Journal Articles

Cancer vaccine delivery

Novel strategies for the delivery of cancer vaccines, including nanotechnology

Mycobacterium tuberculosis PPE60 antigen drives Th1/Th17 responses via Toll-like receptor 2-dependent maturation of dendritic cells

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Targeting of Mycobacterium tuberculosis (MTB) PE/PPE antigens that induce type 1 helper T cell (Th1) and Th17 responses represents a crucial strategy for the development of tuberculosis (TB) vaccines. However, only few PE/PPE antigens induce these responses. Here, we sought to determine how the cell wall-associated antigen PPE60 (Rv3478) activates dendritic cell (DC) maturation and T-cell differentiation. We observed that PPE60 induces DC maturation by augmenting the protein expression of cluster of differentiation 80 (CD80) and CD86, and major histocompatibility complex (MHC) class I and MHC class II on the cell surface. PPE60 also stimulated the production of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, IL-12p70, and IL-23p19, but not IL-10. This induction was mediated by Toll-like receptor 2 (TLR2) and followed by activation of p38, c-Jun N-terminal kinase (JNK), and NF-kappaB signaling. PPE60 enhanced MHC-II expression and promoted antigen processing by DCs in a TLR2-dependent manner. Moreover, PPE60-stimulated DCs directed naive CD4(+) T cells to produce IFN-gamma, IL-2, and IL-17A, expanding the Th1 and Th17 responses, along with activation of T-Bet and RAR-related orphan receptor C (RORgammat), but not GATA-3. Moreover, PPE60 activated the NLRP3 inflammasome, followed by caspase-1-dependent IL-1beta and IL-18 synthesis in DCs. Of note, pharmacological inhibition of NLRP3 activation specifically attenuated IFN-gamma and IL-17A secretion into the supernatant from CD4(+) T cells co-cultured with PPE60-activated DCs. These findings indicate that PPE60 induces Th1 and Th17 immune responses by activating DCs in a TLR2-dependent manner, suggesting PPE60's potential for use in MTB vaccine development.

Author Info: (1) GMU-GIBH Joint School of Life Science, Guangzhou Medical University, China. (2) Guangdong Second Provincial General Hospital, China. (3) GMU-GIBH Joint School of Life Science

Author Info: (1) GMU-GIBH Joint School of Life Science, Guangzhou Medical University, China. (2) Guangdong Second Provincial General Hospital, China. (3) GMU-GIBH Joint School of Life Science, Guangzhou Medical University, China. (4) GMU-GIBH Joint School of Life Science, Guangzhou Medical University, China. (5) State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University, China. (6) State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University, China. (7) Department of Laboratory Medicine and Central Laboratories, Guangdong Second Provincial General Hospital, China. (8) State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University, China.

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Carbonate Apatite Nanoparticles Act as Potent Vaccine Adjuvant Delivery Vehicles by Enhancing Cytokine Production Induced by Encapsulated Cytosine-Phosphate-Guanine Oligodeoxynucleotides

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Vaccine adjuvants that can induce not only antigen-specific antibody responses but also Th1-type immune responses and CD8(+) cytotoxic T lymphocyte responses are needed for the development of vaccines against infectious diseases and cancer. Of many available adjuvants, oligodeoxynucleotides (ODNs) with unmethylated cytosine-phosphate-guanine (CpG) motifs are the most promising for inducing the necessary immune responses, and these adjuvants are currently under clinical trials in humans. However, the development of novel delivery vehicles that enhance the adjuvant effects of CpG ODNs, subsequently increasing the production of cytokines such as type-I interferons (IFNs), is highly desirable. In this study, we demonstrate the potential of pH-responsive biodegradable carbonate apatite (CA) nanoparticles as CpG ODN delivery vehicles that can enhance the production of type-I IFNs (such as IFN-alpha) relative to that induced by CpG ODNs and can augment the adjuvant effects of CpG ODNs in vivo. In contrast to CpG ODNs, CA nanoparticles containing CpG ODNs (designated CA-CpG) induced significant IFN-alpha production by mouse dendritic cells and human peripheral blood mononuclear cells in vitro; and production of interleukin-12, and IFN-gamma was higher in CA-CpG-treated groups than in CpG ODNs groups. In addition, treatment with CA-CpG resulted in higher cytokine production in draining lymph nodes than did treatment with CpG ODNs in vivo. Furthermore, vaccination with CA-CpG plus an antigen, such as ovalbumin or influenza virus hemagglutinin, resulted in higher antigen-specific antibody responses and CD8(+) cytotoxic T lymphocyte responses in vivo, in an interleukin-12- and type-I IFN-dependent manner, than did vaccination with the antigen plus CpG ODNs; in addition, the efficacy of the vaccine against influenza virus was higher with CA-CpG as the adjuvant than with CpG ODNs as the adjuvant. These data show the potential of CA nanoparticles to serve as CpG ODN delivery vehicles that increase the production of cytokines, especially IFN-alpha, induced by CpG ODNs and thus augment the efficacy of CpG ODNs as adjuvants. We expect that the strategy reported herein will facilitate the design and development of novel adjuvant delivery vehicles for vaccines.

Author Info: (1) Vaccine Creation Project, BIKEN Innovative Vaccine Research Alliance Laboratories, Research Institute for Microbial Diseases, Osaka University, Suita, Japan. (2) Vaccine Creation Project, BIKEN Innovative

Author Info: (1) Vaccine Creation Project, BIKEN Innovative Vaccine Research Alliance Laboratories, Research Institute for Microbial Diseases, Osaka University, Suita, Japan. (2) Vaccine Creation Project, BIKEN Innovative Vaccine Research Alliance Laboratories, Research Institute for Microbial Diseases, Osaka University, Suita, Japan. (3) Vaccine Dynamics Project, BIKEN Innovative Vaccine Research Alliance Laboratories, Research Institute for Microbial Diseases, Osaka University, Suita, Japan. Vaccine Dynamics Project, BIKEN Center for Innovative Vaccine Research and Development, The Research Foundation for Microbial Diseases of Osaka University, Suita, Japan. (4) Vaccine Creation Project, BIKEN Center for Innovative Vaccine Research and Development, The Research Foundation for Microbial Diseases of Osaka University, Suita, Japan. (5) Division of Health Sciences, Department of Molecular Pathology, Graduate School of Medicine, Osaka University, Suita, Japan. (6) Division of Health Sciences, Department of Molecular Pathology, Graduate School of Medicine, Osaka University, Suita, Japan. (7) Laboratory of Adjuvant Innovation, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan. Laboratory of Vaccine Science, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan. (8) Laboratory of Adjuvant Innovation, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan. Laboratory of Vaccine Science, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan. (9) Division of Health Sciences, Department of Molecular Pathology, Graduate School of Medicine, Osaka University, Suita, Japan. (10) Vaccine Creation Project, BIKEN Innovative Vaccine Research Alliance Laboratories, Research Institute for Microbial Diseases, Osaka University, Suita, Japan. Vaccine Creation Project, BIKEN Center for Innovative Vaccine Research and Development, The Research Foundation for Microbial Diseases of Osaka University, Suita, Japan. Laboratory of Nano-Design for Innovative Drug Development, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan. Global Center for Medical Engineering and Informatics, Osaka University, Suita, Japan.

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Engineered hybrid spider silk particles as delivery system for peptide vaccines

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The generation of strong T-cell immunity is one of the main challenges for the development of successful vaccines against cancer and major infectious diseases. Here we have engineered spider silk particles as delivery system for a peptide-based vaccination that leads to effective priming of cytotoxic T-cells. The recombinant spider silk protein eADF4(C16) was fused to the antigenic peptide from ovalbumin, either without linker or with a cathepsin cleavable peptide linker. Particles prepared from the hybrid proteins were taken up by dendritic cells, which are essential for T-cell priming, and successfully activated cytotoxic T-cells, without signs of immunotoxicity or unspecific immunostimulatory activity. Upon subcutaneous injection in mice, the particles were taken up by dendritic cells and accumulated in the lymph nodes, where immune responses are generated. Particles from hybrid proteins containing a cathepsin-cleavable linker induced a strong antigen-specific proliferation of cytotoxic T-cells in vivo, even in the absence of a vaccine adjuvant. We thus demonstrate the efficacy of a new vaccine strategy using a protein-based all-in-one vaccination system, where spider silk particles serve as carriers with an incorporated peptide antigen. Our study further suggests that engineered spider silk-based vaccines are extremely stable, easy to manufacture, and readily customizable.

Author Info: (1) Department of Pharmacy, Pharmaceutical Technology & Biopharmaceutics, Ludwig-Maximilians-University Munich, Butenandtstrasse 5, 81377 Munich, Germany; Coriolis Pharma, Fraunhoferstrasse 18B, 82152 Planegg/Martinsried, Germany. (2) Department of

Author Info: (1) Department of Pharmacy, Pharmaceutical Technology & Biopharmaceutics, Ludwig-Maximilians-University Munich, Butenandtstrasse 5, 81377 Munich, Germany; Coriolis Pharma, Fraunhoferstrasse 18B, 82152 Planegg/Martinsried, Germany. (2) Department of Medicine, Faculty of Science, University of Fribourg, Chemin Du Musee 5, 1700 Fribourg, Switzerland; Ecole de Pharmacie Geneve-Lausanne, University of Geneva, Rue Michel-Servet 1, 1211 Geneva, Switzerland; Ecolede Pharmacie Geneve-Lausanne, University of Lausanne, Rue Michel-Servet 1, 1211 Geneva, Switzerland. (3) Department of Medicine, Faculty of Science, University of Fribourg, Chemin Du Musee 5, 1700 Fribourg, Switzerland. (4) Department of Medicine, Faculty of Science, University of Fribourg, Chemin Du Musee 5, 1700 Fribourg, Switzerland. (5) AMSilk GmbH, Am Klopferspitz 19, 82152 Planegg/Martinsried, Germany. (6) University of Bayreuth, Faculty of Engineering Science, Chair for Biomaterials, Universitatsstrasse 30, 95440 Bayreuth, Germany. (7) University of Bayreuth, Faculty of Engineering Science, Chair for Biomaterials, Universitatsstrasse 30, 95440 Bayreuth, Germany. (8) AMSilk GmbH, Am Klopferspitz 19, 82152 Planegg/Martinsried, Germany. (9) Department of Medicine, Faculty of Science, University of Fribourg, Chemin Du Musee 5, 1700 Fribourg, Switzerland. (10) University of Bayreuth, Faculty of Engineering Science, Chair for Biomaterials, Universitatsstrasse 30, 95440 Bayreuth, Germany. (11) Department of Pharmacy, Pharmaceutical Technology & Biopharmaceutics, Ludwig-Maximilians-University Munich, Butenandtstrasse 5, 81377 Munich, Germany. (12) Department of Medicine, Faculty of Science, University of Fribourg, Chemin Du Musee 5, 1700 Fribourg, Switzerland; Ecole de Pharmacie Geneve-Lausanne, University of Geneva, Rue Michel-Servet 1, 1211 Geneva, Switzerland; Department of Anesthesiology, Pharmacology and Intensive Care, Faculty of Medicine, University of Geneva, Rue Michel-Servet 1, 1211, Geneva, Switzerland; Ecolede Pharmacie Geneve-Lausanne, University of Lausanne, Rue Michel-Servet 1, 1211 Geneva, Switzerland. Electronic address: carole.bourquin@unige.ch. (13) Department of Pharmacy, Pharmaceutical Technology & Biopharmaceutics, Ludwig-Maximilians-University Munich, Butenandtstrasse 5, 81377 Munich, Germany. Electronic address: julia.engert@cup.uni-muenchen.de.

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Extra-Large Pore Mesoporous Silica Nanoparticles Enabling Co-Delivery of High Amounts of Protein Antigen and Toll-like Receptor 9 Agonist for Enhanced Cancer Vaccine Efficacy

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Cancer vaccine aims to invoke antitumor adaptive immune responses to detect and eliminate tumors. However, the current dendritic cells (DCs)-based cancer vaccines have several limitations that are mostly derived from the ex vivo culture of patient DCs. To circumvent the limitations, direct activation and maturation of host DCs using antigen-carrying materials, without the need for isolation of DCs from patients, are required. In this study, we demonstrate the synthesis of extra-large pore mesoporous silica nanoparticles (XL-MSNs) and their use as a prophylactic cancer vaccine through the delivery of cancer antigen and danger signal to host DCs in the draining lymph nodes. Extra-large pores of approximately 25 nm and additional surface modification of XL-MSNs resulted in significantly higher loading of antigen protein and toll-like receptor 9 (TLR9) agonist compared with conventional small-pore MSNs. In vitro study showed the enhanced activation and antigen presentation of DCs and increased secretion of proinflammatory cytokines. In vivo study demonstrated efficient targeting of XL-MSNs co-delivering antigen and TLR9 agonist to draining lymph nodes, induction of antigen-specific cytotoxic T lymphocytes (CTLs), and suppression of tumor growth after vaccination. Furthermore, significant prevention of tumor growth after tumor rechallenge of the vaccinated tumor-free mice resulted, which was supported by a high level of memory T cells. These findings suggest that mesoporous silica nanoparticles with extra-large pores can be used as an attractive platform for cancer vaccines.

Author Info: (1) School of Chemical Engineering, School of Pharmacy, Department of Health Sciences and Technology, Samsung Advanced Institute for Health Science & Technology (SAIHST), and Biomedical

Author Info: (1) School of Chemical Engineering, School of Pharmacy, Department of Health Sciences and Technology, Samsung Advanced Institute for Health Science & Technology (SAIHST), and Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University (SKKU), Suwon 16419, Republic of Korea. (2) School of Chemical Engineering, School of Pharmacy, Department of Health Sciences and Technology, Samsung Advanced Institute for Health Science & Technology (SAIHST), and Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University (SKKU), Suwon 16419, Republic of Korea. (3) School of Chemical Engineering, School of Pharmacy, Department of Health Sciences and Technology, Samsung Advanced Institute for Health Science & Technology (SAIHST), and Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University (SKKU), Suwon 16419, Republic of Korea.

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Morphological changes induced by Intraprostatic PSA-based vaccine in prostate Cancer biopsies (phase I clinical trial)

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Immunotherapy is a novel treatment for many tumors including prostate cancer. Little is known about the histological changes in prostate biopsies caused by the prostatic-specific antigen (PSA)-based vaccine. This study evaluated the histopathological effects in prostate biopsies of recombinant fowlpox (rF) virus-based vaccine engineered to present the PSA and three costimulatory molecules (collectively labeled as PSA-TRICOM). This vaccine has shown that it can break tolerance of the PSA, and its administration directly into a tumor enables the affected tumor cells to act as antigen-presenting cells activating new T-cells, and broadening the immune response to recognize and kill tumor. We studied 10 patients with recurrent prostate cancer who had failed radiation therapy and/or androgen-deprivation therapy. Pre- and post-treatment biopsies were compared. Post-treatment biopsies induced 8 cases with residual adenocarcinoma despite evidences treatment effect and inflammation, two cases did not show any residual tumor; and only one case did not have any inflammatory infiltrate or any evidenced treatment effect. The inflammatory infiltrate varied from mild to severe, and was composed of mononuclear cells. Greater numbers amount of infiltrating CD8+ lymphocytes were identified around prostatic glands and within the epithelial lining. The most remarkable feature was the presence of increased eosinophils around the glands and stroma. Three cases showed areas of necrosis surrounded by lymphocytes and palisading epithelioid macrophages arranged in granuloma-like pattern with multinucleated giant cells. This description of l these morphological changes induced by the PSA-TRICOM will help to interpret the results of future intratumoral vaccine therapy trials.

Author Info: (1) Translational Surgical Pathology, Laboratory of Pathology, CCR, NCI, NIH, Bethesda, MD. Electronic address: mjmerino@mail.nih.gov. (2) Urologic Oncology Branch, CCR, NCI, NIH, Bethesda, MD. (3)

Author Info: (1) Translational Surgical Pathology, Laboratory of Pathology, CCR, NCI, NIH, Bethesda, MD. Electronic address: mjmerino@mail.nih.gov. (2) Urologic Oncology Branch, CCR, NCI, NIH, Bethesda, MD. (3) Translational Surgical Pathology, Laboratory of Pathology, CCR, NCI, NIH, Bethesda, MD. (4) Translational Surgical Pathology, Laboratory of Pathology, CCR, NCI, NIH, Bethesda, MD. (5) Laboratory of Tumor Immunology and Biology, CCR, NCI, NIH, Bethesda, MD. (6) Laboratory of Tumor Immunology and Biology, CCR, NCI, NIH, Bethesda, MD.

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Heat shock proteins expressed in the marsupial Tasmanian devil are potential antigenic candidates in a vaccine against devil facial tumour disease

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The Tasmanian devil (Sarcophilus harrisii), the largest extant carnivorous marsupial and endemic to Tasmania, is at the verge of extinction due to the emergence of a transmissible cancer known as devil facial tumour disease (DFTD). DFTD has spread over the distribution range of the species and has been responsible for a severe decline in the global devil population. To protect the Tasmanian devil from extinction in the wild, our group has focused on the development of a prophylactic vaccine. Although this work has shown that vaccine preparations using whole DFTD tumour cells supplemented with adjuvants can induce anti-DFTD immune responses, alternative strategies that induce stronger and more specific immune responses are required. In humans, heat shock proteins (HSPs) derived from tumour cells have been used instead of whole-tumour cell preparations as a source of antigens for cancer immunotherapy. As HSPs have not been studied in the Tasmanian devil, this study presents the first characterisation of HSPs in this marsupial and evaluates the suitability of these proteins as antigenic components for the enhancement of a DFTD vaccine. We show that tissues and cancer cells from the Tasmanian devil express constitutive and inducible HSP. Additionally, this study suggests that HSP derived from DFTD cancer cells are immunogenic supporting the future development of a HSP-based vaccine against DFTD.

Author Info: (1) Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia. (2) Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia. (3)

Author Info: (1) Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia. (2) Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia. (3) Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia. (4) Central Science Laboratory, University of Tasmania, Hobart, Tasmania, Australia. (5) Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia. (6) School of Medicine, University of Tasmania, Hobart, Tasmania, Australia. (7) Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia. School of Medicine, University of Tasmania, Hobart, Tasmania, Australia.

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Utilizing the nanosecond pulse technique to improve antigen intracellular delivery and presentation to treat tongue squamous cell carcinoma

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BACKGROUND: Tongue squamous cell carcinoma is the most common squamous cell carcinoma of the head and neck. Immunotherapy has great potential in the treatment of tongue squamous cell carcinoma because of its unique advantages. However, the efficacy of immunotherapy is limited by the efficiency of antigen phagocytosis by immune cells. MATERIAL AND METHODS: We extracted dendritic cells (DCs) from human peripheral blood. Utilizing a nanosecond pulsed electric field (nsPEF), we deliver the tumour lysate protein into DCs and then incubate the DCs with PBMCs to obtain specific T cells to kill tumour cells. The biosafety of nsPEF was evaluated by the ANNEXIN V-FITC/PI kit. The efficacy of lysate protein delivery was evaluated by flow cytometry. The antitumour efficacy was tested by CCK-8 assay. RESULTS: The nsPEF of the appropriate field strength can significantly improve the phagocytic ability of DCs to tumour lysing proteins and have good biosafety. The tumour cell killing rate of the nsPEF group was higher than the other group (p < 0.05). CONCLUSIONS: Utilizing nsPEF to improve the phagocytic and presenting ability of DCs could greatly activate the adaptive immune cells to enhance the immunotherapeutic effect on tongue squamous cell carcinoma.

Author Info: (1) Department of Periodontology School of Stomatology Lanzhou University, Lanzhou Gansu 730000, China lzukqwj@126.com. (2) (3) (4) (5) (6) (7)

Author Info: (1) Department of Periodontology School of Stomatology Lanzhou University, Lanzhou Gansu 730000, China lzukqwj@126.com. (2) (3) (4) (5) (6) (7)

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TLR agonist combinations that stimulate Th type I polarizing responses from human neonates

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Each year millions of neonates die due to vaccine preventable infectious diseases. Our study seeks to develop novel neonatal vaccines and improve immunogenicity of early childhood vaccines by incorporating TLR agonist-adjuvant combinations that overcome the inherent neonatal Th2 bias and stimulate Th1 polarizing response from neonatal APCs. We systematically stimulated cord blood mononuclear cells with single and multiple combinations of TLR agonists and measured levels of IL-12p70, IFN-gamma, IFN-alpha, IL-10, IL-13, TNF-alpha, IL-6 and IL-1beta from cell culture supernatants. APC-specific surface expression levels of costimulatory markers CD40, CD83 and PD-L1 were assessed by flow cytometry. Whole blood assays were included to account for the effect of plasma inhibitory factors and APC intracellular TNF-alpha and IL-12p40 secretions were measured. We found robust Th1 polarizing IL-12p70, IFN-gamma and IFN-alpha responses when cord blood APCs were stimulated with TLR agonist combinations that contained Poly I:C, Monophosphoryl Lipid A (MPLA) or R848. Addition of class A CpG oligonucleotide (ODN) to Th1 polarizing TLR agonist combinations significantly reduced cord blood IL-12p70 and IFN-gamma levels and addition of a TLR2 agonist induced significantly high Th2 polarizing IL-13. Multi-TLR agonist combinations that included R848 induced lower inhibitory PD-L1 expression on cord blood classical dendritic cells than CpG ODN-containing combinations. Incorporation of combination adjuvants containing TLR3, TLR4 and TLR7/8 agonists to neonatal vaccines may be an effective strategy to overcome neonatal Th2 bias.

Author Info: (1) Center for Infectious Diseases and Immunology, 6932 Rochester General Hospital Research Institute, Rochester, NY, USA. (2) Center for Infectious Diseases and Immunology, 6932 Rochester

Author Info: (1) Center for Infectious Diseases and Immunology, 6932 Rochester General Hospital Research Institute, Rochester, NY, USA. (2) Center for Infectious Diseases and Immunology, 6932 Rochester General Hospital Research Institute, Rochester, NY, USA. (3) Center for Infectious Diseases and Immunology, 6932 Rochester General Hospital Research Institute, Rochester, NY, USA.

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Improved vaccine-induced immune responses via a ROS-triggered nanoparticle-based antigen delivery system

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Subunit vaccines that are designed based on recombinant antigens or peptides have shown promising potential as viable substitutes for traditional vaccines due to their better safety and specificity. However, the induction of adequate in vivo immune responses with appropriate effectiveness remains a major challenge for vaccine development. More recently, the implementation of a nanoparticle-based antigen delivery system has been considered a promising approach to improve the in vivo efficacy for subunit vaccine development. Thus, we have designed and prepared a nanoparticle-based antigen delivery system composed of three-armed PLGA, which is conjugated to PEG via the peroxalate ester bond (3s-PLGA-PO-PEG) and PEI as a cationic adjuvant (PPO NPs). It is known that during a foreign pathogen attack, NADPH, an oxidase, of the host organism is activated and generates an elevated level of reactive oxygen species, hydrogen peroxide (H2O2) primarily, as a defensive mechanism. Considering the sensitivity of the peroxalate ester bond to H2O2 and the cationic property of PEI for the induction of immune responses, this 3s-PLGA-PO-PEG/PEI antigen delivery system is expected to be both ROS responsive and facilitative in antigen uptake without severe toxicity that has been reported with cationic adjuvants. Indeed, our results demonstrated excellent loading capacity and in vitro stability of the PPO NPs encapsulated with the model antigen, ovalbumin (OVA). Co-culturing of bone marrow dendritic cells with the PPO NPs also led to enhanced dendritic cell maturation, antigen uptake, enhanced lysosomal escape, antigen cross-presentation and in vitro CD8+ T cell activation. In vivo experiments using mice further revealed that the administration of the PPO nanovaccine induced robust OVA-specific antibody production, upregulation of splenic CD4+ and CD8+ T cell proportions as well as an increase in memory T cell generation. In summary, we report here a ROS-triggered nanoparticle-based antigen delivery system that could be employed to promote the in vivo efficacy of vaccine-induced immune responses.

Author Info: (1) Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China. yangjing37@hotmail.com

Author Info: (1) Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China. yangjing37@hotmail.com cli0616826@126.com. (2) Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China. yangjing37@hotmail.com cli0616826@126.com. (3) Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China. yangjing37@hotmail.com cli0616826@126.com. (4) Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China. yangjing37@hotmail.com cli0616826@126.com. (5) Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China. yangjing37@hotmail.com cli0616826@126.com. (6) Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China. yangjing37@hotmail.com cli0616826@126.com. (7) Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China. yangjing37@hotmail.com cli0616826@126.com. (8) Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China. yangjing37@hotmail.com cli0616826@126.com and Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin 300071, China. (9) Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China. yangjing37@hotmail.com cli0616826@126.com. (10) Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China. yangjing37@hotmail.com cli0616826@126.com.

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Induction of antitumor cytotoxic lymphocytes using engineered human primary blood dendritic cells

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Wu et al. developed a method for establishing immortalized and constitutively activated human primary blood dendritic cell lines (ihv-DCs) utilizing the viral protein Tax from human T cell leukemia virus type 2 (HTLV-2). They explored several modifications to the DC cells to enhance their ability to prime and activate cytotoxic CD8+ T cells and natural killer cells in order to target various types of cancer.

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Wu et al. developed a method for establishing immortalized and constitutively activated human primary blood dendritic cell lines (ihv-DCs) utilizing the viral protein Tax from human T cell leukemia virus type 2 (HTLV-2). They explored several modifications to the DC cells to enhance their ability to prime and activate cytotoxic CD8+ T cells and natural killer cells in order to target various types of cancer.

Dendritic cell (DC)-based cancer immunotherapy has achieved modest clinical benefits, but several technical hurdles in DC preparation, activation, and cancer/testis antigen (CTA) delivery limit its broad applications. Here, we report the development of immortalized and constitutively activated human primary blood dendritic cell lines (ihv-DCs). The ihv-DCs are a subset of CD11c(+)/CD205(+) DCs that constitutively display costimulatory molecules. The ihv-DCs can be genetically modified to express human telomerase reverse transcriptase (hTERT) or the testis antigen MAGEA3 in generating CTA-specific cytotoxic T lymphocytes (CTLs). In an autologous setting, the HLA-A2(+) ihv-DCs that present hTERT antigen prime autologous T cells to generate hTERT-specific CTLs, inducing cytolysis of hTERT-expressing target cells in an HLA-A2-restricted manner. Remarkably, ihv-DCs that carry two allogeneic HLA-DRB1 alleles are able to prime autologous T cells to proliferate robustly in generating HLA-A2-restricted, hTERT-specific CTLs. The ihv-DCs, which are engineered to express MAGEA3 and high levels of 4-1BBL and MICA, induce simultaneous production of both HLA-A2-restricted, MAGEA3-specific CTLs and NK cells from HLA-A2(+) donor peripheral blood mononuclear cells. These cytotoxic lymphocytes suppress lung metastasis of A549/A2.1 lung cancer cells in NSG mice. Both CTLs and NK cells are found to infiltrate lung as well as lymphoid tissues, mimicking the in vivo trafficking patterns of cytotoxic lymphocytes. This approach should facilitate the development of cell-based immunotherapy for human lung cancer.

Author Info: (1) School of Pharmacy, Jinan University, 510632 Guangzhou, China. Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201. (2) Institute of

Author Info: (1) School of Pharmacy, Jinan University, 510632 Guangzhou, China. Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201. (2) Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201. (3) Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201. (4) Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201; rgallo@ihv.umaryland.edu hua.cheng@ihv.umaryland.edu. Department of Medicine, University of Maryland School of Medicine, Baltimore, MD Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201. (5) Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201; rgallo@ihv.umaryland.edu hua.cheng@ihv.umaryland.edu. Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201. Department of Medicine, University of Maryland School of Medicine, Baltimore, MD Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201.

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