FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2912608618> ?p ?o ?g. }

• W2912608618 abstract "In recent years, cancer immunotherapies significantly advanced the clinical management of metastatic melanoma. In particular, treatment with immune checkpoint inhibitors increased survival rates compared with standard therapy. However, not all patients benefit from checkpoint blockade. Primary treatment resistance is connected to poor T-cell infiltration in the tumors. This can be due to limited activation of antigen-presentation cells such as dendritic cells (DCs) and the high threshold of activating low-affinity T-cells that may respond to the tumor antigens. CD27 signaling in T-cells during activation lowers the T-cell receptor signaling threshold, which may be important to activate tumor-targeting T-cells. Secondary resistance to checkpoint blockade therapy includes loss of MHC-I on the tumor cells. Hence, inducing natural killer (NK) cell activation in parallel to antitumor T-cells may be crucial. LOAd703 was designed to optimize antitumor immune activation. LOAd703 is an oncolytic adenovirus (serotype Ad5/35) carrying two immunostimulatory transgenes; a trimerized membrane-bound CD40 ligand (TMZ-CD40L) and the full-length 4-1BB ligand (4-1BBL) (patent filed: PCT/EP2015/057489). The viral replication is restricted to tumor cells with a hyperphosphorylated retinoblastoma pathway due to a deletion in E1A, but transgenes are expressed under the control of a cytomegalovirus (CMV) promoter, which enables transgene expression even in the surrounding tumor microenvironment. Herein, we investigated LOAd703 in a melanoma model and its immunostimulatory effect on DC maturation to induce antigen-specific T-cell responses. LOAd703 infected the human melanoma cell line 526-mel and efficiently induced tumor cell death as evaluated by MTS viability assay. The viability of infected cells was reduced to 15% at 72 hours post infection compared to uninfected cells. Transgene expression of both TMZ-CD40L and 4-1BBL was confirmed by flow cytometry post infection. To evaluate the immunostimulatory capacity of LOAd703, immature DCs were differentiated from CD14+ monocytes using granulocyte-macrophage colony-stimulating factor and interleukin-4 and infected with virus. LOAd703-infected DCs upregulated the expression of maturation markers, such as CD83, CD86 and MHC molecules as analyzed by flow cytometry. Interestingly, CD70 that is required for CD27 stimuli of T-cells was highly upregulated on the DCs using LOAd703. Furthermore, the chemokine receptor CCR7 and the adhesion molecule ICAM-1 were increased upon LOAd703 infection, which are crucial for lymph node homing and the initiation of a systemic response. Next, the functional capacity of LOAd703-matured DCs to induce antigen-specific T-cell responses was assessed in a CMV model, in which CMV-peptide pulsed DCs are utilized to induce expansion of CMV-specific T-cells. LOAd703-matured DCs from CMV+ donors were pulsed with CMV-peptide and co-cultured with autologous peripheral blood mononuclear cells for 11 days. LOAd703-matured DCs were able to expand CMV-specific T-cells, but to a lower degree than the positive control Poly I:C matured DCs. However, the CMV-specific T-cells expanded from the positive control had higher expression of PD-1 compared to the LOAd703 group, indicating that LOAd703 leads to the expansion of less exhausted and potentially more functional T-cells. Moreover, LOAd703 also induced a massive expansion of NK cells, which is probably driven by 4-1BBL. In conclusion, LOAd703 killed human melanoma cells by oncolysis and induced the expression of TMZ-CD40L and 4-1BBL in infected cells. Furthermore, LOAd703 infection activated DCs to express costimulatory molecules including high levels of CD70 and CCR7, which in turn could promote the expansion of antigen-specific T-cells with low PD-1 expression, as well as the potent expansion of NK cells. Citation Format: Jessica Wenthe, Mantas Silanskas, Emma Eriksson, Angelica Loskog. Combating primary and secondary checkpoint blockade resistance using immunostimulatory CD40L/4-1BBL-encoding oncolytic virotherapy for melanoma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A119." @default.
• W2912608618 created "2019-02-21" @default.
• W2912608618 creator A5003121752 @default.
• W2912608618 creator A5004426426 @default.
• W2912608618 creator A5007118555 @default.
• W2912608618 creator A5008096974 @default.
• W2912608618 date "2019-02-01" @default.
• W2912608618 modified "2023-09-26" @default.
• W2912608618 title "Abstract A119: Combating primary and secondary checkpoint blockade resistance using immunostimulatory CD40L/4-1BBL-encoding oncolytic virotherapy for melanoma" @default.
• W2912608618 doi "https://doi.org/10.1158/2326-6074.cricimteatiaacr18-a119" @default.
• W2912608618 hasPublicationYear "2019" @default.
• W2912608618 type Work @default.
• W2912608618 sameAs 2912608618 @default.
• W2912608618 citedByCount "0" @default.
• W2912608618 crossrefType "proceedings-article" @default.
• W2912608618 hasAuthorship W2912608618A5003121752 @default.
• W2912608618 hasAuthorship W2912608618A5004426426 @default.
• W2912608618 hasAuthorship W2912608618A5007118555 @default.
• W2912608618 hasAuthorship W2912608618A5008096974 @default.
• W2912608618 hasConcept C154317977 @default.
• W2912608618 hasConcept C202751555 @default.
• W2912608618 hasConcept C203014093 @default.
• W2912608618 hasConcept C2776090121 @default.
• W2912608618 hasConcept C2776107976 @default.
• W2912608618 hasConcept C2777658100 @default.
• W2912608618 hasConcept C2777701055 @default.
• W2912608618 hasConcept C2780674031 @default.
• W2912608618 hasConcept C2780851360 @default.
• W2912608618 hasConcept C39347974 @default.
• W2912608618 hasConcept C502942594 @default.
• W2912608618 hasConcept C55493867 @default.
• W2912608618 hasConcept C82210918 @default.
• W2912608618 hasConcept C86803240 @default.
• W2912608618 hasConcept C8891405 @default.
• W2912608618 hasConceptScore W2912608618C154317977 @default.
• W2912608618 hasConceptScore W2912608618C202751555 @default.
• W2912608618 hasConceptScore W2912608618C203014093 @default.
• W2912608618 hasConceptScore W2912608618C2776090121 @default.
• W2912608618 hasConceptScore W2912608618C2776107976 @default.
• W2912608618 hasConceptScore W2912608618C2777658100 @default.
• W2912608618 hasConceptScore W2912608618C2777701055 @default.
• W2912608618 hasConceptScore W2912608618C2780674031 @default.
• W2912608618 hasConceptScore W2912608618C2780851360 @default.
• W2912608618 hasConceptScore W2912608618C39347974 @default.
• W2912608618 hasConceptScore W2912608618C502942594 @default.
• W2912608618 hasConceptScore W2912608618C55493867 @default.
• W2912608618 hasConceptScore W2912608618C82210918 @default.
• W2912608618 hasConceptScore W2912608618C86803240 @default.
• W2912608618 hasConceptScore W2912608618C8891405 @default.
• W2912608618 hasLocation W29126086181 @default.
• W2912608618 hasOpenAccess W2912608618 @default.
• W2912608618 hasPrimaryLocation W29126086181 @default.
• W2912608618 hasRelatedWork W1503867275 @default.
• W2912608618 hasRelatedWork W1964319723 @default.
• W2912608618 hasRelatedWork W1969279205 @default.
• W2912608618 hasRelatedWork W1987636506 @default.
• W2912608618 hasRelatedWork W1993669313 @default.
• W2912608618 hasRelatedWork W2082801423 @default.
• W2912608618 hasRelatedWork W2134778100 @default.
• W2912608618 hasRelatedWork W2425565612 @default.
• W2912608618 hasRelatedWork W2492262272 @default.
• W2912608618 hasRelatedWork W2559919459 @default.
• W2912608618 hasRelatedWork W2585869380 @default.
• W2912608618 hasRelatedWork W2626945863 @default.
• W2912608618 hasRelatedWork W2753875408 @default.
• W2912608618 hasRelatedWork W2913671092 @default.
• W2912608618 hasRelatedWork W2914168980 @default.
• W2912608618 hasRelatedWork W3135379629 @default.
• W2912608618 hasRelatedWork W3137371962 @default.
• W2912608618 hasRelatedWork W3157407185 @default.
• W2912608618 hasRelatedWork W3172349547 @default.
• W2912608618 hasRelatedWork W3204668091 @default.
• W2912608618 isParatext "false" @default.
• W2912608618 isRetracted "false" @default.
• W2912608618 magId "2912608618" @default.
• W2912608618 workType "article" @default.