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Immunomodulatory Therapy of Solid Tumors: With a Focus on Monoclonal Antibodies
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cancer, historically considered a genetic disease, is currently acknowledged to affect the whole body. Our immune system is one key player that can elicit a response against malignant cells but can also promote tumorigenesis. Tumors avoid immune recognition by creating a suppressive microenvironment and inducing tolerance. T-cells are regarded a major effector cell type in tumor immunotherapy. An important ”switch” needed for T-cell activation involves so-called costimulatory and coinhibitory receptors. In this thesis, experimental tumor models were used to investigate the potential of immunomodulatory antibodies to stimulate immune cells and subsequently eliminate tumors.

First, systemic antibody blockade of two negative checkpoint regulators (CTLA-4 and PD-1) present on T-cells was evaluated in combination with local CpG therapy or standard BCG treatment. Indeed, this combinatorial therapy with CpG augmented anti-tumor effects with increased levels of tumor-directed T-cells and reduced tumor-infiltrating Tregs.

Secondly, as these immunomodulatory antibodies elicit severe side effects in patients, a local low-dose delivery regimen was explored as an alternative to systemic bolus treatment. Our results demonstrated that an approximately seven times lower dose of aCTLA-4, compared to systemic delivery, could eradicate both primary and distant tumors.

CD40-expressing APCs are another potential target in antibody-mediated cancer therapy. CD40-stimulated dendritic cells (DCs) have the capability to activate tumor-directed T-cells to kill tumor cells. We next sought to investigate agonistic CD40 antibody efficacy and in vivo biodistribution when delivered locally compared to the equivalent systemic dose. Anti-tumor effects were dependent on CD8+ T-cells, host CD40 expression and the presence of tumor antigen at the injection site. CD40 antibodies were cleared from the circulation and accumulated in lymphoid organs, where, upon repeated aCD40 dosing, target APC populations increased in numbers and upregulated their surface CD40 expression.

Lastly, CD40 agonist antibodies were mixed with nanoparticles to enhance their stimulatory properties. B-cells demonstrated increased proliferative capacity and DCs became more activated when exposed to the cocktail. Further, this combination reduced serum levels of pro-inflammatory cytokines compared to plain antibodies.      

The results herein advocate further exploratory studies of the delivery of monoclonal antibodies at the tumor site in order to improve anti-tumor effects and reduce toxicity.  

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. , 60 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 953
Keyword [en]
in situ checkpoint blockade, antibody-mediated tumor immunotherapy, CTLA-4, CD40, monoclonal antibodies, experimental animal model, Fc gamma receptor
National Category
Immunology in the medical area
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-210080ISBN: 978-91-554-8806-2 (print)OAI: oai:DiVA.org:uu-210080DiVA: diva2:660797
Public defence
2013-12-13, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2013-11-22 Created: 2013-10-30 Last updated: 2014-01-23
List of papers
1. Enhanced tumor eradication by combining CTLA-4 or PD-1 blockade with CpG therapy
Open this publication in new window or tab >>Enhanced tumor eradication by combining CTLA-4 or PD-1 blockade with CpG therapy
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2010 (English)In: Journal of immunotherapy (1997), ISSN 1524-9557, E-ISSN 1537-4513, Vol. 33, no 3, 225-235 p.Article in journal (Refereed) Published
Abstract [en]

Tumor immunotherapy aims to break effector T cell anergy and to block suppressive cell types and ligands allowing effector cells to exert tumor eradication. Previous reports demonstrate that cytotoxic T lymphocyte antigen-4 (CTLA-4)-blocking antibodies promote T cell activation and render T effector cells resistant to T regulatory cells (Tregs) whereas programmed death receptor-1 (PD-1)/ PD-L1 blockade results in loss of peripheral tolerance. Herein, we explored single or combined antibody blockade of CTLA-4 and PD-1 alone or combined with the TLR agonists CpG or bacillus Calmette-Guerin (BCG) for treatment of murine experimental bladder cancer. In therapeutic studies, tumors were rejected by anti-CTLA4 (aCTLA4) while aPD-1 suppressed tumor growth. The combination had no additive effect compared with aCTLA-4 alone. However, elevated levels of circulating CD107a expressing CD8+ T cells were found in the aCTLA-4 plus aPD-1 group. In addition, levels of antinuclear antibodies (ANA) correlated inversely with tumor size. Next, we combined CpG or BCG with aCTLA-4, aPD-1 or aPD-L1 and found that CpG in combination with aCTLA-4 or aPD-1 increased the survival of mice, with aPD-1 plus CpG being superior to either agent alone. CpG plus aCTLA-4 or aPD-1 increased the numbers of circulating tumor-specific CD107a expressing CD8+ T cells as well as activated (CD25+ FoxP3-) CD4+ splenocytes. Further, we investigated the numbers of Tregs in the tumor area of treated animals and detected decreased levels after aCTLA-4 or aPD-1 plus CpG therapy. Thus, the combination of CpG with CTLA-4 or PD-1 blockade improved long-term survival and led to increased levels of tumor-reactive T cells and reduced numbers of Tregs at the tumor site.

Keyword
CTLA-4, PD-1, CpG, BCG, bladder cancer, immunotherapy, combination therapies, MB49, TLR-9
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-110726 (URN)10.1097/CJI.0b013e3181c01fcb (DOI)000276037500001 ()20445343 (PubMedID)
Available from: 2009-11-23 Created: 2009-11-23 Last updated: 2017-12-12Bibliographically approved
2. Local low-dose CTLA-4 antibody blockade is an alternative to systemic high-dose administration in tumor immunotherapy
Open this publication in new window or tab >>Local low-dose CTLA-4 antibody blockade is an alternative to systemic high-dose administration in tumor immunotherapy
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(English)Manuscript (preprint) (Other academic)
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-209735 (URN)
Available from: 2013-10-25 Created: 2013-10-25 Last updated: 2014-01-23
3. Locally delivered CD40 agonist antibody accumulates in secondary lymphoid organs and eradicates experimental disseminated bladder cancer
Open this publication in new window or tab >>Locally delivered CD40 agonist antibody accumulates in secondary lymphoid organs and eradicates experimental disseminated bladder cancer
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2014 (English)In: Cancer Immunology Research, ISSN 2326-6066, Vol. 2, no 1, 80-90 p.Article in journal (Refereed) Published
Abstract [en]

Immunotherapy with intratumoral injection of adenoviral vectors expressing CD40L has yielded positive results in experimental and clinical bladder cancer. We therefore hypothesized that anti-CD40 antibody would be effective in this setting. Agonistic CD40 antibodies were developed as vaccine adjuvants but have later been used as treatment for advanced solid tumors and hematological cancers. Systemic anti-CD40 therapy has been associated with immune-related adverse events such as cytokine release syndrome and liver toxicity and local delivery is an attractive approach that could reduce toxicity. Herein, we compared local and systemic anti-CD40 antibody delivery to evaluate efficacy, toxicity and biodistribution in the experimental MB49 bladder cancer model. Anti-tumor effects were confirmed in the B16 model. In terms of anti-tumor efficacy, local anti-CD40 antibody stimulation was superior to systemic therapy at an equivalent dose and CD8 T-cells were crucial for tumor growth inhibition. Both administration routes were dependent on host CD40 expression for therapeutic efficacy. In vivo biodistribution studies revealed CD40-specific antibody accumulation in tumor-draining lymph nodes and spleen, most likely reflecting organs with frequent target antigen-expressing immune cells. Systemic administration led to higher antibody concentrations in liver and blood compared to local delivery, and was associated with elevated levels of serum haptoglobin. Despite the lack of a slow-release system, local anti-CD40 therapy was dependent on tumor antigen at the injection site for clearance of distant tumors. To summarize, local low-dose administration of anti-CD40 antibody mediates anti-tumor effects in murine models with reduced toxicity and may represent an attractive treatment alternative in the clinic.

National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-209738 (URN)10.1158/2326-6066.CIR-13-0067 (DOI)000340030900010 ()24778163 (PubMedID)
Available from: 2013-10-25 Created: 2013-10-25 Last updated: 2015-03-24Bibliographically approved
4. Synergistic augmentation of CD40-mediated activation of antigen-presenting cells by amphiphilic poly(gamma-glutamic acid) nanoparticles
Open this publication in new window or tab >>Synergistic augmentation of CD40-mediated activation of antigen-presenting cells by amphiphilic poly(gamma-glutamic acid) nanoparticles
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2012 (English)In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 33, no 26, 6230-6239 p.Article in journal (Refereed) Published
Abstract [en]

Agonistic anti-CD40 monoclonal antibodies (mAbs) hold great potential for cancer immunotherapy. However, systemic administration of anti-CD40 mAbs can be associated with severe side effects, such as cytokine release syndrome and liver damage. With the aim to increase the immunostimulatory potency as well as to achieve a local drug retention of anti-CD40 mAbs, we linked an agonistic mAb to immune activating amphiphilic poly(gamma-glutamic acid) nanoparticles (gamma-PGA NPs). We demonstrate that adsorption of anti-CD40 mAb to gamma-PGA NPs (anti-CD40-NPs) improved the stimulatory capacity of the CD40 agonist, resulting in upregulation of costimulatory CD80 and CD86 on antigen-presenting cells, as well as IL-12 secretion. Interestingly, anti-CD40-NP5 induced strong synergistic proliferative effects in B cells, possibly resulting from a higher degree of CD40 multimerization, enabled by display of multiple anti-CD40 mAbs on the NPs. In addition, local treatment with anti-CD40-NPs, compared to only soluble CD40 agonist, resulted in a significant reduction in serum levels of IL-6, IL-10, IL-12 and TNF-alpha in a bladder cancer model. Taken together, our results suggest that anti-CD40-NPs are capable of synergistically enhancing the immunostimulatory effect induced by the CD40 agonist, as well as minimizing adverse side effects associated with systemic cytokine release. This concept of nanomedicine could play an important role in localized immunotherapy of cancer.

Keyword
Drug delivery, Nanoparticle, Immunostimulation, Protein adsorption, Cell proliferation
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-179895 (URN)10.1016/j.biomaterials.2012.05.011 (DOI)000306720400027 ()
Available from: 2012-08-28 Created: 2012-08-27 Last updated: 2017-12-07Bibliographically approved

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