| 11. |
- Fotaki, Grammatiki, et al.
(författare)
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Cancer vaccine based on a combination of an infection-enhanced adenoviral vector and pro-inflammatory allogeneic DCs leads to sustained antigen-specific immune responses in three melanoma models
- 2018
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Ingår i: Oncoimmunology. - 2162-4011 .- 2162-402X. ; 7:3
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Tidskriftsartikel (refereegranskat)abstract
- Autologous patient-derived dendritic cells (DCs) modified ex vivo to present tumor-associated antigens (TAAs) are frequently used as cancer vaccines. However, apart from the stringent logistics in producing DCs on a patient basis, accumulating evidence indicate that ex vivo engineered DCs are poor in migration and in fact do not directly present TAA epitopes to naïve T cells in vivo. Instead, it is proposed that bystander host DCs take up material from vaccine-DCs, migrate and subsequently initiate antitumor T-cell responses. We used mouse models to examine the possibility of using pro-inflammatory allogeneic DCs (alloDCs) to activate host DCs and enable them to promote antigen-specific T-cell immunity. We found that alloDCs were able to initiate host DC activation and migration to draining lymph node leading to T-cell activation. The pro-inflammatory milieu created by alloDCs also led to recruitment of NK cells and neutrophils at the site of injection. Vaccination with alloDCs combined with Ad5M(gp100), an infection-enhanced adenovirus encoding the human melanoma-associated antigen gp100 resulted in generation of CD8+ T cells with a T-cell receptor (TCR) specific for the gp10025-33 epitope (gp100-TCR+). Ad5M(gp100)-alloDC vaccination in combination with transfer of gp100-specific pmel-1 T cells resulted in prolonged survival of B16-F10 melanoma-bearing mice and altered the composition of the tumor microenvironment (TME). We hereby propose that alloDCs together with TAA- or neoepitope-encoding Ad5M can become an “off-the-shelf” cancer vaccine, which can reverse the TME-induced immunosuppression and induce host cellular anti-tumor immune responses in patients without the need of a time-consuming preparation step of autologous DCs.
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| 12. |
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| 13. |
- Fotaki, Grammatiki, et al.
(författare)
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Pro-inflammatory allogeneic DCs promote activation of bystander immune cells and thereby license antigen-specific T-cell responses
- 2018
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Ingår i: Oncoimmunology. - 2162-4011 .- 2162-402X. ; 7:3
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Tidskriftsartikel (refereegranskat)abstract
- Accumulating evidence support an important role for endogenous bystander dendritic cells (DCs) in the efficiency of autologous patient-derived DC-vaccines, as bystander DCs take up material from vaccine-DCs, migrate to draining lymph node and initiate antitumor T-cell responses. We examined the possibility of using allogeneic DCs as vaccine-DCs to activate bystander immune cells and promote antigen-specific T-cell responses. We demonstrate that human DCs matured with polyI:C, R848 and IFN-γ (denoted COMBIG) in combination with an infection-enhanced adenovirus vector (denoted Ad5M) exhibit a pro-inflammatory state. COMBIG/Ad5M-matured allogeneic DCs (alloDCs) efficiently activated T-cells and NK-cells in allogeneic co-culture experiments. The secretion of immunostimulatory factors during the co-culture promoted the maturation of bystander-DCs, which efficiently cross-presented a model-antigen to activate antigen-specific CD8+ T-cells in vitro. We propose that alloDCs, in combination with Ad5M as loading vehicle, may be a cost-effective and logistically simplified DC vaccination strategy to induce anti-tumor immune responses in cancer patients.
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| 14. |
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| 15. |
- Gao, Menghan, et al.
(författare)
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A qPCR-Based Method for Quantification of RCA Contaminants in Oncolytic Adenovirus Products
- 2022
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Ingår i: Frontiers in Molecular Biosciences. - : Frontiers Media S.A.. - 2296-889X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Oncolytic adenovirus is one of the most promising treatments against cancer and is widely evaluated clinically. During high titer production, “Wild-type-” like replication-competent adenovirus (RCA) contaminants can be generated through recombination events due to the DNA sequence similarity between oncolytic virus and host cells. These RCA contaminants raise various safety concerns in clinics. Cell culture-based methods have been developed to detect RCA contaminants in replication-deficient adenovirus vectors. These methods were based on that only RCA contaminants, but not the vectors, are able to grow in and lyse the test cell line. However, these methods are not suitable for distinguishing RCA contaminants from the oncolytic adenovirus products because both can replicate in test cell lines. Herein, we reported a qPCR-based method to quantify RCA contaminants quickly and reliably in E1B-deleted oncolytic adenovirus products. This method is based on specific detection of the E1B gene, which can be acquired during production via recombination events between viral and host cell DNA. The assay is sensitive with the limit of detection at 10 VP of the RCA contaminants and the limit of quantification at 75 VP of the RCA contaminants in each 40 µL qPCR reaction. We have also validated the method on virus batches produced in the non-GMP and GMP conditions. Our results showed that this qPCR-based method was reliable and robust for detecting and quantifying RCA contaminants in oncolytic adenovirus products. The method may also be adapted for other oncolytic adenoviruses products by switching primer sets.
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| 16. |
- Jin, Chuan, 1986-, et al.
(författare)
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CAR T cells expressing a bacterial virulence factor trigger potent bystander antitumour responses in solid cancers
- 2022
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Ingår i: Nature Biomedical Engineering. - : Springer Nature. - 2157-846X. ; 6:7, s. 830-841
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Tidskriftsartikel (refereegranskat)abstract
- Chimeric antigen receptor T cells (CAR T cells) are effective against haematologic malignancies. However, in solid tumours, their potency is hampered by local immunosuppression and by the heterogeneous expression of the antigen that the CAR targets. Here we show that CAR T cells expressing a pluripotent pro-inflammatory neutrophil-activating protein (NAP) from Helicobacter pylori trigger endogenous bystander T-cell responses against solid cancers. In mice with subcutaneous murine pancreatic ductal adenocarcinomas, neuroblastomas or colon carcinomas, CAR(NAP) T cells led to slower tumour growth and higher survival rates than conventional mouse CAR T cells, regardless of target antigen, tumour type and host haplotype. In tumours with heterogeneous antigen expression, NAP secretion induced the formation of an immunologically 'hot' microenvironment that supported dendritic cell maturation and bystander responses, as indicated by epitope spreading and infiltration of cytotoxic CD8(+) T cells targeting tumour-associated antigens other than the CAR-targeted antigen. CAR T cells armed with NAP neither increased off-tumour toxicity nor hampered the efficacy of CAR T cells, and hence may have advantageous translational potential. T cells expressing a pluripotent pro-inflammatory neutrophil-activating protein from Helicobacter pylori trigger endogenous bystander T-cell responses against solid cancers.
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| 17. |
- Jin, Chuan, 1986-, et al.
(författare)
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Intratumoral administration of pro-inflammatory allogeneic dendritic cells improved the anti-turnor response of systemic anti-CTLA-4 treatment via unleashing a T cell-dependent response
- 2022
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Ingår i: Oncoimmunology. - : Informa UK Limited. - 2162-4011 .- 2162-402X. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Immune checkpoint inhibitors (ICIs) have revolutionized the oncology field. However, a significant number of patients do not respond, at least partly due to the lack of preexisting anti-tumor T-cell immunity. Therefore, it is emergent to add an immune-priming step to improve efficacy. Here, we report a combined approach consisting of intratumoral administration of pro-inflammatory allogeneic dendritic cells (AlloDCs) and systemic treatment with alpha CTLA-4 that can drastically improve the anti-tumor efficacy compared to alpha CTLA-4 monotherapy. When evaluated in mice with large established CT-26 tumors, monotherapy with alpha CTLA-4 neither delayed tumor progression nor improved mice survival. However, combination treatment of AlloDCs and alpha CTLA-4 drastically improved the effectiveness, with 70% of mice being cured. This effect was T cell-dependent, and all survived mice rejected a subsequent tumor re-challenge. Further investigation revealed an immune-inflamed tumor microenvironment (TME) in the combination treatment group characterized by enhanced infiltration of activated antigen-presenting endogenous DCs and CD8(+) T cells with a tissue-resident memory (T-RM) phenotype (CD49a(+)CD103(+)). This correlated with elevated levels of tumor-specific CD39(+)CD103(+)CD8(+) T cells in the tumor and "tumor-matching" NKG2D(+)CD39(+)CX3CR1(+)CD8(+) T cells in peripheral blood. Moreover, splenocytes from mice in the combination treatment group secreted significantly higher IFN-gamma upon stimulation with the peptide from the endogenous CT-26 retroviral gp70 (model neoantigen), confirming the induction of a tumor-specific CD8(+) T-cell response. Taken together, these data indicate a strong anti-tumor synergy between AlloDCs and alpha CTLA-4 that warrant further clinical investigation with the corresponding human AlloDC product (ilixadencel) for patients receiving alpha CTLA-4 therapy.
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| 18. |
- Jin, Chuan, 1986-, et al.
(författare)
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Tat‐PTD‐modified Oncolytic Adenovirus Driven by the SCG3 Promoter and ASH1 Enhancer for Neuroblastoma Therapy
- 2013
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Ingår i: Human Gene Therapy. - : Mary Ann Liebert Inc. - 1043-0342 .- 1557-7422. ; 24:8, s. 766-775
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Tidskriftsartikel (refereegranskat)abstract
- Secretogranin III (SGC3) belongs to the granin family and is highly expressed in endocrine and neural tissues. The human SCG3 promoterhas not yet been characterized. We identified that a 0.5 kb DNA fragment upstream of the SCG3 gene can selectively drivetransgene expression in neuroblastoma cell lines. The strength of transgene expression was further increased and specificity maintained,by addition of the human achaete‐scute complex homolog 1 (ASH1) enhancer. We developed an oncolytic serotype 5‐basedadenovirus, where the SCG3 promoter and ASH1 enhancer drive E1A gene expression. The virus was further modified with a cellpenetratingpeptide (Tat‐PTD) in the virus capsid, which we have previously shown results in increased adenovirus transductionefficiency of many neuroblastoma cell lines. The virus, Ad5PTD(ASH1‐SCG3‐E1A), shows selective and efficient killing of neuroblastomacell lines in vitro, including cisplatin‐, etoposide‐ and doxorubicin‐insensitive neuroblastoma cells. Furthermore, it delays tumorgrowth and thereby prolonged survival for nude mice harboring subcutaneous human neuroblastoma xenograft. In conclusion, wereport a novel oncolytic adenovirus with potential use for neuroblastoma therapy.
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| 19. |
- Kang, Naixin, et al.
(författare)
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Antischistosomal Properties of Hederacolchiside A1 Isolated from Pulsatilla chinensis
- 2018
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Ingår i: Molecules. - : MDPI. - 1431-5157 .- 1420-3049. ; 23:6
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Tidskriftsartikel (refereegranskat)abstract
- Background: Schistosomiasis is a major neglected disease for which the current control strategy involves mass treatment with praziquantel, the only available drug. Hence, there is an urgent need to develop new antischistosomal compounds.Methods: The antischistosomal activity of hederacolchiside A1 (HSA) were determined by total or female worm burden reductions in mice harboring Schistosoma japonicum or S. mansoni. Pathology parameters were detected on HSA against 1-day-old S. japonicum-harboring mice. Moreover, we confirmed the antischistosomal effect of HSA on newly transformed schistosomula (NTS) of S. japonicum in vitro.Results: HSA, a natural product isolated from Pulsatilla chinensis (Bunge) Regel, was initially corroborated to possess promising antischistosomal properties. We demonstrated that HSA had high activity against S. japonicum and S. mansoni less in 11 days old parasites harbored in mice. The antischistosomal effect was even more than the currently used drugs, praziquantel, and artesunate. Furthermore, HSA could ameliorate the pathology parameters in mice harboring 1-day-old juvenile S. japonicum. We also confirmed that HSA-mediated antischistosomal activity is partly due to the morphological changes in the tegument system when NTS are exposed to HSA.Conclusions: HSA may have great potential to be an antischistosomal agent for further research.
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| 20. |
- Kang, Nai-xin, et al.
(författare)
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Anemoside B4 inhibits enterovirus 71 propagation in mice through upregulating 14-3-3 expression and type I interferon responses
- 2022
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Ingår i: Acta Pharmacologica Sinica. - : Springer Nature. - 1671-4083 .- 1745-7254. ; 43, s. 977-991
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Tidskriftsartikel (refereegranskat)abstract
- Enterovirus 71 (EV71) is the major pathogens of human hand, foot, and mouth disease (HFMD). EV71 efficiently escapes innate immunity responses of the host to cause infection. At present, no effective antiviral drugs for EV71 are available. Anemoside B4 (B4) is a natural saponin isolated from the roots of Pulsatilla chinensis (Bunge) Regel. P. chinensis extracts that shows a wide variety of biological activities. In this study, we investigated the antiviral activities of B4 against EV71 both in cell culture and in suckling mice. We showed that B4 (12.5-200 mu M) dose dependently increased the viability of EV71-infected RD cells with an IC50 value of 24.95 +/- 0.05 mu M against EV71. The antiviral activity of B4 was associated with enhanced interferon (IFN)-beta response, since knockdown of IFN-beta abolished its antiviral activity. We also confirmed that the enhanced IFN response was mediated via activation of retinoic acid-inducible gene I (RIG-I) like receptors (RLRs) pathway, and it was executed by upregulation of 14-3-3 protein, which disrupted the interaction between yes-associated protein (YAP) and interferon regulatory factor 3 (IRF3). By using amino acids in cell culture (SILAC)-based proteomics profiling, we identified the Hippo pathway as the top-ranking functional cluster in B4-treated EV71-infected cells. In vivo experiments were conducted in suckling mice (2-day-old) infected with EV71 and subsequently B4 (200 mg center dot kg(-1) center dot d(-1), i.p.) was administered for 16 days. We showed that B4 administration effectively suppressed EV71 replication and improved muscle inflammation and limb activity. Meanwhile, B4 administration regulated the expressions of HFMD biomarkers IL-10 and IFN-gamma, attenuating complications of EV71 infection. Collectively, our results suggest that B4 could enhance the antiviral effect of IFN-beta by orchestrating Hippo and RLRs pathway, and B4 would be a potential lead compound for developing an anti-EV71 drug.
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