Book
Harnessing innate inflammatory signals for cancer immunotherapy
Morressier
2017
Abstract
Tumor-associated macrophages (TAMs) are abundant in tumors, assuming an M2-like phenotype that supports tumor growth and immune escape. The identification and delivery of drugs to combat TAM activity has remained a challenge. We hypothesized that such drugs could be i) identified through screening, ii) synthetically optimized for targeted delivery, and iii) delivered by TAM-avid supramolecular nanocarriers to improve therapeutic outcomes.Here, high-content image-based screens identified a potent inducer of the tumor-destructive M1-like phenotype (R848, a synthetic TLR7/8 agonist) which was further optimized for nanoparticle delivery through SAR studies to develop an adamantane-conjugated derivative (R848-Ad). Polyglucose materials are recognized by innate immune phagocyted through surface receptors, driving their rapid uptake. Cyclodextrin nanoparticles (CDNPs; 30nm, -10mV) were therefore developed which encapsulated drugs with excellent efficiency (>10wt% drug) through guest-host complexation and which were rapidly uptaken by TAMs. CDNPs accumulated in the tumor (4.1u00b11.15%ID) and TAMs (>70% of CDNP+ cells), resulting in TAM re-polarization (Fig. 1A). Mono and combination therapy with anti-PD1 were effective in numerous tumor models (Fig. 1B-C). R848-Ad improved nanoparticle affinity, resulting in a drastic reduction in systemic side effects which have previously been dose limiting, preventing clinical efficacy. Toll-like receptor agonists, such as R848, mimic signals associated with infection and tissue injury conditions, making them potent activators of both innate and adaptive immunity. Here, we rationally engineer these signals for nanoparticle delivery to achieve functional re-orientation of the tumor immune microenvoronment toward an active anti-tumor state.
Metrics
9 Record Views
Details
- Title
- Harnessing innate inflammatory signals for cancer immunotherapy
- Creators
- Christopher B Rodell
- Publisher
- Morressier
- Number of pages
- 1 online resource (unknown)
- Resource Type
- Book
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Identifiers
- 991019341847004721