scholarly journals Red blood cell–derived nanoerythrosome for antigen delivery with enhanced cancer immunotherapy

2019 ◽  
Vol 5 (10) ◽  
pp. eaaw6870 ◽  
Author(s):  
Xiao Han ◽  
Shufang Shen ◽  
Qin Fan ◽  
Guojun Chen ◽  
Edikan Archibong ◽  
...  
Keyword(s):  
Blood Cells ◽  
Tumor Recurrence ◽  
Tumor Antigens ◽  
Tumor Model ◽  
Antigen Delivery ◽  
Tumor Cell Membrane ◽  
Programmed Death ◽  
Delivery Platform ◽  
Antigen Presenting

Erythrocytes or red blood cells (RBCs) represent a promising cell-mediated drug delivery platform due to their inherent biocompatibility. Here, we developed an antigen delivery system based on the nanoerythrosomes derived from RBCs, inspired by the splenic antigen-presenting cell targeting capacity of senescent RBCs. Tumor antigens were loaded onto the nanoerythrosomes by fusing tumor cell membrane–associated antigens with nanoerythrosomes. This tumor antigen–loaded nanoerythrosomes (nano-Ag@erythrosome) elicited antigen responses in vivo and, in combination with the anti–programmed death ligand 1 (PD-L1) blockade, inhibited the tumor growth in B16F10 and 4T1 tumor models. We also generated a tumor model showing that “personalized nano-Ag@erythrosomes” could be achieved by fusing RBCs and surgically removed tumors, which effectively reduced tumor recurrence and metastasis after surgery.

scholarly journals 708 Application of a novel mSENS drug delivery technology for mRNA therapeutics

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A750-A750
Author(s):  
Sojin Lee ◽  
Joon Young Park ◽  
Goo-Young Kim ◽  
Sang Woo Jo ◽  
Minhyuk Yun ◽  
...  
Keyword(s):  
Particle Size ◽  
Protein Expression ◽  
Cancer Vaccine ◽  
Encapsulation Efficiency ◽  
Tumor Model ◽  
Cell Responses ◽  
Delivery Platform ◽  
Mrna Therapeutics

BackgroundSuccessful clinical translation of mRNA therapeutics requires an appropriate delivery strategy to overcome instability of mRNA and facilitate cellular uptake into the cells.1 Several lipid based nanoparticle approaches that encapsulate mRNA, notably lipid nanoparticle (LNP), have been developed, but their efficiency for delivery to certain target tissues and toxicity profiles still have room for improvement. The application of a novel polymer based nanoparticle technology platform, so called Stability Enhanced Nano Shells (SENS) for mRNA (mSENS) as a mRNA delivery platform for a cancer vaccine was demonstrated.MethodsThe physicochemical properties of mSENS formulation, particle size and encapsulation efficiency, were characterized using dynamic light scattering (DLS) and gel retardation assay. Using luciferase-encoding mRNA, the protein expression levels in vitro and in vivo were evaluated by luciferase assay or bioluminescence imaging (BLI), respectively. For cancer vaccine studies, antigen (tyrosinase-related protein 2 (Trp-2))-specific T cell responses were assessed by immunophenotyping mouse splenocytes using flow cytometry and by the enzyme-linked immunosorbent spot (ELISPOT) assay. The anti-tumor efficacy was studied in B16F10 lung tumor model in C57BL/6 mice. Liver and systemic toxicity of mSENS treated mice was evaluated through blood chemistry and complete blood count (CBC) tests.ResultsA library of mSENS formulations complexed with luciferase-encoding mRNA, were characterized for their particle size, surface charge, encapsulation efficiency, colloidal stability, and in vitro and in vivo luciferase protein expression level. Upon systemic administration in mice, varying biodistribution profiles were observed, implicating the potential for tailored delivery to target tissues. Particularly, cancer vaccine application was further developed leveraging the formulation with preferential spleen delivery. Following vaccination with Trp-2 mRNA encapsulated with mSENS (Trp-2 mRNA-mSENS) in B16F10 tumor bearing mice, strong Trp-2 antigen-specific IFN-γ T-cell responses were observed. Generated anti-tumor immunity also marked suppression of B16F10 lung tumors were observed in Trp-2-mSENS immunized mice compared to non-immunized controls, demonstrating the potential of mSENS as a mRNA delivery platform for the application for vaccine.ConclusionsProprietary biodegradable polymer based-mSENS platform offers an attractive delivery strategy for mRNA by tailoring to specific therapeutic applications. Depending on the application, whether it’s a vaccine or protein replacement, a rationally designed mSENS formulation can efficiently distribute mRNA to specific tissues. In particular, application of a splenic mSENS formulation for a cancer vaccine has been demonstrated in murine tumor model. In summary, mRNA delivery through mSENS platform is expected to provide significant opportunities in clinical development for mRNA therapeutics.Ethics ApprovalThe study was approved by Samyang Biopharmaceuticals’ IACUC (Institutional Animal Care and Use Committee), approval number SYAU-2027.ReferencePiotr S. Kowalski, Arnab Rudra, Lei Miao, and Daniel G. Anderson, delivering the messenger: advances in technologies for therapeutic mRNA delivery. Molecular Therapy Vol. 27 No 4 April 2019.

Cell-Penetrating Peptide-Mediated Nanovaccine Delivery

2021 ◽  
Vol 22 ◽  
Author(s):  
Jizong Jiang
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Cell Penetrating Peptide ◽  
Antigen Delivery ◽  
Efficient Manner ◽  
Antigen Uptake ◽  
Cell Penetrating ◽  
The Stability ◽  
Antigen Presenting

Abstract: Vaccination with small antigens, such as proteins, peptides, or nucleic acids, is used to activate the immune system and trigger the protective immune responses against a pathogen. Currently, nanovaccines are undergoing development instead of conventional vaccines. The size of nanovaccines is in the range of 10–500 nm, which enables them to be readily taken up by cells and exhibit improved safety profiles. However, low-level immune responses, as the removal of redundant pathogens, trigger counter-effective activation of the immune system invalidly and present a challenging obstacle to antigen recognition and its uptake via antigen-presenting cells (APCs). In addition, toxicity can be substantial. To overcome these problems, a variety of cell-penetrating peptide (CPP)-mediated vaccine delivery systems based on nanotechnology have been proposed, most of which are designed to improve the stability of antigens in vivo and their delivery into immune cells. CPPs are particularly attractive components of antigen delivery. Thus, the unique translocation property of CPPs ensures that they remain an attractive carrier with the capacity to deliver cargo in an efficient manner for the application of drugs, gene transfer, protein, and DNA/RNA vaccination delivery. CPP-mediated nanovaccines can enhance antigen uptake, processing, and presentation by APCs, which are the fundamental steps in initiating an immune response. This review describes the different types of CPP-based nanovaccines delivery strategies.

Processing and cross-presentation of individual HLA-A, -B, or -C epitopes from NY-ESO-1 or an HLA-A epitope for Melan-A differ according to the mode of antigen delivery

Blood ◽  
2010 ◽  
Vol 116 (2) ◽  
pp. 218-225 ◽  
Author(s):  
Neil C. Robson ◽  
Tristan McAlpine ◽  
Ashley J. Knights ◽  
Max Schnurr ◽  
Amanda Shin ◽  
...  
Keyword(s):  
Tumor Antigens ◽  
Human Leukocyte ◽  
Full Length ◽  
Antigen Delivery ◽  
Cross Presentation ◽  
Endosomal Acidification ◽  
Therapeutic Cancer Vaccines ◽  
First Time ◽  
Cancer Testis

Abstract The ability of dendritic cells (DCs) to cross-present protein tumor antigens to cytotoxic T lymphocytes (CTLs) underpins the success of therapeutic cancer vaccines. We studied cross-presentation of the cancer/testis antigen, NY-ESO-1, and the melanoma differentiation antigen, Melan-A by human DC subsets. Monocyte-derived DCs (MoDCs) efficiently cross-presented human leukocyte associated (HLA)–A2-restricted epitopes from either a formulated NY-ESO-1/ISCOMATRIX vaccine or when either antigen was mixed with ISCOMATRIX adjuvant. HLA-A2 epitope generation required endosomal acidification and was proteasome-independent for NY-ESO-1 and proteasome-dependent for Melan-A. Both MoDCs and CD1c+ blood DCs cross-presented NY-ESO-1–specific HLA-A2157-165–, HLA-B760-72–, and HLA-Cw392-100–restricted epitopes when formulated as an NY-ESO-1/ISCOMATRIX vaccine, but this was limited when NY-ESO-1 and ISCOMATRIX adjuvant were added separately to the DC cultures. Finally, cross-presentation of NY-ESO-1157-165/HLA-A2, NY-ESO-160-72/HLA-B7, and NY-ESO-192-100/HLA-Cw3 epitopes was proteasome-dependent when formulated as immune complexes (ICs) but only proteasome-dependent for NY-ESO-160-72/HLA-B7–restricted cross-presentation facilitated by ISCOMATRIX adjuvant. We demonstrate, for the first time, proteasome-dependent and independent cross-presentation of HLA-A–, B–, and C–restricted epitopes within the same full-length tumor antigen by human DCs. Our findings identify important differences in the capacities of human DC subsets to cross-present clinically relevant, full-length tumor antigens and how vaccine formulation impacts CTL responses in vivo.

scholarly journals PGC-1α activator–induced fatty acid oxidation in tumor-infiltrating CTLs enhances effects of PD-1 blockade therapy in lung cancer

2019 ◽  
Vol 106 (1) ◽  
pp. 55-63
Author(s):  
Huan Wan ◽  
Bin Xu ◽  
Ni Zhu ◽  
Baozhong Ren
Keyword(s):  
Lung Cancer ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Tumor Model ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Programmed Death ◽  
Effect Of Pd

Purpose: The present study aims to investigate the efficacy and mechanisms of peroxisome proliferator-activated receptor γ coactivator 1-α agonist, as adjuvant to programmed death-1 (PD-1) blockade in hyporesponsive lung cancer cells–derived in vivo tumor model, using bezafibrate. Methods: Mouse Lewis lung carcinoma (LLC) xenograft models were established and treated with programmed death-ligand 1 (PD-L1) monoclonal antibodies with or without bezafibrate. Tumors or peripheral blood of mice were harvested to investigate the quality, quantity, and function as well as energetic metabolism of cytotoxic T lymphocytes (CTLs) by flow cytometry or quantitative real-time polymerase chain reaction. Results: The combination of bezafibrate plus anti-PD-L1 reached synergistic tumoricidal effect in LLC xenograft mouse models, even though bezafibrate alone had no effect on tumor growth. Bezafibrate significantly facilitated CD8+ T cells infiltrating into tumor tissues by enhancing the expression of CXCL9 and CXCL10 within tumors as well as the receptor CXCR3 in infiltrating CTLs. Activated CTLs within tumors were also significantly upregulated by bezafibrate. Further data demonstrated that bezafibrate treatment could maintain the survival and functional capacity of tumor-infiltrating CTLs. Moreover, cellular reactive oxygen species in infiltrating CTLs and fatty acid oxidation (FAO)–related genes (PGC-1α, Cpt1a, and LCAD) expression within tumors were significantly increased after treatment with bezafibrate. Conclusions: Bezafibrate synergized the tumoricidal effect of PD-1 blockade in hyporesponsive lung cancer by expansion of effector CTLs within tumor microenvironment. The potential mechanism may relate to the capacity of bezafibrate in regulating FAO of tumor-infiltrating CTLs.

scholarly journals A Targeted Vaccine against COVID-19: S1-Fc Vaccine Targeting the Antigen-Presenting Cell Compartment Elicits Protection against SARS-CoV-2 Infection

2020 ◽  
Author(s):  
Andreas Herrmann ◽  
Junki Maruyama ◽  
Chanyu Yue ◽  
Christoph Lahtz ◽  
Heyue Zhou ◽  
...  
Keyword(s):  
Antigen Presenting Cells ◽  
T Cell Response ◽  
Antigen Delivery ◽  
Cell Compartment ◽  
Antigen Presenting Cell ◽  
Live Virus ◽  
Virus Challenge ◽  
Antigen Presenting

AbstractVaccination efficacy is enhanced by targeting the antigen-presenting cell compartment. Here, we show that S1-Fc antigen delivery targeting the FcγR+ antigen-presenting cell compartment elicits anti-SARS-CoV-2 S1-antigen specific IgG production in vivo exerting biologically functional and protective activity against live virus infection, assessed in a stringent experimental virus challenge assay in vitro. The S1-domain of the SARS-CoV-2 spike protein was genetically fused to a human immunoglobulin Fc moiety, which contributes to mediate S1-Fc cellular internalization by FcγR+ antigen-presenting cells. Immediately upon administration intramuscularly, our novel vaccine candidate recombinant rS1-Fc homes to lymph nodes in vivo where FcγR+ antigen-presenting cells reside. Seroconversion is achieved as early as day 7, mounting considerably increased levels of anti-S1 IgGs in vivo. Interestingly, immunization at elevated doses with non-expiring S1-Fc encoding dsDNA favors the education of a desired antigen-specific adaptive T cell response. However, low-dose immunization, safeguarding patient safety, using recombinant rS1-Fc, elicits a considerably elevated protection amplitude against live SARS-CoV-2 infection. Our promising findings on rS1-Fc protein immunization prompted us to further develop an affordable and safe product for delivery to our communities in need for COVID-19 vaccinations.

scholarly journals Hybrid membrane-coated nanosuspensions for multi-modal anti-glioma therapy via drug and antigen delivery

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Wenyan Hao ◽  
Yuexin Cui ◽  
Yueyue Fan ◽  
Mengyu Chen ◽  
Guobao Yang ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Cell Membrane ◽  
Tumor Antigens ◽  
Hybrid Membrane ◽  
Antigen Delivery ◽  
Nano Drug Delivery ◽  
Membrane Antigens ◽  
Membrane Bound ◽  
Cell Membrane Antigens ◽  
Antigen Presenting

Abstract Background Glioma is one of the deadliest human cancers. Although many therapeutic strategies for glioma have been explored, these strategies are seldom used in the clinic. The challenges facing the treatment of glioma not only involve the development of chemotherapeutic drugs and immunotherapeutic agents, but also the lack of a powerful platform that could deliver these two moieties to the targeted sites. Herein, we developed chemoimmunotherapy delivery vehicles based on C6 cell membranes and DC membranes to create hybrid membrane-coated DTX nanosuspensions (DNS-[C6&DC]m). Results Results demonstrated successful hybrid membrane fusion and nanosuspension functionalization, and DNS-[C6&DC]m could be used for different modes of anti-glioma therapy. For drug delivery, membrane coating could be applied to target the source cancer cells via a homotypic-targeting mechanism of the C6 cell membrane. For cancer immunotherapy, biomimetic nanosuspension enabled an immune response based on the professional antigen-presenting characteristic of the dendritic cell membrane (DCm), which carry the full array of cancer cell membrane antigens and facilitate the uptake of membrane-bound tumor antigens for efficient presentation and downstream immune n. Conclusion DNS-[C6&DC]m is a multifunctional biomimetic nano-drug delivery system with the potential to treat gliomas through tumor-targeted drug delivery combined with immunotherapy, thereby presenting a promising approach that may be utilized for multiple modes of cancer therapy. Graphical Abstract

Tumor Antigen-Based Nanovaccines for Cancer Immunotherapy: A Review

2021 ◽  
Vol 17 (11) ◽  
pp. 2099-2113
Author(s):  
Jiaxuan Zhao ◽  
Guangsheng Du ◽  
Xun Sun
Keyword(s):  
Cancer Immunotherapy ◽  
Tumor Antigen ◽  
Tumor Antigens ◽  
Antigenic Specificity ◽  
Tumor Vaccines ◽  
Tumor Cell Membrane ◽  
Peptide Antigens ◽  
Important Means ◽  
Antigen Presenting

As an important means of tumor immunotherapy, tumor vaccines have achieved exciting results in the past few decades. However, there are still many obstacles that hinder tumor vaccines from achieving maximum efficacy, including lack of tumor antigens, low antigen immunogenicity and poor delivery efficiency. To overcome these challenges, researchers have developed and investigated various new types of tumor antigens with higher antigenic specificity and broader antigen spectrum, such as tumor-specific peptide antigens, tumor lysates, tumor cell membrane, tumor associated exosomes, etc. At the same time, different nanoparticulate delivery platforms have been developed to increase the immunogenicity of the tumor antigens, for example by increasing their targeting efficiency of antigen-presenting cells and lymph nodes, and by co-delivering antigens with adjuvants. In this review, we summarized different types of the tumor antigens that have been reported, and introduced several nanovaccine strategies for increasing the immunogenicity of tumor antigens. The review of recent progress in these fields may provide reference for the follow-up studies of tumor antigen-based cancer immunotherapy.

scholarly journals Does B7-1 expression confer antigen-presenting cell capacity to tumors in vivo?

1996 ◽  
Vol 183 (3) ◽  
pp. 769-776 ◽  
Author(s):  
A Y Huang ◽  
A T Bruce ◽  
D M Pardoll ◽  
H I Levitsky
Keyword(s):  
Bone Marrow ◽  
Tumor Antigens ◽  
Cytotoxic T Lymphocyte ◽  
Costimulatory Molecule ◽  
Tumor Vaccines ◽  
Murine Colon Carcinoma ◽  
Immunocompetent Mice ◽  
Antigen Presenting ◽  
Model Tumor

Tumors engineered to express the costimulatory molecule B7-1 can elicit CD8+ cytotoxic T lymphocyte (CTL)-dependent antitumor responses in immunocompetent mice. It has been postulated that this result reflects direct priming of CTL by the modified tumor in vivo. Previous studies of the immune response to a B7-1- murine colon carcinoma expressing influenza nucleoprotein (NP) as a model tumor antigen have demonstrated the crucial role of bone marrow-derived antigen-presenting cells (APCs) in the priming of NP-specific CTL in vivo. In this system, no evidence of direct CTL priming by tumor was detected. We have performed a similar analysis to determine if B7-1 transfectant of this tumor results in the direct priming of CTL, and to compare this response to that primed by host APCs. When H-2b-->H-2bxd bone marrow chimeras were immunized with a single injection of CT26/NP/B7-1 (H-2d), NP-specific CTL were detected that were restricted to the bone marrow haplotype (H-2b), but not to the tumor haplotype. In contrast, CTL recognizing the NP antigenic epitope in the context of the tumor's major histocompatibility complex were detectable only after multiple immunizations. These results suggest that whereas B7-1+ tumor vaccines result in some degree of direct presentation to CD8+ T cells, the dominant mechanism of CTL priming is through the uptake and presentation of tumor antigens by bone marrow-deprived APCs. However, repeated immunization with B7-1+ tumor cells can efficiently expand the directly primed CD8+ CTL population.

scholarly journals The pore size of mesoporous silica nanoparticles regulates their antigen delivery efficiency

2020 ◽  
Vol 6 (25) ◽  
pp. eaaz4462 ◽  
Author(s):  
Xiaoyu Hong ◽  
Xiaofang Zhong ◽  
Guangsheng Du ◽  
Yingying Hou ◽  
Yunting Zhang ◽  
...  
Keyword(s):  
Mesoporous Silica ◽  
Silica Nanoparticles ◽  
Tumor Antigens ◽  
Mesoporous Silica Nanoparticles ◽  
Antigen Delivery ◽  
Antitumor Effects ◽  
Mhc I ◽  
Pore Sizes ◽  
Large Pore

Subunit vaccines generally proceed through a 4-step in vivo cascade—the DUMP cascade—to generate potent cell-mediated immune responses: (1) drainage to lymph nodes; (2) uptake by dendritic cells (DCs); (3) maturation of DCs; and (4) Presentation of peptide-MHC I complexes to CD8+ T cells. How the physical properties of vaccine carriers such as mesoporous silica nanoparticles (MSNs) influence this cascade is unclear. We fabricated 80-nm MSNs with different pore sizes (7.8 nm, 10.3 nm, and 12.9 nm) and loaded them with ovalbumin antigen. Results demonstrated these MSNs with different pore sizes were equally effective in the first three steps of the DUMP cascade, but those with larger pores showed higher cross-presentation efficiency (step 4). Consistently, large-pore MSNs loaded with B16F10 tumor antigens yielded the strongest antitumor effects. These results demonstrate the promise of our lymph node-targeting large-pore MSNs as vaccine-delivery vehicles for immune activation and cancer vaccination.

scholarly journals Development of Mannose-Modified Carboxylated Curdlan-Coated Liposomes for Antigen Presenting Cell Targeted Antigen Delivery

Pharmaceutics ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 754
Author(s):  
Eiji Yuba ◽  
Yoshiki Fukaya ◽  
Shin Yanagihara ◽  
Nozomi Kasho ◽  
Atsushi Harada
Keyword(s):  
Cellular Immunity ◽  
Specific Antigen ◽  
Antigen Delivery ◽  
Antitumor Effects ◽  
Mannose Residue ◽  
Precise Control ◽  
Cross Presentation ◽  
Antigen Presenting ◽  
Induced Aggregation

Specific delivery to antigen presenting cells (APC) and precise control of the intracellular fate of antigens are crucial to induce cellular immunity that directly and specifically attacks cancer cells. We previously achieved cytoplasmic delivery of antigen and activation of APC using carboxylated curdlan-modified liposomes, which led to the induction of cellular immunity in vivo. APCs express mannose receptors on their surface to recognize pathogen specifically and promote cross-presentation of antigen. In this study, mannose-residue was additionally introduced to carboxylated curdlan as a targeting moiety to APC for further improvement of polysaccharide-based antigen carriers. Mannose-modified curdlan derivatives were synthesized by the condensation between amino group-introduced mannose and carboxy group in pH-sensitive curdlan. Mannose residue-introduced carboxylated curdlan-modified liposomes showed higher pH-sensitivity than that of liposomes modified with conventional carboxylated curdlan. The introduction of mannose-residue to the liposomes induced aggregation in the presence of Concanavalin A, indicating that mannose residues were presented onto liposome surface. Mannose residue-introduced carboxylated curdlan-modified liposomes exhibited high and selective cellular association to APC. Furthermore, mannose residue-introduced carboxylated curdlan-modified liposomes promoted cross-presentation of antigen and induced strong antitumor effects on tumor-bearing mice. Therefore, these liposomes are promising as APC-specific antigen delivery systems for the induction of antigen-specific cellular immunity.

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