Nanoparticles Presenting Potent TLR7/8 Agonists Enhance Anti-PD-L1 Immunotherapy in Cancer Treatment

Smith, Anders; Gale, Emily C.; Roth, Gillie A.; Maikawa, Caitlin L.; Correa, Santiago; Yu, Anthony C.; Appel, Eric A.

doi:10.1021/acs.biomac.0c00812

Cited by 55 publications

(47 citation statements)

References 46 publications

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“…TLR7/8a‐PEG–PLA was prepared according to a literature report 26 and the protocols will be briefly described here. Azide‐PEG–PLA was prepared by organocatalytic ring opening polymerization using N 3 ‐PEG‐OH (0.5 g, 5 kDa, 100 μmol) in anhydrous DCM (2.0 ml) with DBU (30 μl, 30 mg, 0.20 mmol) which was added quickly to a stirring solution of LA (2.0 g, 13.9 mmol) in anhydrous DCM (6.0 ml).…”

Section: Methodsmentioning

confidence: 99%

Modulation of injectable hydrogel properties for slow co‐delivery of influenza subunit vaccine components enhance the potency of humoral immunity

Saouaf

Roth

et al. 2021

J Biomedical Materials Res

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Vaccines are critical for combating infectious diseases across the globe. Influenza, for example, kills roughly 500,000 people annually worldwide, despite annual vaccination campaigns. Efficacious vaccines must elicit a robust and durable antibody response, and poor efficacy often arises from inappropriate temporal control over antigen and adjuvant presentation to the immune system. In this work, we sought to exploit the immune system's natural response to extended pathogen exposure during infection by designing an easily administered slow‐delivery influenza vaccine platform. We utilized an injectable and self‐healing polymer‐nanoparticle (PNP) hydrogel platform to prolong the co‐delivery of vaccine components to the immune system. We demonstrated that these hydrogels exhibit unique dynamic physical characteristics whereby physicochemically distinct influenza hemagglutinin antigen and a toll‐like receptor 7/8 agonist adjuvant could be co‐delivered over prolonged timeframes that were tunable through simple alteration of the gel formulation. We show a relationship between hydrogel physical properties and the resulting immune response to immunization. When administered in mice, hydrogel‐based vaccines demonstrated enhancements in the magnitude and duration of humoral immune responses compared to alum, a widely used clinical adjuvant system. We found stiffer hydrogel formulations exhibited slower release and resulted in the greatest improvements to the antibody response while also enabling significant adjuvant dose sparing. In summary, this work introduces a simple and effective vaccine delivery platform that increases the potency and durability of influenza subunit vaccines.

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Section: Methodsmentioning

confidence: 99%

Modulation of injectable hydrogel properties for slow co‐delivery of influenza subunit vaccine components enhance the potency of humoral immunity

Saouaf

Roth

et al. 2021

J Biomedical Materials Res

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“…Similarly, endosomolytic polymerosomes can improve cytosolic STING activation by entrapped cGAMP 111 . By contrast, small hydrophobic or amphiphilic molecules, such as monophosphoryl lipid A (MPL) (a TLR4 agonist) 109 , imiquimod (R837) (a TLR7 agonist) 108 , 109 , resiquimod (R848) (a TLR7/8 agonist) 104 , 105 , 115 and the synthetic TLR7/8a ligand 3M-052 (refs 92 , 116 , 117 ), can be encapsulated in particles made of poly(lactic-co-glycolic acid) (PLGA), N -(2-hydroxypropyl)methacrylamide (HPMA) or poly(propylene sulfide) (PPS) polymers.…”

Section: Designing Spatial and Temporal Controlmentioning

confidence: 99%

“…When TLR7/8a ligands are conjugated to particles, they are efficiently taken up by APCs and induce persistent innate immune activation in lymph nodes, thereby substantially reducing systemic toxicities in comparison with soluble small-molecule TLR7/8a, which shows rapid systemic distribution 105 , 115 . Moreover, improved trafficking by activated dendritic cells increases activation of T H 1-type CD4 + and CD8 + T cell responses and leads to higher antibody titres and improved antibody affinity maturation compared with immunization with soluble TLR7/8a ligands.…”

Section: Designing Spatial and Temporal Controlmentioning

confidence: 99%

Designing spatial and temporal control of vaccine responses

et al. 2021

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Vaccines are the key technology to combat existing and emerging infectious diseases. However, increasing the potency, quality and durability of the vaccine response remains a challenge. As our knowledge of the immune system deepens, it becomes clear that vaccine components must be in the right place at the right time to orchestrate a potent and durable response. Material platforms, such as nanoparticles, hydrogels and microneedles, can be engineered to spatially and temporally control the interactions of vaccine components with immune cells. Materials-based vaccination strategies can augment the immune response by improving innate immune cell activation, creating local inflammatory niches, targeting lymph node delivery and controlling the time frame of vaccine delivery, with the goal of inducing enhanced memory immunity to protect against future infections. In this Review, we highlight the biological mechanisms underlying strong humoral and cell-mediated immune responses and explore materials design strategies to manipulate and control these mechanisms.

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“…(1‐(4‐(amino‐methyl)benzyl)‐2‐(ethoxymethyl)‐1H‐imidazo[4,5‐c]quinolin‐4‐amine) TLR agonist (TLR7/8a‐1) was synthesized as described previously. [ 30 ] HBP post fractional precipitation (100 mg) was dissolved in 1 mL of DMSO. 1.05 equiv.…”

Section: Methodsmentioning

confidence: 99%

Enhanced Humoral Immune Response by High Density TLR Agonist Presentation on Hyperbranched Polymers

Liong

Smith

Mann

et al. 2021

Advanced Therapeutics

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Prophylactic vaccines often exploit adjuvants to drive potent and directed immune responses. Small‐molecule toll‐like receptor (TLR) agonists are promising adjuvant candidates; however, the poor pharmacokinetics and rapid distribution of these relatively hydrophilic small molecules results in systemic side effects that have limited their usage to topical application. In this study, TLR7/8 agonists are covalently attached to the highly dense end‐groups of hyperbranched polymers synthesized by controlled radical polymerization techniques. Subcutaneous administration of these adjuvants results in a potent and prolonged type I interferon response. When co‐administered in a model subunit vaccine, with ovalbumin or the HIV envelope glycoprotein gp120, these hyperbranched polymeric adjuvants potentiate an enhanced immunoglobulin response and near‐immediate type‐switching to IgG2c, suggesting they promote the type of strong T helper cell 1 immune response that is desirable for the treatment of intracellular pathogens such as mycobacterial and viral infections. Controlling the pharmacokinetics of potent TLR agonists through conjugation to hyperbranched polymers, therefore, enables the development of potent adjuvants in vaccines to drive durable and high‐quality humoral immunity.

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Nanoparticles Presenting Potent TLR7/8 Agonists Enhance Anti-PD-L1 Immunotherapy in Cancer Treatment

Cited by 55 publications

References 46 publications

Modulation of injectable hydrogel properties for slow co‐delivery of influenza subunit vaccine components enhance the potency of humoral immunity

Modulation of injectable hydrogel properties for slow co‐delivery of influenza subunit vaccine components enhance the potency of humoral immunity

Designing spatial and temporal control of vaccine responses

Enhanced Humoral Immune Response by High Density TLR Agonist Presentation on Hyperbranched Polymers

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