EVALUATION COMMITTEE

The Faculty Council has appointed the following adjudication committee to evaluate the thesis and the associated lecture: 

• Senior Researcher/Group Leader, Ranveig Braathen, Department of Immunology, Clinic for Diagnostic and Intervention, Oslo University Hospital, Norway, 
• Associate Professor, Daniel Hargbøl Madsen, Department of Immunology and Microbiology, University of Copenhagen. 

Chairman: Associate Professor Louiza Bohn Thomsen, HST, Aalborg Universitet

Moderator: Associate Professor Ralf Agger, HST, Aalborg Universitet

ABSTRACT

Vaccination is among the most effective strategies for preventing infectious diseases and has for decades been investigated as a potential tool for cancer therapy. Promising results have been obtained in animal experiments but, unfortunately, clinical trials have not yet shown a clear benefit for cancer patients. A major problem in cancer is the suppression that is imposed on the immune system by the cancer cells. The suppression, evident in the tumor microenvironment but also measurable in the draining lymph nodes and beyond, affects critical immune cells such as antigen-presenting cells (APCs), particularly dendritic cells (DCs). These cells are essential for initiating robust T cell responses that can kill cancer cells. Because of this, the potential success of therapeutic cancer vaccines could very well rely on their complementation with potent adjuvants that might break the tolerance enforced by the cancer cells. Adjuvants influence not only the strength but also the type of immune response. In the context of cancer, those capable of promoting cellular immunity are particularly interesting, such as the synthetic RNA analog poly(I:C) or DNA. 

Traditionally, adjuvants are mixed with vaccine and the two injected together. In this situation some cells may take up the vaccine without being stimulated by the adjuvant. Other cells may take up the adjuvant without the vaccine. There is, however, a growing recognition that this may not be ideal. Consequently, new forms of vaccines that integrate antigen and adjuvant to ensure that the cells that internalize the vaccine are also activated by the adjuvant component are being investigated.

This dissertation encompasses three experimental studies that investigate two novel experimental cancer vaccines with built-in adjuvants. One of them is a recombinant fusion protein that specifically target murine DCs, whereas the other is not targeting a particular type of APC. The first two studies, concerning the untargeted vaccine, demonstrated that the vaccine effectively activated APCs and was able to elicit strong antibody responses in mice. When the vaccine was used in a prophylactic tumor model, a significant delayed tumor growth was observed. In the third study, the design, production and purification of a DC-targeted fusion protein vaccine is described. Using the CRISPR/Cas9 system, a cell line permanently producing the vaccine was generated. It was established that the yield of vaccine could be increased by the addition of sodium butyrate to the cell culture. Finally, a method for purifying the vaccine from cell culture medium was set up, and proof that the purified vaccine retained its ability to bind to DCs was obtained.   

Together, findings of this PhD dissertation demonstrate the potential of novel vaccines with built-in adjuvants to enhance immune activation and offers insights into the development of DC-targeted vaccines.