Antibody-based immunotherapy of cancer : From optimization to novel approaches
Sammanfattning: 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.
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