uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
CD40L Gene Therapy for Solid Tumors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
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 [en]
CD40L, adenovirus, tumor immunology, tumor microenvironment, immunotherapy, local immunotherapy, antigen presentation
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
URN: urn:nbn:se:uu:diva-222705ISBN: 978-91-554-8943-4 (print)OAI: oai:DiVA.org:uu-222705DiVA: diva2:712095
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
List of papers
1. CD40L gene therapy tilts the myeloid cell profile and promotes infiltration of activated T lymphocytes
Open this publication in new window or tab >>CD40L gene therapy tilts the myeloid cell profile and promotes infiltration of activated T lymphocytes
Show others...
2014 (English)In: Cancer Gene Therapy, ISSN 0929-1903, E-ISSN 1476-5500, Vol. 21, no 3, 95-102 p.Article in journal (Refereed) Published
Abstract [en]

CD40 ligand (CD40L) is a potent stimulator of tumor immunity via its activation of dendritic cells, which in turn initiate T-cell activation. However, T cells are inhibited by suppressive myeloid cells, which constitute an important part of immune evasion. We hypothesized that CD40L may revert the function of suppressive myeloid cells to generate a T-cell stimulatory environment, and this was investigated in the murine bladder cancer model MB49/C57BL/6. Upon intratumoral adenoviral CD40L (AdCD40L) gene therapy, the infiltration of CD11b(+)Gr-1(+) cells was significantly reduced, whereas activated T cells were increased. In vitro, CD40L-expressing MB49 cells tilted the myeloid subpopulations in favor of granulocytic CD11b(+)Gr-1(high) myeloid cells instead of monocytic CD11b(+)Gr-1(int/low) myeloid cells. Further, the level of macrophages in splenocyte co-cultures with MB49 cells was evaluated. In cultures with MB49 cells expressing CD40L, the overall level of macrophages was reduced and the remaining cells were differentiated into M1-like cells. Hence, these data support that CD40L tilts myeloid immune cell populations in favor of anti-tumor immunity (M1) instead of immunosuppression (CD11b(+)Gr-1(int/low) and M2), and this was accompanied by an increased level of activated T cells in the tumor tissue.

Keyword
AdCD40L, myeloid-suppressor cells, M1 macrophages MB49, tumor microenvironment, tumor immunology
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-223902 (URN)10.1038/cgt.2014.2 (DOI)000333069600002 ()
Note

De två sista författarna delar sista författarskapet.

Available from: 2014-05-05 Created: 2014-04-28 Last updated: 2017-12-05Bibliographically approved
2. Enhanced therapeutic anti-tumor immunity induced by co-administration of 5-fluorouracil and adenovirus expressing CD40 ligand
Open this publication in new window or tab >>Enhanced therapeutic anti-tumor immunity induced by co-administration of 5-fluorouracil and adenovirus expressing CD40 ligand
Show others...
2014 (English)In: Cancer Immunology and Immunotherapy, ISSN 0340-7004, E-ISSN 1432-0851, Vol. 63, no 3, 273-282 p.Article in journal (Refereed) Published
Abstract [en]

Bystander immune activation by chemotherapy has recently gained extensive interest and provided support for the clinical use of chemotherapeutic agents in combination with immune enhancers. The CD40 ligand (CD40L; CD154) is a potent regulator of the anti-tumor immune response and recombinant adenovirus (RAd)-mediated CD40L gene therapy has been effective in various cancer models and in man. In this study we have assessed the combined effect of local RAd-CD40L and 5-fluorouracil (5-FU) administration on a syngeneic MB49 mouse bladder tumor model. Whereas MB49 cells implanted into immunocompetent mice responded poorly to RAd-CD40L or 5-FU alone, administration of both agents dramatically decreased tumor growth, increased survival of the mice and induced systemic MB49-specific immunity. This combination treatment was ineffective in athymic nude mice, highlighting an important role for T cell mediated anti-tumor immunity for full efficacy. 5-FU up-regulated the expression of Fas and immunogenic cell death markers in MB49 cells and cytotoxic T lymphocytes from mice receiving RAd-CD40L immunotherapy efficiently lysed 5-FU treated MB49 cells in a Fas ligand-dependent manner. Furthermore, local RAd-CD40L and 5-FU administration induced a shift of myeloid-derived suppressor cell phenotype into a less suppressive population. Collectively, these data suggest that RAd-CD40L gene therapy is a promising adjuvant treatment to 5-FU for the management of bladder cancer.

National Category
Immunology in the medical area
Research subject
Oncology
Identifiers
urn:nbn:se:uu:diva-219570 (URN)10.1007/s00262-013-1507-6 (DOI)000331643400007 ()24357147 (PubMedID)
Funder
EU, European Research CouncilEU, FP7, Seventh Framework Programme, 223151
Available from: 2014-03-04 Created: 2014-03-04 Last updated: 2017-12-05Bibliographically approved
3. A Hexon and Fiber-modified Adenovirus Expressing CD40L Improves the Antigen Presentation Capacity of Dendritic Cells
Open this publication in new window or tab >>A Hexon and Fiber-modified Adenovirus Expressing CD40L Improves the Antigen Presentation Capacity of Dendritic Cells
Show others...
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.

Keyword
CD40, CD40L, adenovirus, PTD, local immunotherapy, antigen presentation
National Category
Immunology in the medical area
Research subject
Immunology; Oncology
Identifiers
urn:nbn:se:uu:diva-222025 (URN)10.1097/CJI.0000000000000028 (DOI)000333158300003 ()
Available from: 2014-04-07 Created: 2014-04-07 Last updated: 2017-12-05Bibliographically approved

Open Access in DiVA

fulltext(2047 kB)246 downloads
File information
File name FULLTEXT01.pdfFile size 2047 kBChecksum SHA-512
3af01646b242e0dc3e57513ba462cc8812377bc90114bf033b81a5c819d83ffb9ed32d907edfdb539e5a31420c28928197be4141031d00a7dca132619c26274a
Type fulltextMimetype application/pdf
Buy this publication >>

By organisation
Department of Immunology, Genetics and Pathology
Immunology in the medical area

Search outside of DiVA

GoogleGoogle Scholar
Total: 246 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 538 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf