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Enhanced tumor eradication by combining CTLA-4 or PD-1 blockade with CpG therapy
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
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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.

Place, publisher, year, edition, pages
2010. Vol. 33, no 3, 225-235 p.
Keyword [en]
CTLA-4, PD-1, CpG, BCG, bladder cancer, immunotherapy, combination therapies, MB49, TLR-9
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:uu:diva-110726DOI: 10.1097/CJI.0b013e3181c01fcbISI: 000276037500001PubMedID: 20445343OAI: oai:DiVA.org:uu-110726DiVA: diva2:278085
Available from: 2009-11-23 Created: 2009-11-23 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Immunological Checkpoint Blockade and TLR Stimulation for Improved Cancer Therapy
Open this publication in new window or tab >>Immunological Checkpoint Blockade and TLR Stimulation for Improved Cancer Therapy
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
TLR-stimulering och CTLA-4 samt PD-1 blockad för förbättrad cancerterapi
Abstract [en]

This thesis concerns the investigation of novel immunotherapies for cancer eradication. CpG therapy was used in order to target antigen-presenting cells (APCs), facilitating antigen presentation and activation of T cells. Blockade of the two major immune checkpoint regulators (CTLA-4 and PD-1) was also studied to ensure proper and sustained T cell activation. The therapies were investigated alone and compared to BCG, the standard immunotherapy in the clinic today for bladder cancer. In addition, CpG as well as BCG was combined with CTLA-4 or PD-1 blockade to examine if the combination could improve therapy.

Single and combination strategies were assessed in an experimental bladder cancer model. In addition, one of the therapies (local aCTLA-4 administration) was evaluated in an experimental pancreatic cancer model. To be able to study the effects of CpG in humans, a human whole blood loop system has been used. This allowed us to dissect the potential interplay between CpG and complement.

CpG was found to be superior to the conventional therapy, BCG, in our experimental model and T cells were required in order for effective therapy to occur. Used as a monotherapy, CTLA-4 blockade but not PD-1 blockade, prolonged survival of mice. When CTLA-4 or PD-1 blockade was combined with CpG, survival was enhanced and elevated levels of activated T cells were found in treated mice. In addition, Treg levels were decreased in the tumor area compared to tumors in control treated mice. CTLA-4 blockade was also effective when administrated locally, in proximity to the tumor. Compared to systemic CTLA-4 blockade, local administration gave less adverse events and sustained therapeutic success.

When CpG was investigated in a human whole blood loop system it was found to tightly interact with complement proteins. This is an interesting finding which warrants further investigation into the role of TLRs in complement biology. Tumor therapy could be affected either negatively or positively by this interaction.

The results presented herein are a foundation for incorporating these combination therapies into the clinic, specifically for bladder cancer but in a broader perspective, also for other solid tumors such as pancreatic cancer.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 95 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 506
Keyword
CpG ODNs, TLR-9, CTLA-4, PD-1, PD-L1, B7. H1, immunotherapy, checkpoint blockade, bladder cancer, cancer, complement, TLRs, Compstatin, properdin, C3, experimental animal model, whole blood loop system, combination therapies
National Category
Immunology in the medical area Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-110147 (URN)978-91-554-7675-5 (ISBN)
Public defence
2010-01-29, Rudbeck laboratory, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2009-12-23 Created: 2009-11-05 Last updated: 2009-12-23Bibliographically approved
2. Immunomodulatory Therapy of Solid Tumors: With a Focus on Monoclonal Antibodies
Open this publication in new window or tab >>Immunomodulatory Therapy of Solid Tumors: With a Focus on Monoclonal Antibodies
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
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:nbn:se:uu:diva-210080 (URN)978-91-554-8806-2 (ISBN)
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

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Mangsbo, SaraTötterman, Thomas

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