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In situ CTLA-4 blockade mediates regression of local and distant tumors with minimal side effects
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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(English)Manuscript (preprint) (Other academic)
Abstract [en]

 Preclinical and clinical studies describe powerful anti-tumor effects of systemic anti(a)CTLA-4 antibody therapy but also indicate that blocking immune regulatory checkpoints may precipitate severe autoimmune complications. In this study we compared conventional high-dose systemic aCTLA-4 with peritumoral low-dose injection in murine models of pancreatic (Panc02) and bladder (MB49) cancer. Tumor growth and autoimmune adverse events were monitored. Peritumoral aCTLA-4 therapy reduced tumor growth in an inverse dose-response manner, as 3x30mg was superior to 3x90mg. The local low-dose was compared with systemic administration of 200mg antibody and similar results were observed as to tumor regression and survival. Both local and systemic high-dose administrations lead to Treg accumulation in the tumor-draining lymph node. Lymphocytes from treated mice (irrespectively of treatment route) secreted IFNg upon tumor cell stimulation. Remarkably, local therapy was effective on both distant Panc02 tumors as well as the irrelevant tumor MB49, demonstrating its potential in treatment of metastatic disease. Systemic delivery of aCTLA-4 was associated with elevated autoantibody levels, splenomegaly and acute gastritis compared with local treatment. Taken together, in situ immunomodulation of tumors with aCTLA-4 can affect the regression and the cure of primary and distant tumors at reduced toxicity compared to systemic administration, and should be considered for patients with solid tumors.

Keyword [en]
CTLA-4, Immunotherapy, Local administration, Panc02, MB49, cancer, checkpoint blockade, antibody therapy, local CTLA-4 blockade
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:uu:diva-110727OAI: oai:DiVA.org:uu-110727DiVA: diva2:278083
Available from: 2009-11-23 Created: 2009-11-23
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

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