Journal Articles

Cancer vaccine delivery

Novel strategies for the delivery of cancer vaccines, including nanotechnology

Vaccine and immune cell therapy in non-small cell lung cancer

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Despite new advances in therapeutics, lung cancer remains the first cause of mortality among different types of malignancies. To improve survival, different strategies have been developed such as chemotherapy combinations, targeted therapies and more recently immunotherapy. Immunotherapy is based on the capability of the immune system to differentiate cancer cells from normal cells to fight against the tumor. The two main checkpoint inhibitors that have been widely studied in non-small cell lung cancer (NSCLC) are PD-1/PD-L1 and CTLA-4. However, interactions between tumor and immune system are much more complex with several different elements that take part and probably many new interactions to be discovered and studied for a better comprehension of those pathways. Vaccines are part of the prophylaxis and of the treatment for different infectious diseases. For that reason, they have allowed us to improve global survival worldwide. This same idea can be used for cancer treatment. First reports in clinical trials that used therapeutic vaccines in NSCLC were discouraging, but currently vaccines have a new chance in cancer therapy with the identification of new targetable antigens, adjuvant treatments and most interestingly, the combination of vaccines with anti-PD-1/PD-L1 and anti-CTLA-4 drugs. The aim of this article is to describe the scientific evidence that has been reported for the different types of vaccines and their mechanisms of action in the fight against NSCLC tumors to improve disease control.

Author Info: (1) Phase I-Early Clinical Trials Unit, Antwerp University Hospital, Edegem, Belgium. Department of Oncology, Parc Tauli Hospital, Sabadell, Spain. (2) Oncology Department, Clinica Alemana Santiago

Author Info: (1) Phase I-Early Clinical Trials Unit, Antwerp University Hospital, Edegem, Belgium. Department of Oncology, Parc Tauli Hospital, Sabadell, Spain. (2) Oncology Department, Clinica Alemana Santiago, Santiago, Chile. (3) Phase I-Early Clinical Trials Unit, Antwerp University Hospital, Edegem, Belgium. Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology Palermo, University of Palermo, Palermo, Italy. (4) Phase I-Early Clinical Trials Unit, Antwerp University Hospital, Edegem, Belgium. Center for Oncological Research Antwerp, University of Antwerp, Antwerp, Belgium. (5) Center for Oncological Research Antwerp, University of Antwerp, Antwerp, Belgium. Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, Edegem, Belgium. (6) University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA.

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Delineating the cell death mechanisms associated with skin electroporation

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The immune responses elicited following delivery of DNA vaccines to the skin has previously been shown to be significantly enhanced by the addition of electroporation (EP) to the treatment protocol. Principally, EP increases the transfection of pDNA into the resident skin cells. In addition to increasing the levels of in vivo transfection, the physical insult induced by EP is associated with activation of innate pathways which are believed to mediate an adjuvant effect, further enhancing DNA vaccine responses. Here, we have investigated the possible mechanisms associated with this adjuvant effect, primarily focusing on the cell death pathways associated with the skin EP procedure independent of pDNA delivery. Using the minimally invasive CELLECTRA(R)-3P intradermal electroporation device that penetrates the epidermal and dermal layers of the skin, we have investigated apoptotic and necrotic cell death in relation to the vicinity of the electrode needles and electric field generated. Employing the well-established TUNEL assay, we detected apoptosis beginning as early as one hour after EP and peaking at the 4 hour time point. The majority of the apoptotic events were detected in the epidermal region directly adjacent to the electrode needle. Using a novel propidium iodide in vivo necrotic cell death assay, we detected necrotic events concentrated in the epidermal region adjacent to the electrode. Furthermore, we detected up-regulation of calreticulin expression on skin cells after EP, thus labeling these cells for uptake by dendritic cells and macrophages. These results allow us to delineate the cell death mechanisms occurring in the skin following intradermal EP independently of pDNA delivery. We believe these events contribute to the adjuvant effect observed following electroporation at the skin treatment site.

Author Info: (1) Inovio Pharmaceuticals, R&D, San Diego, California, United States ; kschultheis@inovio.com. (2) Inovio Pharmaceuticals, R&D, San Diego, California, United States ; tsmith@inovio.com. (3) The Scripps

Author Info: (1) Inovio Pharmaceuticals, R&D, San Diego, California, United States ; kschultheis@inovio.com. (2) Inovio Pharmaceuticals, R&D, San Diego, California, United States ; tsmith@inovio.com. (3) The Scripps Research Institute, Core Microscope Facility, La Jolla, California, United States ; wkiosses@scripps.edu. (4) Inovio Pharmaceuticals Inc, 19679, Plymouth Meeting, Pennsylvania, United States ; kkraynyak@inovio.com. (5) Inovio Pharmaceuticals, R&D, San Diego, California, United States ; amlawong@gmail.com. (6) Inovio Pharmaceuticals, R&D, San Diego, California, United States ; janethjoh@gmail.com. (7) Inovio Pharmaceuticals, R&D, San Diego, California, United States ; kbroderick@inovio.com.

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Antibodies conjugated with viral antigens elicit a cytotoxic T cell response against primary CLL ex vivo

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Chronic lymphocytic leukemia (CLL) is the most frequent B cell malignancy in Caucasian adults. The therapeutic armamentarium against this incurable disease has recently seen a tremendous expansion with the introduction of specific pathway inhibitors and innovative immunotherapy. However, none of these approaches is curative and devoid of side effects. We have used B-cell-specific antibodies conjugated with antigens (AgAbs) of the Epstein-Barr virus (EBV) to efficiently expand memory CD4(+) cytotoxic T lymphocytes (CTLs) that recognized viral epitopes in 12 treatment-naive patients with CLL. The AgAbs carried fragments from the EBNA3C EBV protein that is recognized by the large majority of the population. All CLL cells pulsed with EBNA3C-AgAbs elicited EBV-specific T cell responses, although the intensity varied across the patient collective. Interestingly, a large proportion of the EBV-specific CD4(+) T cells expressed granzyme B (GrB), perforin, and CD107a, and killed CLL cells loaded with EBV antigens with high efficiency in the large majority of patients. The encouraging results from this preclinical ex vivo study suggest that AgAbs have the potential to redirect immune responses toward CLL cells in a high percentage of patients in vivo and warrant the inception of clinical trials.

Author Info: (1) German Cancer Research Center (DKFZ), Unit F100, 69120, Heidelberg, Germany. Faculty of Biosciences, Heidelberg University, 69120, Heidelberg, Germany. Institut National de la Sante et

Author Info: (1) German Cancer Research Center (DKFZ), Unit F100, 69120, Heidelberg, Germany. Faculty of Biosciences, Heidelberg University, 69120, Heidelberg, Germany. Institut National de la Sante et de la Recherche Medicale (INSERM) Unit U1074, DKFZ, 69120, Heidelberg, Germany. German Center for Infection Research (DZIF), 69120, Heidelberg, Germany. (2) German Cancer Research Center (DKFZ), Unit F100, 69120, Heidelberg, Germany. Institut National de la Sante et de la Recherche Medicale (INSERM) Unit U1074, DKFZ, 69120, Heidelberg, Germany. German Center for Infection Research (DZIF), 69120, Heidelberg, Germany. (3) Department of Internal Medicine V, Heidelberg University Hospital, 69120, Heidelberg, Germany. (4) German Cancer Research Center (DKFZ), Unit F100, 69120, Heidelberg, Germany. Faculty of Biosciences, Heidelberg University, 69120, Heidelberg, Germany. Institut National de la Sante et de la Recherche Medicale (INSERM) Unit U1074, DKFZ, 69120, Heidelberg, Germany. German Center for Infection Research (DZIF), 69120, Heidelberg, Germany. (5) German Cancer Research Center (DKFZ), Unit F100, 69120, Heidelberg, Germany. Institut National de la Sante et de la Recherche Medicale (INSERM) Unit U1074, DKFZ, 69120, Heidelberg, Germany. German Center for Infection Research (DZIF), 69120, Heidelberg, Germany. Nierenzentrum Heidelberg, 69120, Heidelberg, Germany. (6) Research Unit Gene Vectors, Helmholtz Zentrum Munchen, 81377, Munich, Germany. Children's Hospital Technische Universitat Munchen, 80804, Munich, Germany. DZIF, 81377, Munich, Germany. (7) German Cancer Research Center (DKFZ), Unit F100, 69120, Heidelberg, Germany. h.delecluse@dkfz.de. Faculty of Biosciences, Heidelberg University, 69120, Heidelberg, Germany. h.delecluse@dkfz.de. Institut National de la Sante et de la Recherche Medicale (INSERM) Unit U1074, DKFZ, 69120, Heidelberg, Germany. h.delecluse@dkfz.de. German Center for Infection Research (DZIF), 69120, Heidelberg, Germany. h.delecluse@dkfz.de.

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Combined immunization against TGF-beta1 enhances HPV16 E7-specific vaccine-elicited antitumour immunity in mice with grafted TC-1 tumours

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Therapeutic vaccine appears to be a potential approach for the treatment of human papillomavirus (HPV)-associated tumours, but its efficacy can be dampened by immunosuppressive factors such as transforming growth factor (TGF)-beta1. We sought to investigate whether active immunity against TGF-beta1 enhances the anti-tumour immunity elicited by an HPV16 E7-specific vaccine that we developed previously. In this study, virus-like particles of hepatitis B virus core antigen were used as vaccine carriers to deliver either TGF-beta1 B cell epitopes or E7 cytotoxic T-lymphocyte epitope. The combination of preventive immunization against TGF-beta1 and therapeutic immunization with the E7 vaccine significantly reduced the growth of grafted TC-1 tumours in C57 mice, showing better efficacy than immunization with only one of the vaccines. The improved efficacy of combined immunization is evidenced by elevated IFN-gamma and decreased IL-4 and TGF-beta1 levels in cultured splenocytes, increased E7-specific IFN-gamma-expressing splenocytes, and increased numbers of CD4(+)IFN-gamma(+) and CD8(+)IFN-gamma(+) cells and decreased numbers of Treg (CD4(+)Foxp3(+)) cells in the spleen and tumours. The results strongly indicate that targeting TGF-beta1 through active immunization might be a potent approach to enhancing antigen-specific therapeutic vaccine-induced anti-tumour immune efficacy and providing a combined strategy for effective cancer immunotherapy.

Author Info: (1) a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China. b Yunnan Key Laboratory of

Author Info: (1) a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China. b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China. c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China. (2) a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China. b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China. c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China. (3) a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China. b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China. c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China. (4) a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China. b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China. c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China. (5) a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China. b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China. c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China. (6) a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China. b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China. c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China. (7) a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China. b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China. c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China. (8) a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China. b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China. c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China. (9) a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China. b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China. c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China. (10) a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China. b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China. c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China. (11) a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China. b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China. c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China.

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A novel potential effective strategy for enhancing the antitumor immune response in breast cancer patients using a viable cancer cell-dendritic cell-based vaccine

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Dendritic cells (DCs) have been used in a number of clinical trials for cancer immunotherapy; however, they have achieved limited success in solid tumors. Consequently the aim of the present study was to identify a novel potential immunotherapeutic target for breast cancer patients through in vitro optimization of a viable DC-based vaccine. Immature DCs were primed by viable MCF-7 breast cancer cells and the activity and maturation of DCs were assessed through measuring CD83, CD86 and major histocompatibility complex (MHC)-II expression, in addition to different T cell subpopulations, namely CD4(+) T cells, CD8(+) T cells, and CD4(+)CD25(+) forkhead box protein 3 (Foxp3)(+) regulatory T cells (Tregs), by flow cytometric analysis. Foxp3 level was also measured by enzyme-linked immunosorbent assay (ELISA) in addition to reverse-transcription quantitative polymerase chain reaction. The levels of interleukin-12 (IL-12) and interferon-gamma (IFN-gamma) were determined by ELISA. Finally, the cytotoxicity of cytotoxic T lymphocytes (CTLs) was evaluated through measuring lactate dehydrogenase (LDH) release by ELISA. The results demonstrated that CD83(+), CD86(+) and MHC-II(+) DCs were significantly elevated (P<0.001) following priming with breast cancer cells. In addition, there was increased activation of CD4(+) and CD8(+) T-cells, with a significant decrease of CD4(+)CD25(+)Foxp3(+) Tregs (P<0.001). Furthermore, a significant downregulation of FOXP3 gene expression (P<0.001) was identified, and a significant decrease in the level of its protein following activation (P<0.001) was demonstrated by ELISA. Additionally, significant increases in the secretion of IL-12 and IFN-gamma (P=0.001) were observed. LDH release was significantly increased (P<0.001), indicating a marked cytotoxicity of CTLs against cancer cells. Therefore viable breast cancer cell-DC-based vaccines could expose an innovative avenue for a novel breast cancer immunotherapy.

Author Info: (1) Medical Biochemistry and Molecular Biology Unit, Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo 11976, Egypt. (2) Medical Biochemistry and Molecular Biology

Author Info: (1) Medical Biochemistry and Molecular Biology Unit, Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo 11976, Egypt. (2) Medical Biochemistry and Molecular Biology Unit, Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo 11976, Egypt. (3) Department of Clinical Pathology, National Cancer Institute, Cairo University, Cairo 11976, Egypt. (4) Department of Pathology, National Cancer Institute, Cairo University, Cairo 11976, Egypt. (5) Department of Zoology, Faculty of Science, Tanta University, Tanta, Gharbia 31511, Egypt. (6) Medical Biochemistry and Molecular Biology Unit, Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo 11976, Egypt.

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'Minimalist' Nanovaccine Constituted from Near Whole Antigen for Cancer Immunotherapy

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One of the major challenges in vaccine design has been the over dependence on incorporation of abundant adjuvants, that in fact is in violation of the 'minimalist' principle. In the present study, a compact nanovaccine derived from a near whole antigen (up to 97 wt%) was developed. The nanovaccine structure was stabilized by free cysteines within each antigen (ovalbumin, OVA) which were tempo-spatially exposed and heat-driven to form extensive intermolecular disulfide network. This process enables the engineering of a nanovaccine upon integration of the danger signal (CpG-SH) into the network during the synthetic process. The 50 nm-sized nanovaccine was developed comprising of approximately 500 antigen molecules per nanoparticle. The nanovaccine prophylactically protected 70% of mice from tumorigenesis (0% for the control group) in murine B16-OVA melanoma. Significant tumor inhibition was achieved by strongly nanovaccine-induced cytotoxic T lymphocytes. This strategy can be adapted for the future design of vaccine for a minimalist composition in clinical settings.

Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10)

Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10)

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mRNA Delivery System for Targeting Antigen-Presenting Cells In Vivo

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The encapsulation of mRNA in nanosystems as gene vaccines for immunotherapy purposes has experienced an exponential increase in recent years. Despite the many advantages envisaged within these approaches, their application in clinical treatments is still limited due to safety issues. These issues can be attributed, in part, to liver accumulation of most of the designed nanosystems and to the inability to transfect immune cells after an intravenous administration. In this context, this study takes advantage of the known versatile properties of the oligopeptide end-modified poly (beta-amino esters) (OM-PBAEs) to complex mRNA and form discrete nanoparticles. Importantly, it is demonstrated that the selection of the appropriate end-oligopeptide modifications enables the specific targeting and major transfection of antigen-presenting cells (APC) in vivo, after intravenous administration, thus enabling their use for immunotherapy strategies. Therefore, with this study, it can be confirmed that OM-PBAE are appropriate systems for the design of mRNA-based immunotherapy approaches aimed to in vivo transfect APCs and trigger immune responses to fight either tumors or infectious diseases.

Author Info: (1) Sagetis Biotech SL, 08017, Barcelona, Spain. Grup d'Enginyeria de Materials (GEMAT), Institut Quimic de Sarria (IQS), Universitat Ramon Llull (URL), 08017, Barcelona, Spain. (2)

Author Info: (1) Sagetis Biotech SL, 08017, Barcelona, Spain. Grup d'Enginyeria de Materials (GEMAT), Institut Quimic de Sarria (IQS), Universitat Ramon Llull (URL), 08017, Barcelona, Spain. (2) CIBER of Biomaterials, Bioengineering and Nanomedicine (CIBER-BBN), 08034, Barcelona, Spain. Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), 08034, Barcelona, Spain. (3) Sagetis Biotech SL, 08017, Barcelona, Spain. (4) Sagetis Biotech SL, 08017, Barcelona, Spain. (5) CIBER of Biomaterials, Bioengineering and Nanomedicine (CIBER-BBN), 08034, Barcelona, Spain. (6) Grup d'Enginyeria de Materials (GEMAT), Institut Quimic de Sarria (IQS), Universitat Ramon Llull (URL), 08017, Barcelona, Spain. (7) Sagetis Biotech SL, 08017, Barcelona, Spain. Grup d'Enginyeria de Materials (GEMAT), Institut Quimic de Sarria (IQS), Universitat Ramon Llull (URL), 08017, Barcelona, Spain. (8) CIBER of Biomaterials, Bioengineering and Nanomedicine (CIBER-BBN), 08034, Barcelona, Spain. Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), 08034, Barcelona, Spain. (9) CIBER of Biomaterials, Bioengineering and Nanomedicine (CIBER-BBN), 08034, Barcelona, Spain. Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), 08034, Barcelona, Spain. (10) Sagetis Biotech SL, 08017, Barcelona, Spain. Grup d'Enginyeria de Materials (GEMAT), Institut Quimic de Sarria (IQS), Universitat Ramon Llull (URL), 08017, Barcelona, Spain. CIBER of Biomaterials, Bioengineering and Nanomedicine (CIBER-BBN), 08034, Barcelona, Spain.

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Listeria Monocytogenes: A Model Pathogen Continues to Refine Our Knowledge of the CD8 T Cell Response

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Listeria monocytogenes (Lm) infection induces robust CD8 T cell responses, which play a critical role in resolving Lm during primary infection and provide protective immunity to re-infections. Comprehensive studies have been conducted to delineate the CD8 T cell response after Lm infection. In this review, the generation of the CD8 T cell response to Lm infection will be discussed. The role of dendritic cell subsets in acquiring and presenting Lm antigens to CD8 T cells and the events that occur during T cell priming and activation will be addressed. CD8 T cell expansion, differentiation and contraction as well as the signals that regulate these processes during Lm infection will be explored. Finally, the formation of memory CD8 T cell subsets in the circulation and in the intestine will be analyzed. Recently, the study of CD8 T cell responses to Lm infection has begun to shift focus from the intravenous infection model to a natural oral infection model as the humanized mouse and murinized Lm have become readily available. Recent findings in the generation of CD8 T cell responses to oral infection using murinized Lm will be explored throughout the review. Finally, CD8 T cell-mediated protective immunity against Lm infection and the use of Lm as a vaccine vector for cancer immunotherapy will be highlighted. Overall, this review will provide detailed knowledge on the biology of CD8 T cell responses after Lm infection that may shed light on improving rational vaccine design.

Author Info: (1) Department of Molecular Genetics & Microbiology, Center for Infectious Diseases, Stony Brook University, Stony Brook, NY 11790, USA. Zhijuan.Qiu@stonybrook.edu. (2) Department of Molecular Genetics

Author Info: (1) Department of Molecular Genetics & Microbiology, Center for Infectious Diseases, Stony Brook University, Stony Brook, NY 11790, USA. Zhijuan.Qiu@stonybrook.edu. (2) Department of Molecular Genetics & Microbiology, Center for Infectious Diseases, Stony Brook University, Stony Brook, NY 11790, USA. Camille.Khairallah@stonybrook.edu. (3) Department of Molecular Genetics & Microbiology, Center for Infectious Diseases, Stony Brook University, Stony Brook, NY 11790, USA. Brian.Sheridan@stonybrook.edu.

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Enhancement of peptide vaccine immunogenicity by increasing lymphatic drainage and boosting serum stability

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Antitumor T-cell responses have the potential to be curative in cancer patients, but the induction of potent T-cell immunity through vaccination remains a largely unmet goal of immunotherapy. We previously reported that the immunogenicity of peptide vaccines could be increased by maximizing delivery to lymph nodes (LNs), where T-cell responses are generated. This was achieved by conjugating the peptide to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-PEG (DSPE-PEG) to promote albumin binding, which resulted in enhanced lymphatic drainage and improved T-cell responses. Here, we expanded upon these findings and mechanistically dissected the properties that contribute to the potency of this amphiphile-vaccine (amph-vaccine). We found that multiple linkage chemistries could be used to link peptides with DSPE-PEG, and further, that multiple albumin-binding moieties conjugated to peptide antigens enhanced LN accumulation and subsequent T-cell priming. In addition to enhancing lymphatic trafficking, DSPE-PEG conjugation increased the stability of peptides in serum. DSPE-PEG-peptides trafficked beyond immediate draining LNs to reach distal nodes, with antigen presented for at least a week in vivo, whereas soluble peptide presentation quickly decayed. Responses to amph-vaccines were not altered in mice deficient in the albumin-binding neonatal Fc receptor (FcRn), but required Batf3-dependent dendritic cells (DCs). Amph-peptides were processed by human DCs equivalently to unmodified peptides. These data define design criteria for enhancing the immunogenicity of molecular vaccines to guide the design of next-generation peptide vaccines.

Author Info: (1) Biological Engineering, MIT. (2) MIT. (3) Biological Engineering, MIT. (4) Biological Engineering, MIT. (5) Simpson Querrey Institute for BioNanotechnology, Northwestern. (6) Ragon Institute of

Author Info: (1) Biological Engineering, MIT. (2) MIT. (3) Biological Engineering, MIT. (4) Biological Engineering, MIT. (5) Simpson Querrey Institute for BioNanotechnology, Northwestern. (6) Ragon Institute of MGH, MIT and Harvard. (7) Koch Institute for Integrated Cancer Research, Massachusetts Institute of Technology. (8) MIT. (9) Koch Institute, MIT. (10) Health Sciences and Technology, Massachusetts Institute of Technology. (11) MIT. (12) Ragon Institute of MGH, MIT and Harvard. (13) (14) Biological Engineering, MIT djirvine@mit.edu.

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Augmenting vaccine immunogenicity through the use of natural human anti-rhamnose antibodies

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Utilizing natural antibodies to augment vaccine immunogenicity is a promising approach towards cancer immunotherapy. Anti-rhamnose (anti-Rha) antibodies are some of the most common natural anti-carbohydrate antibodies present in human serum. Therefore, rhamnose can be utilized as a targeting moiety for a rhamnose-containing vaccine to prepare an effective vaccine formulation. It was shown previously that anti-Rha antibody generated in mice binds effectively with Rha-conjugated vaccine and is picked up by antigen presenting cells (APCs) through stimulatory Fc receptors. This leads to the effective uptake and processing of antigen and eventually presentation by major histocompatibility complex (MHC) molecules. In this article, we show that natural human anti-Rha antibodies can also be used in a similar mechanism and immunogenicity can be enhanced by targeting Rha-conjugated antigens. In doing so, we have purified human anti-Rha antibody from human serum using a rhamnose affinity column. In vitro, human anti-Rha antibodies are shown to enhance the uptake of a model antigen, Rha-ovalbumin (Rha-Ova), by APCs. In-vivo, they improved the priming of CD4+ T cells to Rha-Ova in comparison to non-anti-Rha human antibodies. Additionally, increased priming of both CD4+ and CD8+ T cells towards the cancer antigen MUC1-Tn was observed in mice that received human anti-Rha antibodies prior to vaccination with a rhamnose-modified MUC1-Tn cancer vaccine. The vaccine conjugate contained Pam3CysSK4, a Toll-like receptor (TLR) agonist linked via copper-free cycloaddition chemistry to a 20-amino-acid glycopeptide derived from the tumor marker MUC-1 containing the tumor-associated carbohydrate antigen alpha-N-acetyl galactosamine (GalNAc). The primed CD8+ T cells released IFN-gamma and killed tumor cells. Therefore, we have confirmed that human anti-Rha antibodies can be effectively utilized as a targeting moiety for making an effective vaccine.

Author Info: (1) (2) (3) (4) (5)

Author Info: (1) (2) (3) (4) (5)

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