Co-encapsulation of synthetic lipidated TLR4 and TLR7/8 agonists in the liposomal bilayer results in a rapid, synergistic enhancement of vaccine-mediated humoral immunity

Short, Kristopher K.; Miller, Shannon M.; Walsh, Lois; Cybulski, Van; Bazin, Hélène G.; Evans, Jay T.; Burkhart, David J.

doi:10.1016/j.jconrel.2019.10.025

Cited by 36 publications

(28 citation statements)

References 64 publications

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“…In addition, the total IL-12p70 levels triggered by SD-101 and R848 NE/SD-101 combination were slightly higher than those triggered by R848 or R848 NE. In contrast to the previous report on the synergistic IL-12p70 production by co-activation of duo TLRs [50][51][52][53], IL-12p70 production was not increased by TLR7/8 and TLR9 co-activation (Figure 4C).…”

Section: In Vivo Antitumor Efficacycontrasting

confidence: 99%

A Squalene-Based Nanoemulsion for Therapeutic Delivery of Resiquimod

et al. 2021

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Agonists for toll-like receptors (TLRs) have shown promising activities against cancer. In the present study, a squalene-based nanoemulsion (NE) was loaded with resiquimod, a TLR7/8 agonist for therapeutic delivery. R848 NE was developed and characterized for long-term stability. In vitro and in vivo antitumor immunity of R848 NE were also evaluated in combination with SD-101, a CpG-containing TLR9 agonist. In vitro studies demonstrated strong long-term stability and immune responses to R848 NE. When combined with SD-101, strong antitumor activity was observed in MC38 murine colon carcinoma model with over 80% tumor growth inhibition. The combination treatment showed a 4-fold increase in systemic TNFa production and a 2.6-fold increase in Cd8a expression in tumor tissues, suggesting strong cell-mediated immune responses against the tumor. The treatment not only demonstrated a strong antitumor immunity by TLR7/8 and TLR9 activations but also induced PD-L1 upregulation in tumors, suggesting a potential therapeutic synergy with immune checkpoint inhibitors.

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Section: In Vivo Antitumor Efficacycontrasting

confidence: 99%

A Squalene-Based Nanoemulsion for Therapeutic Delivery of Resiquimod

et al. 2021

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“…This method spares both antigen and adjuvant. Several studies showed that co-encapsulated formulation has a superior immune response than separately loaded adjuvant formulations [17,[29][30][31]. Previously, we also demonstrated that co-encapsulation of TLR9 and TLR3 ligands increased cytokine production (IL-6, type I and II IFNs) in vitro and induced longer IgG2c production after in vivo administration compared to the free and separately loaded dual-adjuvant formulations [17].…”

Section: Discussionmentioning

confidence: 57%

“…In another study in vivo administration of co-encapsulation of TLR4 and TLR7/8 ligands with an antigen elevated IgG2a levels more than 6.5 fold compared to the separately loaded liposomal mixtures. These studies indicated that by delivering both ligands into the same cell, coencapsulation assures ligands are activating and enhancing crosstalk between activated pathways [31]. Such simultaneous activation of pathways is important to observe synergism and overcome potential antagonism between signaling axes.…”

Section: Discussionmentioning

confidence: 99%

Dual-adjuvant effect of pH-sensitive liposomes loaded with STING and TLR9 agonists regress tumor development by enhancing Th1 immune response

Kocabaş

Almacioglu

Bulut

et al. 2020

Journal of Controlled Release

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“…Previous work has shown combinations of TLR agonists delivered in soluble form and on biomaterials have elicited inflammatory cytokine responses in vitro and enhanced vaccine responses in vivo. [34][35][36][37]63] For example, codelivered MPLA and CpG stimulate stronger interferon (IFN)-𝛽 and IL-12p70 responses from GM-CSF BMDCs. [34,35,37] Though this does not correlate with an enhanced migratory response in vitro, there is still strong potential for combination adjuvants to induce strong immune responses in vivo.…”

Section: Discussionmentioning

confidence: 99%

Soluble and Microparticle‐Based Delivery of TLR4 and TLR9 Agonists Differentially Modulate 3D Chemotaxis of Bone Marrow‐Derived Dendritic Cells

Atalis

Dixon

Roy

2021

Adv Healthcare Materials

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Vaccines are commonly administered subcutaneously or intramuscularly, and local immune cells, notably dendritic cells (DCs), play a significant role in transporting vaccine antigens and adjuvants to draining lymph nodes. Here, it is compared how soluble and biomaterial‐mediated delivery of Toll‐like receptor (TLR)‐targeted adjuvants, monophosphoryl lipid A (MPLA, TLR4 ligand) and 5'‐C‐phosphate‐G‐3' DNA (CpG DNA, TLR9 ligand), modulate 3D chemotaxis of bone marrow‐derived dendritic cells (BMDCs) toward lymphatic chemokine gradients. Within microfluidic devices containing 3D collagen‐based matrices to mimic tissue conditions, soluble MPLA increases BMDC chemotaxis toward gradients of CCL19 and CCL21, while soluble CpG has no effect. Delivering CpG on poly(lactic‐co‐glycolic) acid microparticles (MPs) enhances BMDC chemotaxis compared to MPLA‐encapsulated MPs, and when co‐delivered, MPLA and CpG do not synergistically enhance BMDC migration. It is concluded that supplementing granulocyte‐macrophage colony stimulating factor‐derived BMDC culture with interleukin‐4 is necessary to induce CCR7 expression and chemotaxis of BMDCs. Different cell subsets in BMDC culture upregulate CCR7 in response to soluble versus biomaterial‐loaded MPLA and CpG, and CCR7 expression does not consistently correlate with functional migration. The results show both adjuvant type and delivery method influence chemotaxis of DCs, and these findings uncover new directions for the rational design of vaccine formulations.

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Co-encapsulation of synthetic lipidated TLR4 and TLR7/8 agonists in the liposomal bilayer results in a rapid, synergistic enhancement of vaccine-mediated humoral immunity

Cited by 36 publications

References 64 publications

A Squalene-Based Nanoemulsion for Therapeutic Delivery of Resiquimod

A Squalene-Based Nanoemulsion for Therapeutic Delivery of Resiquimod

Dual-adjuvant effect of pH-sensitive liposomes loaded with STING and TLR9 agonists regress tumor development by enhancing Th1 immune response

Soluble and Microparticle‐Based Delivery of TLR4 and TLR9 Agonists Differentially Modulate 3D Chemotaxis of Bone Marrow‐Derived Dendritic Cells

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