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Local checkpoint inhibition of CTLA-4 as a monotherapy or in combination with anti-PD1 prevents the growth of murine bladder cancer
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada.
Alligator Bioscience AB, Lund, Sweden; Department of Immunotechnology, Lund University, Lund, Sweden.
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2017 (English)In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 47, no 2, p. 385-393Article in journal (Refereed) Published
Abstract [en]

Checkpoint blockade of CTLA-4 results in long-lasting survival benefits in metastatic cancer patients. However, patients treated with CTLA-4 blockade have suffered from immune-related adverse events, most likely due to the breadth of the induced T-cell activation. Here, we investigated the efficacy of a local low-dose anti-CTLA-4 administration for treatment of subcutaneous or orthotopic murine bladder 49 (MB49) bladder carcinoma in C57BL/6 mice. When MB49 tumors were grown s.c., peritumoral (p.t.) injection of anti-CTLA-4 treatment was equally effective as intravenous or s.c. (nontumor bearing flank) administration. Notably, p.t. injection was associated with lower circulating antibody levels and decreased IL-6 serum levels as compared to systemic treatment. Ultrasound-guided intratumoral anti-CTLA-4 antibody treatment of orthotopically growing MB49 tumors resulted in tumor regression, with more than tenfold reduction in systemic antibody levels as compared to i.v. or s.c. administration, in line with the compartmentally restrained nature of the bladder. Local anti-CTLA-4 therapy in combination with anti-PD-1 therapy resulted in complete responses, superior to each therapy alone. In addition, p.t. anti-CTLA-4 therapy was potentiated by depletion of regulatory T cells. Our results demonstrate that local anti-CTLA-4 antibody therapy is equally effective as systemic administration, but reduces systemic antibody levels and cytokine release, and enhances the response to anti-PD1 therapy.

Place, publisher, year, edition, pages
2017. Vol. 47, no 2, p. 385-393
Keywords [en]
Bladder cancer, CTLA-4, Checkpoint inhibitors, Immunotherapy, Local low-dose, MB49, PD-1
National Category
Basic Medicine Immunology in the medical area
Identifiers
URN: urn:nbn:se:uu:diva-318999DOI: 10.1002/eji.201646583ISI: 000394839800018PubMedID: 27873300OAI: oai:DiVA.org:uu-318999DiVA, id: diva2:1085775
Funder
EU, FP7, Seventh Framework Programme, MCA-ITN 317445Swedish Cancer SocietySwedish Research CouncilSwedish Society for Medical Research (SSMF)Göran Gustafsson Foundation for Research in Natural Sciences and MedicineAvailable from: 2017-03-30 Created: 2017-03-30 Last updated: 2018-09-21Bibliographically approved
In thesis
1. Antibody-based immunotherapy of cancer: From optimization to novel approaches
Open this publication in new window or tab >>Antibody-based immunotherapy of cancer: From optimization to novel approaches
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Antibody immunotherapy is a successful therapeutic approach to treat cancer. The overall aim of this thesis is to investigate the mechanisms of antibody-based immunotherapies and the role of the tumor microenvironment in mediating the anti-tumor immune response, in order to aid the development of improved immunotherapies for cancer patients.

Agonistic CD40 antibodies activate dendritic cells and improve anti-tumor T-cell responses. In Paper I we demonstrate that their efficacy can be enhanced by co-treatment with sunitinib, a multi-targeted tyrosine kinase inhibitor. The combination therapy restrains immunosuppression, synergistically increases endothelial activation and improves tumor T-cell recruitment, resulting in restrained tumor growth and prolonged survival.  

CTLA-4 and PD-1 negatively regulate the anti-tumor T-cell response and blocking these immune checkpoints with antibodies enhances anti-tumor immunity. However, CTLA-4 checkpoint blockade is associated with severe adverse events. In Paper II, a local low-dose administration of CTLA-4 antibodies is demonstrated to be equally effective as systemic administration in treating experimental bladder cancer. Importantly, antibody spread is reduced, indicating that local administration may be an effective strategy to reduce side effects associated with CTLA-4 blockade.

Tumor-derived expression of Galectin-1 enhances angiogenesis and suppresses anti-tumor immunity. In Paper III, endogenous antibodies are induced against Gal-1 using TRX-Gal-1 fusion proteins to break self-tolerance. Vaccination induces anti-Gal-1 endogenous antibodies, resulting in improved vessel perfusion, improved immune-cell infiltration and decreased tumor growth.

Immunotherapy for glioma is constrained by the immunosuppressive microenvironment. In Paper IV we demonstrate that in vivo activation of B cells enhances tertiary lymphoid structure formation in the brain. Mice with induced tertiary lymphoid structures have an increase of B cells with a regulatory phenotype and CD8+ T-cell activation is suppressed. The response to PD-1 checkpoint blockade is also inhibited, suggesting tertiary lymphoid structures impair the response to immunotherapy.

This thesis demonstrates that immunotherapy can be improved by the addition of anti-angiogenic drugs and that local administration of antibodies is a feasible alternative to the systemic administration conventionally used in the clinic. In addition, therapeutic vaccination and induction of tertiary lymphoid structures by agonistic CD40 antibodies are novel approaches to employ antibodies to modulate the anti-tumor immune response.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 67
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1433
Keywords
Cancer immunotherapy, CD40, CTLA-4, PD-1, Gal-1, tertiary lymphoid structures
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-342799 (URN)978-91-513-0246-1 (ISBN)
Public defence
2018-04-13, Rudbecksalen, Rudbeck laboratory, Dag Hammarskjölds väg 20, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2018-03-23 Created: 2018-02-23 Last updated: 2018-04-24

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van Hooren, LuukSandin, Linda C.Dimberg, AnnaTötterman, ThomasMangsbo, Sara

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