Sökning: onr:"swepub:oai:DiVA.org:uu-110147" >
Immunological Check...
Immunological Checkpoint Blockade and TLR Stimulation for Improved Cancer Therapy
-
- Mangsbo, Sara, 1981- (författare)
- Uppsala universitet,Enheten för klinisk immunologi
-
- Tötterman, Thomas, Professor (preses)
- Uppsala universitet,Enheten för klinisk immunologi
-
- Loskog, Angelica, PhD (preses)
- Uppsala universitet,Enheten för klinisk immunologi
-
visa fler...
-
- Kiessling, Rolf, Professor (opponent)
- KI, Department of Oncology-Pathology
-
visa färre...
-
(creator_code:org_t)
- ISBN 9789155476755
- Uppsala : Acta Universitatis Upsaliensis, 2009
- Engelska 95 s.
-
Serie: Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 1651-6206 ; 506
- Relaterad länk:
-
https://uu.diva-port... (primary) (Raw object)
-
visa fler...
-
https://urn.kb.se/re...
-
visa färre...
Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Immunology in the medical area (hsv//eng)
Nyckelord
- 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
- Clinical immunology
- Klinisk immunologi
- Tumour immunology
- Tumörimmunologi
- immunologi
- Immunology
Publikations- och innehållstyp
- vet (ämneskategori)
- dok (ämneskategori)
Hitta via bibliotek
Till lärosätets databas