Micellar formulation provides potent and tolerable TLR7 agonist treatment for anti-cancer immunotherapy
Description
Data file for manuscript This study aimed at improving the therapeutic index for TLR7 agonists by formulating the agonist in nanoparticles. Initially, we investigated the optimal nanoparticle formulation with regards to anti-PEG antibody response and accelerated blood clearance in vivo. Following this, we determined biodistribution as well as anti-tumor activity of 1V270-micelles against a commonly used TLR7 agonist using syngeneic cancer models. The immunological mechanism of action was characterized for immediate and adaptive immunological changes on a single cell level using flow cytometry and on mRNA level using Nanostring. Anti-tumor activity was evaluated in additional subcutaneous syngeneic cancer models in combination with checkpoint blockade. The immediate effects were then confirmed in cancer models having showed differential efficacy. Finally, tolerability was evaluated in cynomolgus monkeys in a dose escalating study. All experiments were based on protocols with specific research questions, with a clear design and plan for analysis. Treatment of tumor-bearing animals were only conducted on established tumors (mean volume of ≈100 mm3), which for most models occurred between 7-14 days post inoculation, and after being subjected to a stratified block randomization based on tumor volume. Group sizes were determined based on prior experience. Experimental groups were typically composed of five to ten animals per group to ensure statistical power. Lower number of animals were used with larger animals for ethical reasons. In non-tumor bearing mouse studies, mice were subjected to a stratified block randomization based on weight before treatments. No exclusion criteria were defined. Animals were kept under controlled circumstances (light conditions and air temperature and humidity) and acclimatized for at least 5 days prior to study conduct. Investigators were blinded during some of the efficacy studies and treatment and measurements order was random in some experiments. Laboratory animals’ care was in accordance with institutional guidelines. No outliers were removed from data.
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Institutions
- Danmarks Tekniske Universitet