt1-5

Preclinical evaluation of oncolytic potential human rotavirus Wt 1-5 in gastric adenocarcinoma

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