Design, synthesis and evaluation of small molecule immunomodulators and immunoconstructs for improved drug delivery in cancer immunotherapy

Cancer is a group of complex diseases and one of the major threats of global health with over 19 million new cases and 10 million cancer related deaths estimated worldwide in 2020. As opposed to the conventional cancer therapies: surgery, chemo- and radiotherapy, immunotherapy aims at utilizing the patient’s own immune system to combat cancer. This can achieve complete eradication of cancer cells, and long-term protecting from disease recurrence. Immunotherapy has gained increasing attention in the past decades and is now seen as the fourth pillar of cancer therapy.
However, due to the powerful responses the immune system can elicit, immunotherapy faces a number of challenges with respect to safety and efficacy. Some of these are addressed in various ways in the work of this Ph.D. thesis. The thesis is divided into three parts.
The first part addresses the stimulation and maturation of immune cells, predominantly antigen presenting cells. This was done by developing novel potent TLR7 agonists, optimized for liposomal remote loading. The goal of this project was to achieve high encapsulation of the TLR7 agonists within the liposomes. This was achieved with minimal leakage of the encapsulated drugs, with some even precipitated in the interior compartment.
The second part of this thesis addresses the immunosuppressive tumor microenvironment, by developing a novel class of TGF-β inhibitors, suited for liposomal drug delivery as well. These compounds were likewise efficiently encapsulated into liposomes, with a tendency to precipitate in the interior. The stability profile of the loaded liposomes showed minimal leakage in buffer, and within the first 24 hr in the presence of FBS, thereafter a significant increase in the release was observed. In relation to both the first and the second part of this thesis, targeted delivery and controlled release of small molecule immunomodulators is of great importance to achieve a safe and efficacious cancer treatment.
The third part describes the development of immunoconstructs, functioning as targeting modules and as theranostic tools, for treatment with a specialized UniCAR T cell platform. These constructs were successfully synthesized and radiolabeled for in vivo imaging. This will aid the evaluation and expand our understanding of the UniCAR T system as cancer treatment.
Taken together, the strategies presented in this thesis, contribute to the emerging field of drug delivery in cancer immunotherapy. The thesis work has hopefully expanded the knowledge and understanding of how we, in a sophisticated manner, tackle the challenges immunotherapy will face in the future.