Exploiting lymphatic transport and complement activation in nanoparticle vaccines

Reddy, Sai T.; Vlies, André J. van der; Simeoni, Eleonora; Angeli, Véronique; Randolph, Gwendalyn J.; O’Neil, Conlin P.; Lee, Leslie K.; Swartz, Melody A.; Hubbell, Jeffrey A.

doi:10.1038/nbt1332

Cited by 1,180 publications

(1,090 citation statements)

References 31 publications

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“…Helper CD4 + T cells play an important role in initiating cellular immunity by triggering the differentiation of cytotoxic CD8 + T cells, and in initiating humoral immunity by stimulating B cells to produce antibodies 41. At the antigen and adjuvant doses in our experiments, treatment of mice with APN‐CpG led to a significantly greater proportion of CD8 + T cells secreting IFN‐γ than treatment with OVA + CpG or Algel2% + CpG (Figure 4D), even though the treatments APN‐CpG and OVA + CpG led to similar proportions of CD4 + T cells secreting IFN‐γ (Figure 4C).…”

Section: Resultsmentioning

confidence: 99%

Turning the Old Adjuvant from Gel to Nanoparticles to Amplify CD8⁺ T Cell Responses

et al. 2017

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Due to its safety and efficacy, aluminum hydroxide is used as an immune adjuvant in human vaccines for over 80 years. Being a Th2 stimulator, the classical gel‐like adjuvant, however, fails to generate CD8+ T cell responses, which are important for cancer vaccines. Here, aluminum hydroxide is turned from gel into nano‐sized vaccine carriers AlO(OH)‐polymer nanoparticles (APNs) to promote their lymphatic migration. After actively uptaken via scavenger receptor‐A by antigen‐presenting cells (APCs) resident in lymph nodes (LNs), APNs destabilize lysosomes resulting in efficient cytosolic delivery and cross‐presentation of antigens. It is demonstrated that administration of APNs loaded with ovalbumin (OVA) and CpG led to the codelivery of both cargos into APCs in LNs, leading to their activation and subsequent adaptive immunity. A prime‐boost strategy with low doses of OVA (1.5 µg) and CpG (0.45 µg) induces potent CD8+ T cell responses and dramatically prolongs the survival of B16‐OVA tumor‐bearing mice. More impressively, when using B16F10 lysates instead of OVA as antigen, substantial antitumor effects on B16F10 tumor model are observed by using APN‐CpG. These results suggest the great potential of APNs as vaccine carriers that activate CD8+ T cell responses and the bright prospect of aluminum adjuvant in a nanoparticle formulation.

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Section: Resultsmentioning

confidence: 99%

Turning the Old Adjuvant from Gel to Nanoparticles to Amplify CD8⁺ T Cell Responses

et al. 2017

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“…19,22,38 As a model protein cargo, we examined the assembly of multilayers containing ovalbumin (ova), a 45 KDa globular protein routinely used as a model vaccine antigen. [39][40][41] We first prepared PEM films by alternating adsorption of Poly-1 and ova from aqueous buffers onto glass slides, utilizing electrostatic interactions between the protein and polymer to mediate assembly and monitoring protein incorporation via the absorbance of fluorophore-conjugated ova. Based on the pI of ova (~4.6) and the pK a of Poly-1 (between 4.5 -8), we tested film assembly at pH 5 -7, varying the pH of both Poly-1 and ova adsorption solutions ( Figure S2).…”

Section: Resultsmentioning

confidence: 99%

Layer-by-Layer-Assembled Multilayer Films for Transcutaneous Drug and Vaccine Delivery

Su¹,

Kim²,

Kim³

et al. 2009

ACS Nano

156

120

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We describe protein-and oligonucleotide-loaded layer-by-layer (LbL)-assembled multiplayer films incorporating a hydrolytically degradable polymer for transcutaneous drug or vaccine delivery. Films were constructed based on electrostatic interactions between a cationic poly(β-amino ester) (denoted Poly-1) with a model protein antigen, ovalbumin (ova), and/or immunostimulatory CpG (Cytosine-phosphate diester-Guanine rich) DNA oligonucleotide adjuvant molecules. Linear growth of nanoscale Poly-1/ova bilayers was observed. Dried ova protein-loaded films rapidly deconstructed when rehydrated in saline solutions, releasing ova as non-aggregated/non-degraded protein, suggesting that the structure of biomolecules integrated into these multilayer films are preserved during release. Using confocal fluorescence microscopy and an in vivo murine ear skin model, we demonstrated delivery of ova from LbL films into barrierdisrupted skin, uptake of the protein by skin-resident antigen-presenting cells (Langerhans cells), and transport of the antigen to the skin-draining lymph nodes. Dual incorporation of ova and CpG oligonucleotides into the nanolayers of LbL films enabled dual release of the antigen and adjuvant with distinct kinetics for each component; ova was rapidly released while CpG was released in a relatively sustained manner. Applied as skin patches, these films delivered ova and CpG to Langerhans Cells in the skin. To our knowledge, this is the first demonstration of LbL films applied for the delivery of biomolecules into skin. This approach provides a new route for storage of vaccines and other immunotherapeutics in a solid-state thin film for subsequent delivery into the immunologically-rich milieu of the skin.

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“…To obtain BMDM, about 1 × 10 7 bone marrow cells were cultured in DMEM containing 10% FBS, antibiotics and conditioned media from L929 cell culture. After 6 to 7 days, mature macrophages were harvested and cultured on 12-well plates for experiments 5 . Total RNAs were extracted by TRIzol (Invitrogen) from cells or tissues according to the manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

“…Spatio-temporal control of antigen transport to the secondary lymphoid organs, cytosolic delivery and cross-presentation in the APCs in coordination with innate stimulation is essential to achieve robust tumor-specific T cell response. Although nanoparticles (<50 nm in diameter) can selectively accumulate inside the lymph nodes 4,5 , few studies had shown their ability to simultaneously promote antigen presentation and stimulate innate immune response without incorporation of adjuvants (e.g., CpG, Poly(I:C)). Recently, our lab has developed a library of ultra-pH sensitive (UPS) nanoparticles (20–50 nm in diameter) that are finely tunable in a broad range of physiological pH (4-7.4) 6 .…”

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confidence: 99%

A STING-activating nanovaccine for cancer immunotherapy

et al. 2017

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Generation of tumor-specific T cells is critically important for cancer immunotherapy1,2. A major challenge in achieving a robust T cell response is the spatio-temporal orchestration of antigen cross-presentation in antigen presenting cells (APCs) with innate stimulation. Here we report a minimalist nanovaccine by a simple physical mixture of an antigen with a synthetic polymeric nanoparticle, PC7A NP, which generated a strong cytotoxic T cell response with low systemic cytokine expression. Mechanistically, PC7A NP achieved efficient cytosolic delivery of tumor antigens to APCs in draining lymph nodes leading to increased surface presentation while simultaneously activating type I interferon-stimulated genes. This effect was dependent on STING but not Toll-like receptor or MAVS pathway. Nanovaccine produced potent tumor growth inhibition in melanoma, colon cancer, and human papilloma virus-E6/E7 tumor models. Combination of PC7A nanovaccine with an anti-PD-1 antibody showed great synergy with 100% survival over 60 days in a TC-1 tumor model. Rechallenging of these tumor-free animals with TC-1 cells led to complete inhibition of tumor growth, suggesting generation of long-term antitumor memory. The STING-activating nanovaccine offers a simple, safe and robust strategy in boosting anti-tumor immunity for cancer immunotherapy.

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Exploiting lymphatic transport and complement activation in nanoparticle vaccines

Cited by 1,180 publications

References 31 publications

Turning the Old Adjuvant from Gel to Nanoparticles to Amplify CD8⁺ T Cell Responses

Turning the Old Adjuvant from Gel to Nanoparticles to Amplify CD8⁺ T Cell Responses

Layer-by-Layer-Assembled Multilayer Films for Transcutaneous Drug and Vaccine Delivery

A STING-activating nanovaccine for cancer immunotherapy

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Exploiting lymphatic transport and complement activation in nanoparticle vaccines

Cited by 1,180 publications

References 31 publications

Turning the Old Adjuvant from Gel to Nanoparticles to Amplify CD8+ T Cell Responses

Turning the Old Adjuvant from Gel to Nanoparticles to Amplify CD8+ T Cell Responses

Layer-by-Layer-Assembled Multilayer Films for Transcutaneous Drug and Vaccine Delivery

A STING-activating nanovaccine for cancer immunotherapy

Contact Info

Product

Resources

About

Turning the Old Adjuvant from Gel to Nanoparticles to Amplify CD8⁺ T Cell Responses

Turning the Old Adjuvant from Gel to Nanoparticles to Amplify CD8⁺ T Cell Responses