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EBioMedicine Jun 2024Pancreatic ductal adenocarcinoma (PDAC) is a tumour entity with unmet medical need. To assess the therapeutic potential of oncolytic virotherapy (OVT) against PDAC,...
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is a tumour entity with unmet medical need. To assess the therapeutic potential of oncolytic virotherapy (OVT) against PDAC, different oncolytic viruses (OVs) are currently investigated in clinical trials. However, systematic comparisons of these different OVs in terms of efficacy against PDAC and biomarkers predicting therapeutic response are lacking.
METHODS
We screened fourteen patient-derived PDAC cultures which reflect the intra- and intertumoural heterogeneity of PDAC for their sensitivity to five clinically relevant OVs, namely serotype 5 adenovirus Ad5-hTERT, herpes virus T-VEC, measles vaccine strain MV-NIS, reovirus jin-3, and protoparvovirus H-1PV. Live cell analysis, quantification of viral genome/gene expression, cell viability as well as cytotoxicity assays and titration of viral progeny were conducted. Transcriptome profiling was employed to identify potential predictive biomarkers for response to OV treatment.
FINDINGS
Patient-derived PDAC cultures showed individual response patterns to OV treatment. Twelve of fourteen cultures were responsive to at least one OV, with no single OV proving superior or inferior across all cultures. Known host factors for distinct viruses were retrieved as potential biomarkers. Compared to the classical molecular subtype, the quasi-mesenchymal or basal-like subtype of PDAC was found to be more sensitive to H-1PV, jin-3, and T-VEC. Generally, expression of viral entry receptors did not correlate with sensitivity to OV treatment, with one exception: Expression of Galectin-1 (LGALS1), a factor involved in H-1PV entry, positively correlated with H-1PV induced cell killing. Rather, cellular pathways controlling immunological, metabolic and proliferative signaling appeared to determine outcome. For instance, high baseline expression of interferon-stimulated genes (ISGs) correlated with relative resistance to oncolytic measles virus, whereas low cyclic GMP-AMP synthase (cGAS) expression was associated with exceptional response. Combination treatment of MV-NIS with a cGAS inhibitor improved tumour cell killing in several PDAC cultures and cells overexpressing cGAS were found to be less sensitive to MV oncolysis.
INTERPRETATION
Considering the heterogeneity of PDAC and the complexity of biological therapies such as OVs, no single biomarker can explain the spectrum of response patterns. For selection of a particular OV, PDAC molecular subtype, ISG expression as well as activation of distinct signaling and metabolic pathways should be considered. Combination therapies can overcome resistance in specific constellations. Overall, oncolytic virotherapy is a viable treatment option for PDAC, which warrants further development. This study highlights the need for personalised treatment in OVT. By providing all primary data, this study provides a rich source and guidance for ongoing developments.
FUNDING
German National Science Foundation (Deutsche Forschungsgemeinschaft, DFG), German Cancer Aid (Deutsche Krebshilfe), German National Academic Scholarship Foundation (Studienstiftung des deutschen Volkes), Survival with Pancreatic Cancer Foundation.
PubMed: 38941955
DOI: 10.1016/j.ebiom.2024.105219 -
Investigational New Drugs Jun 2024HCC is the most common fatal malignancy. Although surgical resection is the primary treatment strategy, most patients are not eligible for resection due to tumor...
HCC is the most common fatal malignancy. Although surgical resection is the primary treatment strategy, most patients are not eligible for resection due to tumor heterogeneity, underlying liver disease, or comorbidities. Therefore, this study explores the possibility of multi-molecular targeted drug delivery in treating HCC. In this study, we constructed the recombinant adenovirus co-expressing apoptin and melittin (MEL) genes. The inhibitory effect of the recombinant adenovirus on hepatocellular carcinoma cells was detected through experiments on cell apoptosis, migration, invasion, and other factors. The tumor inhibitory effect in vivo was assessed using subcutaneous HCC mice. Results showed that recombinant adenovirus co-expressing anti-tumor genes TAT and apoptin, RGD and MEL can significantly inhibit the proliferation, migration, and invasion of HCC cells by inducing an increase in reactive oxygen species (ROS) levels, upregulation of apoptotic proteins such as Bax, cleaved caspase-3, and cleaved caspase-9, and downregulation of the anti-apoptotic protein Bcl-2. In subcutaneous HCC mice, recombinant adenovirus induced significant apoptosis in tumor, and inhibited tumor growth. In conclusion, recombinant adenovirus co-expressing apoptin and MEL can inhibit the growth and proliferation of tumor cells both in vivo and in vitro.
PubMed: 38935191
DOI: 10.1007/s10637-024-01453-z -
Vaccines Jun 2024Though children infected by SARS-CoV-2 generally experience milder symptoms compared to adults, severe cases can occur. Additionally, children can transmit the virus to...
Immunogenicity, Safety, and Immune Persistence of One Dose of SARS-CoV-2 Recombinant Adenovirus Type-5 Vectored Vaccine in Children and Adolescents Aged 6-17 Years: An Immunobridging Trial.
BACKGROUND
Though children infected by SARS-CoV-2 generally experience milder symptoms compared to adults, severe cases can occur. Additionally, children can transmit the virus to others. Therefore, the availability of safe and effective COVID-19 vaccines for children and adolescents is crucial.
METHOD
A single-center, randomized, double-blind clinical trial was conducted in Funing County, Yancheng City, Jiangsu Province, China. Healthy children and adolescents were divided into two subgroups (6-12 years old or 13-17 years old) and randomly assigned to one of three groups to receive one dose of Ad5-nCoV (3 × 10 vp/dose). Another group, aged 18-59, received one dose of Ad5-nCoV (5 × 10 vp/dose) as the control group. At 28, 90, 180, and 360 days post-vaccination, we measured the geometric mean titer (GMT)/concentration (GMC) of neutralizing and binding antibodies against the prototype SARS-CoV-2 strain, as well as serum antibody levels against the BA.4/5 variant. We also evaluated the incidence of adverse events within 28 days post-vaccination.
RESULTS
A total of 2413 individuals were screened from 3 June 2021 to 25 July 2021, of whom 2021 eligible participants were enrolled, including 1009 aged 6~17 years in the children and adolescent group and 1012 aged 18-59 years in the adults group. The GMT of anti-wild SARS-CoV-2 neutralizing antibodies was 18.6 (95% CI, 16.6-20.9) in children and adolescents and 13.2 (95% CI, 11.6-15.0) in adults on day 28. The incidence of solicited adverse reactions between the adult group (49.4% [124/251]) and the children and adolescent group (46.3% [156/337]) was not statistically significant. The neutralizing antibody levels decreased by a factor of 3.29 from day 28 to day 360 post-vaccination.
CONCLUSIONS
A single dose of Ad5-nCoV at 3 × 10 virus particles/dose is safe in children and adolescents, and it elicited significant immune response, which was not only non-inferior but also superior to that in adults aged 18-59 years.
PubMed: 38932412
DOI: 10.3390/vaccines12060683 -
Vaccines Jun 2024Inactivated and live attenuated vaccines are the mainstays of preventing viral poultry diseases. However, the development of recombinant DNA technology in recent years... (Review)
Review
Inactivated and live attenuated vaccines are the mainstays of preventing viral poultry diseases. However, the development of recombinant DNA technology in recent years has enabled the generation of recombinant virus vector vaccines, which have the advantages of preventing multiple diseases simultaneously and simplifying the vaccination schedule. More importantly, some can induce a protective immune response in the presence of maternal antibodies and offer long-term immune protection. These advantages compensate for the shortcomings of traditional vaccines. This review describes the construction and characterization of primarily poultry vaccine vectors, including fowl poxvirus (FPV), fowl adenovirus (FAdV), Newcastle disease virus (NDV), Marek's disease virus (MDV), and herpesvirus of turkey (HVT). In addition, the pathogens targeted and the immunoprotective effect of different poultry recombinant virus vector vaccines are also presented. Finally, this review discusses the challenges in developing vector vaccines and proposes strategies for improving immune efficacy.
PubMed: 38932359
DOI: 10.3390/vaccines12060630 -
Vaccines Jun 2024The objective of this study was to conduct preclinical immunogenicity and efficacy studies with several therapeutic vaccines for human papillomavirus (HPV)-16-associated...
The objective of this study was to conduct preclinical immunogenicity and efficacy studies with several therapeutic vaccines for human papillomavirus (HPV)-16-associated cancers expressing the early antigens E5, E6, and E7 with or without E2. The viral oncoproteins were either expressed by themselves as fusion proteins or the fusion proteins were inserted genetically into herpes simplex virus (HSV)-1 glycoprotein D (gD) which, upon binding to the herpes virus entry mediator (HVEM), inhibits an early T cell checkpoint mediated by the B and T cell mediator (BTLA). This, in turn, lowers the threshold for T cell activation and augments and broadens CD8 T cell responses to the antigens. The fusion antigens were expressed by chimpanzee adenovirus (AdC) vectors. Expression of the HPV antigens within gD was essential for vaccine immunogenicity and efficacy against challenge with TC-1 cells, which express E7 and E6 of HPV-16 but neither E5 nor E2. Unexpectedly, inclusion of E2 increased both CD8 T cell responses to the other oncoproteins of HPV-16 and the effectiveness of the vaccines to cause the regression of sizable TC-1 tumors.
PubMed: 38932345
DOI: 10.3390/vaccines12060616 -
Viruses Jun 2024Pathogenic adenovirus (Ad) infections are widespread but typically mild and transient, except in the immunocompromised. As vectors for gene therapy, vaccine, and... (Review)
Review
Pathogenic adenovirus (Ad) infections are widespread but typically mild and transient, except in the immunocompromised. As vectors for gene therapy, vaccine, and oncology applications, Ad-based platforms offer advantages, including ease of genetic manipulation, scale of production, and well-established safety profiles, making them attractive tools for therapeutic development. However, the immune system often poses a significant challenge that must be overcome for adenovirus-based therapies to be truly efficacious. Both pre-existing anti-Ad immunity in the population as well as the rapid development of an immune response against engineered adenoviral vectors can have detrimental effects on the downstream impact of an adenovirus-based therapeutic. This review focuses on the different challenges posed, including pre-existing natural immunity and anti-vector immunity induced by a therapeutic, in the context of innate and adaptive immune responses. We summarise different approaches developed with the aim of tackling these problems, as well as their outcomes and potential future applications.
Topics: Humans; Adenoviridae; Genetic Vectors; Genetic Therapy; Adaptive Immunity; Animals; Immunity, Innate; Immune System; Adenoviridae Infections
PubMed: 38932265
DOI: 10.3390/v16060973 -
Microorganisms May 2024The highly conserved C129R protein of AFSV was utilized in the development of an ASFV recombinant adenovirus vaccine, demonstrating strong immunogenicity. In this study,...
The highly conserved C129R protein of AFSV was utilized in the development of an ASFV recombinant adenovirus vaccine, demonstrating strong immunogenicity. In this study, we immunized 6-week-old female C57BL/6J mice via subcutaneous injection with 10 μg of purified C129R protein. Humoral and cellular immune effects were assessed using ELISA, flow cytometry, and ELISpot assays. Additionally, 19 peptides of the C129R protein were synthesized and screened for the use of bioinformatics. Positive T-cell epitopes were screened using ELISpot. The results indicated a higher proportion of CD4+ and CD8+ T lymphocytes in immunized mice compared to control mice. ELISA analysis revealed a serum titer of approximately 1:1, 638, 400 in the experimental group of mice. Additionally, peptides C11, C14, C16, and C18 from the C129R protein were able to activate mice spleen lymphocytes to produce IFN-γ. These findings suggest that the C129R protein significantly enhances both humoral and cellular immunity in immunized mice. Moreover, peptides C11, C14, C16, and C18 may serve as potential T-cell epitopes for the C129R protein. These results lay the groundwork for the further exploration of ASFV C129R protein and the identification of novel ASF vaccine antigens.
PubMed: 38930438
DOI: 10.3390/microorganisms12061056 -
PLoS Pathogens Jun 2024Viral haemorrhagic fevers (VHF) pose a significant threat to human health. In recent years, VHF outbreaks caused by Ebola, Marburg and Lassa viruses have caused...
Viral haemorrhagic fevers (VHF) pose a significant threat to human health. In recent years, VHF outbreaks caused by Ebola, Marburg and Lassa viruses have caused substantial morbidity and mortality in West and Central Africa. In 2022, an Ebola disease outbreak in Uganda caused by Sudan virus resulted in 164 cases with 55 deaths. In 2023, a Marburg disease outbreak was confirmed in Equatorial Guinea and Tanzania resulting in over 49 confirmed or suspected cases; 41 of which were fatal. There are no clearly defined correlates of protection against these VHF, impeding targeted vaccine development. Any vaccine developed should therefore induce strong and preferably long-lasting humoral and cellular immunity against these viruses. Ideally this immunity should also cross-protect against viral variants, which are known to circulate in animal reservoirs and cause human disease. We have utilized two viral vectored vaccine platforms, an adenovirus (ChAdOx1) and Modified Vaccinia Ankara (MVA), to develop a multi-pathogen vaccine regime against three filoviruses (Ebola virus, Sudan virus, Marburg virus) and an arenavirus (Lassa virus). These platform technologies have consistently demonstrated the capability to induce robust cellular and humoral antigen-specific immunity in humans, most recently in the rollout of the licensed ChAdOx1-nCoV19/AZD1222. Here, we show that our multi-pathogen vaccines elicit strong cellular and humoral immunity, induce a diverse range of chemokines and cytokines, and most importantly, confers protection after lethal Ebola virus, Sudan virus and Marburg virus challenges in a small animal model.
PubMed: 38924060
DOI: 10.1371/journal.ppat.1012262 -
Nano Letters Jun 2024Enhancing the antitumor immune response and targeting ability of oncolytic viruses will improve the effect of tumor immunotherapy. Through infecting neural stem cells...
Enhancing the antitumor immune response and targeting ability of oncolytic viruses will improve the effect of tumor immunotherapy. Through infecting neural stem cells (NSCs) with a capsid dual-modified oncolytic adenovirus (CRAd), we obtained and characterized the "oncolytic extracellular vesicles" (CRAdEV) with improved targeted infection and tumor killing activity compared with CRAd. Both and studies revealed that CRAdEV activated innate immune cells and importantly enhanced the immunomodulatory effect compared to CRAd. We found that CRAdEV effectively increased the number of DCs and activated CD4 and CD8 T cells, significantly increased the number and activation of B cells, and produced higher levels of tumor-specific antibodies, thus eliciting enhanced antitumor activity compared with CRAd in a B16 xenograft immunocompetent mice model. This study provides a novel approach to oncolytic adenovirus modification and demonstrates the potential of "oncolytic extracellular vesicles" in antitumor immunotherapy.
PubMed: 38922640
DOI: 10.1021/acs.nanolett.4c02279 -
Pathogens (Basel, Switzerland) Jun 2024Enteric infections due to viral pathogens are a major public health concern. Detecting the risk areas requires a strong surveillance system for pathogenic viruses in...
Enteric infections due to viral pathogens are a major public health concern. Detecting the risk areas requires a strong surveillance system for pathogenic viruses in sources such as wastewater. Towards building an environmental surveillance system in Zambia, we aimed to identify group A rotavirus (RVA) and human adenovirus (HAdV) in wastewater. Convenient sampling was conducted at four study sites every Tuesday for five consecutive weeks. The research team focused on three different methods of viral concentration to determine the suitability in terms of cost and applicability for a regular surveillance system: the bag-mediated filtration system (BMFS), polyethylene glycol-based (PEG) precipitation, and skimmed milk (SM) flocculation. We screened 20 wastewater samples for HAdV and RVA using quantitative polymerase chain reaction (qPCR) and conventional polymerase chain reaction (cPCR). Of the 20 samples tested using qPCR, 18/20 (90%) tested positive for HAdV and 14/20 (70%) tested positive for RVA. For the genetic sequencing, qPCR positives were subjected to cPCR, of which 12 positives were successfully amplified. The human adenovirus was identified with a nucleotide identity range of 98.48% to 99.53% compared with the reference genome from GenBank. The BMFS and SM flocculation were the most consistent viral concentration methods for HAdV and RVA, respectively. A statistical analysis of the positives showed that viral positivity differed by site ( < 0.001). SM and PEG may be the most appropriate options in resource-limited settings such as Zambia due to the lower costs associated with these concentration methods. The demonstration of HAdV and RVA detection in wastewater suggests the presence of the pathogens in the communities under study and the need to establish a routine wastewater surveillance system for the identification of pathogens.
PubMed: 38921784
DOI: 10.3390/pathogens13060486