Title: Liposome-based delivery of chemotherapy and immunotherapy for stimulation of antitumor immunity
Time: 7 June 2019, at 13:00
Place: Bldg. 341, aud. 23
Principal supervisor: Professor Thomas Lars. Andresen
Co supervisor: Senior Researcher Ladan Parhamifer
Co supervisor: Postdoc Gael Clergeaud
Examiners:
Associate Professor Andrew Urquhart, DTU Health Tech
Associate Director Austin Boesch, Torque Therapeutics
Associate Professor Jesper Nyelandsted, Danish Cancer Society
Chairperson at defence:
TBA
Abstract;
Continuous efforts to uncover the complexity of cancer biology create the foundation for development of new therapies and strategic application of already existing therapies. Today it is well-acknowledged that the immune system is greatly involved in cancer development and elimination, and development of immunotherapies to boost antitumor immunity is therefore a field of intense research. The present thesis, consisting of three manuscripts, focused on the application of liposomes for encapsulation of cancer therapies for more targeted delivery of the drugs to generate antitumor immunity.
The first manuscript describes the use of liposomes for delivery of a conventional chemotherapeutic drug, mitoxantrone, with the aim of killing cancer cells in a way that stimulates the immune system to eliminate cancer cells. This type of cell death is referred to as immunogenic cell death (ICD), and has previously been demonstrated to induce antitumor immunity, which accounts for a great part of the therapeutic efficacy of specific chemotherapeutic drugs including mitoxantrone. We demonstrated that mitoxantrone encapsulated in liposomes induced ICD in vitro, which further stimulated the maturation of dendritic cells key for initiation of adaptive antitumor immune responses. Furthermore, promising results were obtained in tumor-bearing mice where tumor growth was significantly suppressed, and several mice were tumor-free upon combination with an immunotherapeutic drug, an anti-programmed death receptor (PD1) antibody. In addition, the modulation of immune cell tumor infiltration and state of maturation was studied in response to treatment.
The second and third manuscripts focus on the use of cationic liposomes for targeted delivery of a toll-like receptor-7 (TLR7) agonist to monocytes in human peripheral blood. The second manuscript presents studies aiming to establish proteins and receptors involved in the association of cationic TLR-agonist-containing liposomes to monocytes with a particular focus on complement proteins. The studies served to provide insight into the mode of action of cationic liposomes once exposed to full blood.
In the third manuscript, the cationic liposomes carrying TLR agonist were further characterized for their ability to target and activate monocytes in human blood from healthy individuals and from individuals diagnosed with cancer that were either treatment-naïve or had received prior anticancer therapy. Cationic liposomes induced several antitumor- and pro-inflammatory cytokines thus substantiating effective TLR7 agonist delivery to the endosomal target site. The cytokine profile generated in response to liposomal TLR7 agonist relative to agonist administered as a free drug suggested a therapeutic benefit of TLR agonist delivery in the context of liposomes. Furthermore, the studies provide proof-of-concept for the application of this drug delivery system for treatment of lung, melanoma and breast cancer in combination with immunogenic cell death-inducing therapy or checkpoint inhibitors.