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Article ; Online: Immunostimulatory Gene Therapy Using Oncolytic Viruses as Vehicles.

Loskog, Angelica

2015 Volume 7, Issue 11, Page(s) 5780–5791

Abstract: Immunostimulatory gene therapy has been developed during the past twenty years. The aim of immunostimulatory gene therapy is to tilt the suppressive tumor microenvironment to promote anti-tumor immunity. Hence, like a Trojan horse, the gene vehicle can ... ...

Abstract	Immunostimulatory gene therapy has been developed during the past twenty years. The aim of immunostimulatory gene therapy is to tilt the suppressive tumor microenvironment to promote anti-tumor immunity. Hence, like a Trojan horse, the gene vehicle can carry warriors and weapons into enemy territory to combat the tumor from within. The most promising immune stimulators are those activating and sustaining Th1 responses, but even if potent effects were seen in preclinical models, many clinical trials failed to show objective responses in cancer patients. However, with new tools to control ongoing immunosuppression in cancer patients, immunostimulatory gene therapy is now emerging as an interesting option. In parallel, oncolytic viruses have been shown to be safe in patients. To prolong immune stimulation and to increase efficacy, these two fields are now merging and oncolytic viruses are armed with immunostimulatory transgenes. These novel agents are racing towards approval as established cancer immunotherapeutics.
MeSH term(s)	Animals ; Genetic Therapy/methods ; Genetic Vectors ; Humans ; Immunotherapy/methods ; Neoplasms/therapy ; Oncolytic Viruses/genetics ; Oncolytic Viruses/growth & development
Language	English
Publishing date	2015-11-06
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v7112899
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Article ; Online: CD40 stimulation via CD40 ligand enhances adenovirus-mediated tumour immunogenicity including 'find-me', 'eat-me', and 'kill-me' signalling.

Naseri, Sedigheh / Cordova, Mariela Mejia / Wenthe, Jessica / Lövgren, Tanja / Eriksson, Emma / Loskog, Angelica / Ullenhag, Gustav J

Journal of cellular and molecular medicine

2024 Volume 28, Issue 7, Page(s) e18162

Abstract: Immunostimulatory gene therapy using oncolytic viruses is currently evaluated as a promising therapy for cancer aiming to induce anti-tumour immunity. Here, we investigate the capacity of oncolytic adenoviruses (LOAd) and their transgenes to induce ... ...

Abstract	Immunostimulatory gene therapy using oncolytic viruses is currently evaluated as a promising therapy for cancer aiming to induce anti-tumour immunity. Here, we investigate the capacity of oncolytic adenoviruses (LOAd) and their transgenes to induce immunogenicity in the infected tumour cells. Oncolysis and death-related markers were assessed after infection of eight human solid cancer cell lines with different LOAd viruses expressing a trimerized, membrane-bound (TMZ)-CD40L, TMZ-CD40L and 41BBL, or no transgenes. The viruses induced transgene expression post infection before they were killed by oncolysis. Death receptors TRAIL-R1, TRAIL-R2 and Fas as well as immunogenic cell death marker calreticulin were upregulated in cell lines post infection. Similarly, caspase 3/7 activity was increased in most cell lines. Interestingly, in CD40
MeSH term(s)	Humans ; CD40 Ligand/genetics ; Adenoviridae/genetics ; B7-H1 Antigen/genetics ; Calreticulin/genetics ; CD40 Antigens ; Neoplasms
Chemical Substances	CD40 Ligand (147205-72-9) ; B7-H1 Antigen ; Calreticulin ; CD40 Antigens
Language	English
Publishing date	2024-03-17
Publishing country	England
Document type	Journal Article
ZDB-ID	2074559-X
ISSN	1582-4934 ; 1582-4934 ; 1582-1838
ISSN (online)	1582-4934
ISSN	1582-4934 ; 1582-1838
DOI	10.1111/jcmm.18162
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Article ; Online: The signaling and the metabolic differences of various CAR T cell designs.

Razavi, Azadeh Sadat / Loskog, Angelica / Razi, Sepideh / Rezaei, Nima

International immunopharmacology

2022 Volume 114, Page(s) 109593

Abstract: Chimeric antigen receptor (CAR) T cell therapy is introduced as an effective, rapidly evolving therapeutic to treat cancer, especially cancers derived from hematological cells, such as B cells. CAR T cell gene constructs combine a tumor-targeting device ... ...

Abstract	Chimeric antigen receptor (CAR) T cell therapy is introduced as an effective, rapidly evolving therapeutic to treat cancer, especially cancers derived from hematological cells, such as B cells. CAR T cell gene constructs combine a tumor-targeting device coupled to the T cell receptor (TCR) zeta chain domain with different signaling domains such as domains derived from CD28 or 4-1BB (CD137). The incorporation of each specific co-stimulatory domain targets the immunometabolic pathways of CAR T cells as well as other signaling pathways. Defining the immunometabolic and signaling pathways by which CAR T cells become and remain active, survive, and eliminate their targets may represent a huge step forward in this relatively young research field as the CAR gene can be tailored to gain optimal function also for solid tumors with elaborate immunosuppression and protective stroma. There is a close relationship between different signaling domains applied in CAR T cells, and difficult to evaluate the benefit from different tested CAR gene constructs. In this review, we attempt to collect the latest findings regarding the CAR T cell signaling pathways that affect immunometabolic pathways.
MeSH term(s)	Humans ; T-Lymphocytes ; Receptors, Chimeric Antigen/genetics ; Receptors, Chimeric Antigen/metabolism ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/metabolism ; Immunotherapy, Adoptive ; Signal Transduction ; Neoplasms/drug therapy ; CD28 Antigens/genetics ; CD28 Antigens/metabolism
Chemical Substances	Receptors, Chimeric Antigen ; Receptors, Antigen, T-Cell ; CD28 Antigens
Language	English
Publishing date	2022-12-20
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2043785-7
ISSN	1878-1705 ; 1567-5769
ISSN (online)	1878-1705
ISSN	1567-5769
DOI	10.1016/j.intimp.2022.109593
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Article ; Online: The Tumor Microenvironment: A Milieu Hindering and Obstructing Antitumor Immune Responses.

Labani-Motlagh, Alireza / Ashja-Mahdavi, Mehrnoush / Loskog, Angelica

Frontiers in immunology

2020 Volume 11, Page(s) 940

Abstract: The success of cancer immunotherapy relies on the knowledge of the tumor microenvironment and the immune evasion mechanisms in which the tumor, stroma, and infiltrating immune cells function in a complex network. The potential barriers that profoundly ... ...

Abstract	The success of cancer immunotherapy relies on the knowledge of the tumor microenvironment and the immune evasion mechanisms in which the tumor, stroma, and infiltrating immune cells function in a complex network. The potential barriers that profoundly challenge the overall clinical outcome of promising therapies need to be fully identified and counteracted. Although cancer immunotherapy has increasingly been applied, we are far from understanding how to utilize different strategies in the best way and how to combine therapeutic options to optimize clinical benefit. This review intends to give a contemporary and detailed overview of the different roles of immune cells, exosomes, and molecules acting in the tumor microenvironment and how they relate to immune activation and escape. Further, current and novel immunotherapeutic options will be discussed.
MeSH term(s)	Animals ; Clinical Trials as Topic ; Exosomes/immunology ; Exosomes/pathology ; Humans ; Immunotherapy, Adoptive/methods ; Mice ; Tumor Escape ; Tumor Microenvironment/immunology
Language	English
Publishing date	2020-05-15
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2020.00940
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Article ; Online: Donor-derived urologic cancers after renal transplantation: A retrospective non-randomized scientific analysis.

Hellström, Vivan / Tufveson, Gunnar / Loskog, Angelica / Bengtsson, Mats / Enblad, Gunilla / Lorant, Tomas

PloS one

2022 Volume 17, Issue 9, Page(s) e0271293

Abstract: Background: Malignancies in the urinary tract and the kidney graft are quite common after kidney transplantation. In some selected cases tumours develop from donor-derived tissue.: Objectives: We hypothesised that there is a clinical value to ... ...

Abstract	Background: Malignancies in the urinary tract and the kidney graft are quite common after kidney transplantation. In some selected cases tumours develop from donor-derived tissue. Objectives: We hypothesised that there is a clinical value to investigate donor/recipient origin in urologic malignancies in renal transplant recipients. Methods: In this retrospective study, including patients transplanted between the years 1969 and 2014 at Uppsala University Hospital, Sweden, 11 patients with malignancies in urinary tract and 4 patients with malignancies in kidney transplants were investigated. Donor/recipient origin of tumour tissue was analysed by polymerase chain reaction (PCR) of human leucocyte antigen (HLA) genotypes or by fluorescence in situ hybridization (FISH analysis) of sex chromosomes. HLA genotype and sex chromosomes of the tumour were compared to the known HLA genotype and sex chromosomes of recipient and donor. Results: Three of ten cancers in the urinary tract and three of four cancers in the kidney transplants were donor-derived. Conclusions: We suggest that urologic malignancies in renal transplant recipients can be investigated for transplant origin. In addition to conventional therapy the allograft immune response against these tumours can be valuable to treat donor-derived cancers.
MeSH term(s)	Graft Survival ; HLA Antigens ; Humans ; In Situ Hybridization, Fluorescence ; Kidney Transplantation/adverse effects ; Retrospective Studies ; Tissue Donors ; Urologic Neoplasms/genetics
Chemical Substances	HLA Antigens
Language	English
Publishing date	2022-09-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0271293
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Article ; Online: Immunostimulatory gene therapy targeting CD40, 4-1BB and IL-2R activates DCs and stimulates antigen-specific T-cell and NK-cell responses in melanoma models.

Wenthe, Jessica / Eriksson, Emma / Hellström, Ann-Charlotte / Moreno, Rafael / Ullenhag, Gustav / Alemany, Ramon / Lövgren, Tanja / Loskog, Angelica

Journal of translational medicine

2023 Volume 21, Issue 1, Page(s) 506

Abstract: Background: The activation of dendritic cells (DCs) is pivotal for generating antigen-specific T-cell responses to eradicate tumor cells. Hence, immunotherapies targeting this interplay are especially intriguing. Moreover, it is of interest to modulate ... ...

Abstract	Background: The activation of dendritic cells (DCs) is pivotal for generating antigen-specific T-cell responses to eradicate tumor cells. Hence, immunotherapies targeting this interplay are especially intriguing. Moreover, it is of interest to modulate the tumor microenvironment (TME), as this harsh milieu often impairs adaptive immune responses. Oncolytic viral therapy presents an opportunity to overcome the immunosuppression in tumors by destroying tumor cells and thereby releasing antigens and immunostimulatory factors. These effects can be further amplified by the introduction of transgenes expressed by the virus. Methods: Lokon oncolytic adenoviruses (LOAd) belong to a platform of chimeric serotype Ad5/35 viruses that have their replication restricted to tumor cells, but the expression of transgenes is permitted in all infected cells. LOAd732 is a novel oncolytic adenovirus that expresses three essential immunostimulatory transgenes: trimerized membrane-bound CD40L, 4-1BBL and IL-2. Transgene expression was determined with flow cytometry and ELISA and the oncolytic function was evaluated with viability assays and xenograft models. The activation profiles of DCs were investigated in co-cultures with tumor cells or in an autologous antigen-specific T cell model by flow cytometry and multiplex proteomic analysis. Statistical differences were analyzed with Kruskal-Wallis test followed by Dunn's multiple comparison test. Results: All three transgenes were expressed in infected melanoma cells and DCs and transgene expression did not impair the oncolytic activity in tumor cells. DCs were matured post LOAd732 infection and expressed a multitude of co-stimulatory molecules and pro-inflammatory cytokines crucial for T-cell responses. Furthermore, these DCs were capable of expanding and stimulating antigen-specific T cells in addition to natural killer (NK) cells. Strikingly, the addition of immunosuppressive cytokines TGF-β1 and IL-10 did not affect the ability of LOAd732-matured DCs to expand antigen-specific T cells and these cells retained an enhanced activation profile. Conclusions: LOAd732 is a novel immunostimulatory gene therapy based on an oncolytic adenovirus that expresses three transgenes, which are essential for mediating an anti-tumor immune response by activating DCs and stimulating T and NK cells even under imunosuppressive conditions commonly present in the TME. These qualities make LOAd732 an appealing new immunotherapy approach.
MeSH term(s)	Humans ; T-Lymphocytes ; Proteomics ; Melanoma/genetics ; Melanoma/therapy ; Killer Cells, Natural ; Cytokines/metabolism ; Genetic Therapy ; Dendritic Cells ; Tumor Microenvironment
Chemical Substances	Cytokines
Language	English
Publishing date	2023-07-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2118570-0
ISSN	1479-5876 ; 1479-5876
ISSN (online)	1479-5876
ISSN	1479-5876
DOI	10.1186/s12967-023-04374-2
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Article ; Online: Correction to: Whole body FDG PET/MR for progression free and overall survival prediction in patients with relapsed/refractory large B-cell lymphomas undergoing CAR T-cell therapy.

Sjöholm, Therese / Korenyushkin, Alexander / Gammelgård, Gustav / Sarén, Tina / Lövgren, Tanja / Loskog, Angelica / Essand, Magnus / Kullberg, Joel / Enblad, Gunilla / Ahlström, Håkan

Cancer imaging : the official publication of the International Cancer Imaging Society

2023 Volume 23, Issue 1, Page(s) 46

Language	English
Publishing date	2023-05-19
Publishing country	England
Document type	Published Erratum
ZDB-ID	2104862-9
ISSN	1470-7330 ; 1470-7330
ISSN (online)	1470-7330
ISSN	1470-7330
DOI	10.1186/s40644-023-00548-9
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Article: Systemic immunity upon local oncolytic virotherapy armed with immunostimulatory genes may be supported by tumor-derived exosomes.

Labani-Motlagh, Alireza / Naseri, Sedigheh / Wenthe, Jessica / Eriksson, Emma / Loskog, Angelica

Molecular therapy oncolytics

2021 Volume 20, Page(s) 508–518

Abstract: Immunostimulatory gene therapy utilizing oncolytic viruses (OVs) as gene vehicles is a promising immunotherapy for cancer. Since viruses are immunogenic, systemic delivery can be troublesome due to neutralizing antibodies. Nevertheless, local delivery by ...

Abstract	Immunostimulatory gene therapy utilizing oncolytic viruses (OVs) as gene vehicles is a promising immunotherapy for cancer. Since viruses are immunogenic, systemic delivery can be troublesome due to neutralizing antibodies. Nevertheless, local delivery by intratumoral injection seems to induce systemic immune reactions. In this study, we demonstrate a novel mechanism of action of armed OV therapy suggesting that exosomes released by tumor cells infected with armed OV may participate to activate the immune system and this may also support systemic immunity. Tumor cell-derived exosomes commonly exert immunosuppressive functions. We hypothesized that exosomes derived from OV-infected tumor cells may instead be immunostimulatory. Human melanoma cells were infected by OVs armed with costimulatory molecules CD40 ligand (CD40L) and 4-1BB ligand (4-1BBL). Exosomes were purified and investigated for the presence of CD40L/4-1BBL mRNA and protein, and for their capacity to stimulate immune responses. The results show that the exosomes cargo transgenes. The exosomes from CD40L/4-1BBL-expressing tumor cells, or the viruses themselves, could stimulate robust dendritic cell (DC) activation with an enhanced level of major histocompatibility complex (MHC) and costimulatory molecules. Hence, exosomes after OV infection can locally activate immune responses at the tumor site and encounter immune cells such as DCs.
Language	English
Publishing date	2021-02-17
Publishing country	United States
Document type	Journal Article
ISSN	2372-7705
ISSN	2372-7705
DOI	10.1016/j.omto.2021.02.007
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Article: Immune priming using DC- and T cell-targeting gene therapy sensitizes both treated and distant B16 tumors to checkpoint inhibition.

Wenthe, Jessica / Naseri, Sedigheh / Hellström, Ann-Charlotte / Moreno, Rafael / Ullenhag, Gustav / Alemany, Ramon / Lövgren, Tanja / Eriksson, Emma / Loskog, Angelica

Molecular therapy oncolytics

2022 Volume 24, Page(s) 429–442

Abstract: Immune checkpoint inhibitors have revolutionized the treatment of metastatic melanoma, but most tumors show resistance. Resistance is connected to a non-T cell inflamed phenotype partially caused by a lack of functional dendritic cells (DCs) that are ... ...

Abstract	Immune checkpoint inhibitors have revolutionized the treatment of metastatic melanoma, but most tumors show resistance. Resistance is connected to a non-T cell inflamed phenotype partially caused by a lack of functional dendritic cells (DCs) that are crucial for T cell priming. Herein, we investigated whether the adenoviral gene vehicle mLOAd703 carrying both DC- and T cell-activating genes can lead to inflammation in a B16-CD46 model and thereby overcome resistance to checkpoint inhibition therapy. B16-CD46 cells were injected subcutaneously in one or both flanks of immunocompetent C57BL/6J mice. mLOAd703 treatments were given intratumorally alone or in combination with intraperitoneal checkpoint inhibition therapy (anti-PD-1, anti-PD-L1, or anti-TIM-3). Tumor, lymph node, spleen, and serum samples were analyzed for the presence of immune cells and cytokines/chemokines. B16-CD46 tumors were non-inflamed and resistant to checkpoint blockade. In contrast, mLOAd703 treatment led to infiltration of the tumor by CD8
Language	English
Publishing date	2022-01-10
Publishing country	United States
Document type	Journal Article
ISSN	2372-7705
ISSN	2372-7705
DOI	10.1016/j.omto.2022.01.003
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Article ; Online: Whole body FDG PET/MR for progression free and overall survival prediction in patients with relapsed/refractory large B-cell lymphomas undergoing CAR T-cell therapy.

Sjöholm, Therese / Korenyushkin, Alexander / Gammelgård, Gustav / Sarén, Tina / Lövgren, Tanja / Loskog, Angelica / Essand, Magnus / Kullberg, Joel / Enblad, Gunilla / Ahlström, Håkan

Cancer imaging : the official publication of the International Cancer Imaging Society

2022 Volume 22, Issue 1, Page(s) 76

Abstract: Background: To find semi-quantitative and quantitative Positron Emission Tomography/Magnetic Resonance (PET/MR) imaging metrics of both tumor and non-malignant lymphoid tissue (bone marrow and spleen) for Progression Free Survival (PFS) and Overall ... ...

Abstract	Background: To find semi-quantitative and quantitative Positron Emission Tomography/Magnetic Resonance (PET/MR) imaging metrics of both tumor and non-malignant lymphoid tissue (bone marrow and spleen) for Progression Free Survival (PFS) and Overall Survival (OS) prediction in patients with relapsed/refractory (r/r) large B-cell lymphoma (LBCL) undergoing Chimeric Antigen Receptor (CAR) T-cell therapy. Methods: A single-center prospective study of 16 r/r LBCL patients undergoing CD19-targeted CAR T-cell therapy. Whole body 18F-fluorodeoxyglucose (FDG) PET/MR imaging pre-therapy and 3 weeks post-therapy were followed by manual segmentation of tumors and lymphoid tissues. Semi-quantitative and quantitative metrics were extracted, and the metric-wise rate of change (Δ) between post-therapy and pre-therapy calculated. Tumor metrics included maximum Standardized Uptake Value (SUV Results: Pre-therapy (p < 0.05, FDR < 0.05) and Δ (p < 0.05, FDR > 0.05) total tumor burden structural and metabolic metrics were associated with PFS and/or OS. According to Kaplan-Meier analysis, a longer PFS was reached for patients with pre-therapy MTV ≤ 39.5 ml, ΔMTV≤1.35 and ΔTLG≤1.35. ΔSUV Conclusions: MTV, tumor ADC Trial registration: EudraCT 2016-004043-36.
MeSH term(s)	Humans ; Fluorodeoxyglucose F18/metabolism ; Radiopharmaceuticals ; Disease-Free Survival ; Immunotherapy, Adoptive ; Prospective Studies ; Prognosis ; Positron-Emission Tomography/methods ; Magnetic Resonance Imaging ; Lymphoma, Large B-Cell, Diffuse/diagnostic imaging ; Lymphoma, Large B-Cell, Diffuse/therapy ; Magnetic Resonance Spectroscopy ; Retrospective Studies ; Positron Emission Tomography Computed Tomography ; Tumor Burden
Chemical Substances	Fluorodeoxyglucose F18 (0Z5B2CJX4D) ; Radiopharmaceuticals
Language	English
Publishing date	2022-12-27
Publishing country	England
Document type	Journal Article
ZDB-ID	2104862-9
ISSN	1470-7330 ; 1470-7330
ISSN (online)	1470-7330
ISSN	1470-7330
DOI	10.1186/s40644-022-00513-y
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