Preclinical evaluation of TLR7/8 agonist drug delivery systems for cancer immunotherapy

Camilla Stavnsbjerg

Research output: Book/ReportPh.D. thesisResearch

Abstract

Cancer is a devastating disease estimated to affect 40% of all men and women during their lifetime. It is also a leading cause of death in both low and high-income countries worldwide. Conventional treatment for cancer includes surgical resection of tumors, radiotherapy and chemotherapy; however, not all patients respond to these treatments. Cancer immunotherapy is an emerging treatment option that has the potential of inducing durable remissions. One approach to cancer immunotherapy is stimulation of the immune response in tumors to reverse the immunosuppressive and tumor-promoting tumor microenvironment.
Immune stimulants are often associated with toxicity due to overt systemic activation of the immune system. Thus, we sought to develop a drug delivery system that could allow safe administration of the small molecule, 1V270, capable of stimulating Toll-like receptor (TLR) 7/8.
1V270 was formulated in polyethylene glycosylated (PEGylated) liposomes that shield the agonist in the bloodstream when administered intravenously Unfortunately, these liposomes induced hypersensitivity reactions in mice when dosed repeatedly. We discovered that hypersensitivity was associated with accelerated blood clearance and the generation of anti-PEG antibodies in mice. Moreover, we showed that anti-PEG IgG is responsible for hypersensitivity reactions. Consequently, PEGylated liposomes were discarded as a drug delivery system for 1V270.
Instead, 1V270 were formulated in micelles with DSPE-PEG2k, because previous studies show that smaller nanoparticles are not subject to accelerated blood clearance. No hypersensitivity was observed with 1V270 micelles, and repeated dosing in CT26 tumor-bearing mice showed impressive anti-cancer efficacy. In fact, eight out of nine mice became tumor-free and rejected rechallenge, demonstrating the generation of an immunological memory response. The treatment was well-tolerated in mice and non-human primates, even in high doses compared to the literature.
In conclusion, we developed a drug delivery system that allowed safe administration of a TLR7/8 agonist capable of activating the immune system to develop durable anti-cancer responses. These results are very promising for future clinical translation of 1V270 micelles.
Original languageEnglish
PublisherDTU Health Technology
Number of pages149
Publication statusPublished - 2020

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