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A Hexon and Fiber-modified Adenovirus Expressing CD40L Improves the Antigen Presentation Capacity of Dendritic Cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
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2014 (English)In: Journal of immunotherapy (1997), ISSN 1524-9557, E-ISSN 1537-4513, Vol. 37, no 3, 155-162 p.Article in journal (Refereed) Published
Abstract [en]

CD40 ligand (CD40L), a strong stimulator of Th1 immune responses, acts via dendritic cells to trigger T-cell activation. AdCD40L therapy introduces the CD40L gene into the tumor microenvironment with an adenoviral vector and has shown promising results in experimental tumor models, dogs, and patients (phase I-II trials). The transduction efficiency of AdCD40L is dependent on the expression of CAR (coxsackie/adenovirus adhesion receptor), which is commonly downregulated on tumor cells. To enhance transduction efficiency, and therefore the therapeutic efficacy, a double-modified adenovirus was developed. The double-modified Ad5PTDf35(mCD40L) had a protein transduction domain (PTD) inserted into the hexon protein and the virus fiber is switched from serotype 5 to serotype 35. These modifications enable transduction of a wider range of cell types. In comparison with Ad5(mCD40L), Ad5PTDf35(mCD40L) showed increased transduction capacity on a variety of murine cells. Furthermore, antigen presentation was improved after transduction with Ad5PTDf35(mCD40L). This was demonstrated in an antigen presentation assay, both in vitro and in vivo, in which transduced dendritic cells were loaded with suboptimal concentrations of the human gp100 peptide and allowed to interact with gp100-specific transgenic T cells (pmel). Finally, Ad5PTDf35(mCD40L) could delay tumor growth in a murine cancer model at a particle load, wherein therapeutic efficacy of the Ad5(mCD40L) vector was lost. Hence, the Ad5PTDf35(CD40L) vector holds great promise as a second-generation immune stimulatory therapy, as it not only targets tumor cells but also antigen-presenting cells that are, among other cells, present in the tumor microenvironment.

Place, publisher, year, edition, pages
2014. Vol. 37, no 3, 155-162 p.
Keyword [en]
CD40, CD40L, adenovirus, PTD, local immunotherapy, antigen presentation
National Category
Immunology in the medical area
Research subject
Immunology; Oncology
Identifiers
URN: urn:nbn:se:uu:diva-222025DOI: 10.1097/CJI.0000000000000028ISI: 000333158300003OAI: oai:DiVA.org:uu-222025DiVA: diva2:710565
Available from: 2014-04-07 Created: 2014-04-07 Last updated: 2017-12-05Bibliographically approved
In thesis
1. CD40L Gene Therapy for Solid Tumors
Open this publication in new window or tab >>CD40L Gene Therapy for Solid Tumors
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Adenoviral CD40L gene therapy (AdCD40L) is a strong inducer of anti-tumor immune responses via its activation of dendritic cells (DCs). Activated DCs can in turn activate T cells, which are key players in an efficient anti-tumor response.

This thesis includes three papers that focus on different aspects of AdCD40L gene therapy. In the first paper, the infiltration of suppressive CD11b+Gr-1+ cells in orthotopic MB49 bladder tumors was investigated and found to be significantly reduced while activated T cells were increased when the tumors had been treated with local AdCD40L gene therapy. Further, AdCD40L could tilt the cells in the tumor microenvironment in favor of an efficient anti-tumor immunity (M1 macrophages and activated T cells) instead of an immunosuppressive environment (CD11b+Gr-1int/low myeloid cells and M2 macrophages).

Immunotherapy combined with chemotherapy has shown promising results, and the second paper investigates the combination of AdCD40L gene therapy together with the chemotherapeutic drug 5-Fluorouracil (5-FU). A synergistic effect of the combination treatment on orthotopic MB49 bladder tumors could be demonstrated. The combination therapy resulted in decreased tumor growth, increased survival and systemic MB49-specific immunity, whereas AdCD40L or 5-FU therapy alone had a poor effect on tumor growth.

Efficient AdCD40L therapy is dependent on high transduction efficiency in both cancer cells and cells present in the tumor microenvironment. In an attempt to enhance the transduction efficiency, and thereby the therapeutic efficacy, a modified adenovirus was developed for paper three. This modified Ad5PTDf35(mCD40L) could, in comparison with the unmodified Ad5(mCD40L), demonstrate increased transduction capacity of a variety of murine cells. Further, the ability of antigen presenting cells (APCs) to present antigens to T cells was improved after transduction with Ad5PTDf35(mCD40L).

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 55 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 996
Keyword
CD40L, adenovirus, tumor immunology, tumor microenvironment, immunotherapy, local immunotherapy, antigen presentation
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-222705 (URN)978-91-554-8943-4 (ISBN)
Public defence
2014-06-03, Fåhraeussalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2014-05-13 Created: 2014-04-14 Last updated: 2014-06-30

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Liljenfeldt, LinaYu, DiMangsbo, Sara

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