Journal Articles

Cancer vaccine delivery

Novel strategies for the delivery of cancer vaccines, including nanotechnology

Nanoparticulate vaccine inhibits tumor growth via improved T cell recruitment into melanoma and huHER2 breast cancer

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Nanoparticulate vaccines are promising tools to overcome cancer immune evasion. However, a deeper understanding on nanoparticle-immune cell interactions and treatments regime are required for optimal efficacy. We provide a comprehensive study of treatment schedules and mode of antigen-association to nanovaccines on the modulation of T cell immunity in vivo, under steady-state and tumor-bearing mice. The coordinated delivery of antigen and two adjuvants (Monophosphoryl lipid A, oligodeoxynucleotide cytosine-phosphate-guanine motifs (CpG)) by nanoparticles was crucial for dendritic cell activation. A single vaccination dictated a 3-fold increase on cytotoxic memory-T cells and raised antigen-specific immune responses against B16.M05 melanoma. It generated at least a 5-fold increase on IFN-gamma cytokine production, and presented over 50% higher lymphocyte count in the tumor microenvironment, compared to the control. The number of lymphocytes at the tumor site doubled with triple immunization. This lymphocyte infiltration pattern was confirmed in mammary huHER2 carcinoma, with significant tumor reduction.

Author Info: (1) Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal; Department of Immunology, Weizmann Institute of Science, Rehovot, Israel; Center for

Author Info: (1) Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal; Department of Immunology, Weizmann Institute of Science, Rehovot, Israel; Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Faculty of Medicine (Polo I), Coimbra, Portugal. (2) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (3) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (4) Department of Physiology and Pharmacology, Sackler School of Medicine, Room 607, Tel Aviv University, Tel Aviv, Israel. (5) Flow Cytometry unit, Biological Services Department, Weizmann Institute of Science, Rehovot, Israel. (6) Chemistry and Biochemistry Center, Sciences Faculty, Universidade de Lisboa, Lisbon, Portugal. (7) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel; Immunology research center, Tel Aviv Sourasky Medical Center (TASMC), Tel Aviv, Israel. (8) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel; Immunology research center, Tel Aviv Sourasky Medical Center (TASMC), Tel Aviv, Israel. (9) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel; Immunology research center, Tel Aviv Sourasky Medical Center (TASMC), Tel Aviv, Israel. (10) Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Faculty of Medicine (Polo I), Coimbra, Portugal;; Faculty of Pharmacy (FFUC), University of Coimbra, Polo das Ciencias da Saude, Azinhaga de Santa Comba, Coimbra, Portugal. (11) Department of Physiology and Pharmacology, Sackler School of Medicine, Room 607, Tel Aviv University, Tel Aviv, Israel. (12) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (13) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (14) Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal. Electronic address: hflorindo@ff.ul.pt.

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Supramolecular Peptide Nanofibers Engage Mechanisms of Autophagy in Antigen-Presenting Cells

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Supramolecular peptide nanofibers are attractive for applications in vaccine development due to their ability to induce strong immune responses without added adjuvants or associated inflammation. Here, we report that self-assembling peptide nanofibers bearing CD4+ or CD8+ T cell epitopes are processed through mechanisms of autophagy in antigen-presenting cells (APCs). Using standard in vitro antigen presentation assays, we confirmed loss and gain of the adjuvant function using pharmacological modulators of autophagy and APCs deficient in multiple autophagy proteins. The incorporation of microtubule-associated protein 1A/1B-light chain-3 (LC3-II) into the autophagosomal membrane, a key biological marker for autophagy, was confirmed using microscopy. Our findings indicate that autophagy in APCs plays an essential role in the mechanism of adjuvant action of supramolecular peptide nanofibers.

Author Info: (1) Department of Pharmacology & Toxicology, Department of Microbiology and Immunology, and Sealy Center for Vaccine Development, University of Texas Medical Branch, 301 University Blvd

Author Info: (1) Department of Pharmacology & Toxicology, Department of Microbiology and Immunology, and Sealy Center for Vaccine Development, University of Texas Medical Branch, 301 University Blvd, Route 0617, Galveston, Texas 77555, United States. Department of Pharmacology & Toxicology, Department of Microbiology and Immunology, and Sealy Center for Vaccine Development, University of Texas Medical Branch, 301 University Blvd, Route 0617, Galveston, Texas 77555, United States. (2) Immunobiology and Transplant Science Center, Houston Methodist Research Institute, 6565 Fannin Street, Houston, Texas 77030, United States. (3) Department of Pharmacology & Toxicology, Department of Microbiology and Immunology, and Sealy Center for Vaccine Development, University of Texas Medical Branch, 301 University Blvd, Route 0617, Galveston, Texas 77555, United States. (4) Department of Pharmacology & Toxicology, Department of Microbiology and Immunology, and Sealy Center for Vaccine Development, University of Texas Medical Branch, 301 University Blvd, Route 0617, Galveston, Texas 77555, United States. Department of Pharmacology & Toxicology, Department of Microbiology and Immunology, and Sealy Center for Vaccine Development, University of Texas Medical Branch, 301 University Blvd, Route 0617, Galveston, Texas 77555, United States. (5) Division of Surgical Oncology, Robert Wood Johnson Medical School, Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, RM 3035, New Brunswick, New Jersey 08903, United States. (6) Immunobiology and Transplant Science Center, Houston Methodist Research Institute, 6565 Fannin Street, Houston, Texas 77030, United States. (7) Department of Pathology and Laboratory Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, 6431 Fannin Street, P.O. Box 20708, Houston, Texas 77030, United States.

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Translating Science into Survival: Report on the Third International Cancer Immunotherapy Conference

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On September 6 to 9, 2017, in Mainz, Germany, the Third International Cancer Immunotherapy Conference was hosted jointly by the Cancer Research Institute, the Association for Cancer Immunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research. For the third straight year, more than 1,400 people attended the four-day event, which covered the latest advances in cancer immunology and immunotherapy. This report provides an overview of the main topics discussed. Cancer Immunol Res; 6(1); 10-13. (c)2017 AACR.

Author Info: (1) TRON - Translational Oncology, University Medical Center of Johannes Gutenberg University, Mainz, Germany. (2) TRON - Translational Oncology, University Medical Center of Johannes Gutenberg

Author Info: (1) TRON - Translational Oncology, University Medical Center of Johannes Gutenberg University, Mainz, Germany. (2) TRON - Translational Oncology, University Medical Center of Johannes Gutenberg University, Mainz, Germany. (3) Cancer Research Institute, New York, New York. abrodsky@cancerresearch.org.

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Langerhans-type dendritic cells electroporated with TRP-2 mRNA stimulate cellular immunity against melanoma: Results of a phase I vaccine trial

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Purpose: We conducted a phase I vaccine trial to determine safety, toxicity, and immunogenicity of autologous Langerhans-type dendritic cells (LCs), electroporated with murine tyrosinase-related peptide-2 (mTRP2) mRNA in patients with resected AJCC stage IIB, IIC, III, or IV (MIa) melanoma. Experimental Design: Nine patients received a priming immunization plus four boosters at three week intervals. Vaccines comprised 10 x 10(6) mRNA-electroporated LCs, based on absolute number of CD83(+)CD86(bright)HLA-DR(bright)CD14(neg) LCs by flow cytometry. Initial vaccines used freshly generated LCs, whereas booster vaccines used viably thawed cells from the cryopreserved initial product. Post-vaccination assessments included evaluation of delayed-type hypersensitivity (DTH) reactions after booster vaccines and immune response assays at one and three months after the final vaccine. Results: All patients developed mild DTH reactions at injection sites after booster vaccines, but there were no toxicities exceeding grade 1 (CTCAE, v4.0). At one and three months post-vaccination, antigen-specific CD4 and CD8 T cells increased secretion of proinflammatory cytokines (IFN-gamma, IL-2, and TNF-alpha), above pre-vaccine levels, and also upregulated the cytotoxicity marker CD107a. Next-generation deep sequencing of the TCR-V-beta CDR3 documented fold-increases in clonality of 2.11 (range 0.85-3.22) for CD4 and 2.94 (range 0.98-9.57) for CD8 T cells at one month post-vaccines. Subset analyses showed overall lower fold-increases in clonality in three patients who relapsed (CD4: 1.83, CD8: 1.54) versus non-relapsed patients (CD4: 2.31, CD8: 3.99). Conclusions: TRP2 mRNA-electroporated LC vaccines are safe and immunogenic. Responses are antigen-specific in terms of cytokine secretion, cytolytic degranulation, and increased TCR clonality, which correlates with clinical outcomes.

Author Info: (1) Laboratory of Cellular Immunobiology, Memorial Sloan Kettering Cancer Center, New York, NY. Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York

Author Info: (1) Laboratory of Cellular Immunobiology, Memorial Sloan Kettering Cancer Center, New York, NY. Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY. Division of Hematologic Oncology, Memorial Sloan Kettering Cancer Center, New York, NY. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. Memorial Sloan Kettering Cancer Center, New York, NY. The Rockefeller University, New York, NY. Weill Cornell Medical College, New York, NY, USA. (2) Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, New York, NY. Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. Memorial Sloan Kettering Cancer Center, New York, NY. Weill Cornell Medical College, New York, NY, USA. (3) Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, New York, NY. Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. Memorial Sloan Kettering Cancer Center, New York, NY. Weill Cornell Medical College, New York, NY, USA. (4) Laboratory of Cellular Immunobiology, Memorial Sloan Kettering Cancer Center, New York, NY. Memorial Sloan Kettering Cancer Center, New York, NY. (5) Laboratory of Cellular Immunobiology, Memorial Sloan Kettering Cancer Center, New York, NY. Memorial Sloan Kettering Cancer Center, New York, NY. (6) Laboratory of Cellular Immunobiology, Memorial Sloan Kettering Cancer Center, New York, NY. Memorial Sloan Kettering Cancer Center, New York, NY. (7) Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, New York, NY. Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. Memorial Sloan Kettering Cancer Center, New York, NY. (8) Sarcoma Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY. Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. Memorial Sloan Kettering Cancer Center, New York, NY. Weill Cornell Medical College, New York, NY, USA. (9) Sarcoma Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY. Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. Memorial Sloan Kettering Cancer Center, New York, NY. Weill Cornell Medical College, New York, NY, USA. (10) Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, New York, NY. Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. Memorial Sloan Kettering Cancer Center, New York, NY. The Rockefeller University, New York, NY. Weill Cornell Medical College, New York, NY, USA. (11) Laboratory of Cellular Immunobiology, Memorial Sloan Kettering Cancer Center, New York, NY. Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY. Division of Hematologic Oncology, Memorial Sloan Kettering Cancer Center, New York, NY. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. Immunology Program, Sloan Kettering Institute for Cancer Research. Memorial Sloan Kettering Cancer Center, New York, NY. The Rockefeller University, New York, NY. Weill Cornell Medical College, New York, NY, USA.

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Innate transcriptional effects by adjuvants on the magnitude, quality, and durability of HIV envelope responses in NHPs

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Adjuvants have a critical role for improving vaccine efficacy against many pathogens, including HIV. Here, using transcriptional RNA profiling and systems serology, we assessed how distinct innate pathways altered HIV-specific antibody responses in nonhuman primates (NHPs) using 8 clinically based adjuvants. NHPs were immunized with a glycoprotein 140 HIV envelope protein (Env) and insoluble aluminum salts (alum), MF59, or adjuvant nanoemulsion (ANE) coformulated with or without Toll-like receptor 4 (TLR4) and 7 agonists. These were compared with Env administered with polyinosinic-polycytidylic acid:poly-L-lysine, carboxymethylcellulose (pIC:LC) or immune-stimulating complexes. Addition of the TLR4 agonist to alum enhanced upregulation of a set of inflammatory genes, whereas the TLR7 agonist suppressed expression of alum-responsive inflammatory genes and enhanced upregulation of antiviral and interferon (IFN) genes. Moreover, coformulation of the TLR4 or 7 agonists with alum boosted Env-binding titers approximately threefold to 10-fold compared with alum alone, but remarkably did not alter gene expression or enhance antibody titers when formulated with ANE. The hierarchy of adjuvant potency was established after the second of 4 immunizations. In terms of antibody durability, antibody titers decreased approximately 10-fold after the final immunization and then remained stable after 65 weeks for all adjuvants. Last, Env-specific Fc-domain glycan structures and a series of antibody effector functions were assessed by systems serology. Antiviral/IFN gene signatures correlated with Fc-receptor binding across all adjuvant groups. This study defines the potency and durability of 8 different clinically based adjuvants in NHPs and shows how specific innate pathways can alter qualitative aspects of Env antibody function.

Author Info: (1) Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD. (2) The Center for Infectious Disease Research, Seattle

Author Info: (1) Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD. (2) The Center for Infectious Disease Research, Seattle, WA. (3) Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, MA. (4) Novartis Vaccines and Diagnostics, Cambridge, MA. GlaxoSmithKline, Siena, Italy. (5) The Center for Infectious Disease Research, Seattle, WA. (6) Statistical Center for HIV/AIDS Research and Prevention, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA. (7) Duke Human Vaccine Institute, Durham, NC. (8) Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, MA. (9) Novartis Vaccines and Diagnostics, Cambridge, MA. GlaxoSmithKline, Siena, Italy. (10) Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD. (11) Novartis Vaccines and Diagnostics, Cambridge, MA. Moderna Therapeutics, Cambridge, MA. (12) Novartis Vaccines and Diagnostics, Cambridge, MA. (13) Novartis Vaccines and Diagnostics, Cambridge, MA. Bill & Melinda Gates Foundation, Washington, DC. (14) Novartis Vaccines and Diagnostics, Cambridge, MA. (15) Novartis Vaccines and Diagnostics, Cambridge, MA. Takeda Pharmaceuticals, Cambridge, MA; and. (16) Novartis Vaccines and Diagnostics, Cambridge, MA. (17) Thayer School of Engineering, Dartmouth College, Hanover, NH. (18) Duke Human Vaccine Institute, Durham, NC. (19) Duke Human Vaccine Institute, Durham, NC. (20) Duke Human Vaccine Institute, Durham, NC. (21) Novartis Vaccines and Diagnostics, Cambridge, MA. GlaxoSmithKline, Siena, Italy. (22) The Center for Infectious Disease Research, Seattle, WA. (23) Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, MA. (24) Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.

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Vaccination with autologous myeloblasts admixed with GM-K562 cells in patients with advanced MDS or AML after allogeneic HSCT

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We report a clinical trial testing vaccination of autologous myeloblasts admixed with granulocyte-macrophage colony-stimulating factor secreting K562 cells after allogeneic hematopoietic stem cell transplantation (HSCT). Patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) with >/=5% marrow blasts underwent myeloblast collection before HSCT. At approximately day +30, 6 vaccines composed of irradiated autologous myeloblasts mixed with GM-K562 were administered. Tacrolimus-based graft-versus-host disease (GVHD) prophylaxis was not tapered until vaccine completion ( approximately day 100). Thirty-three patients with AML (25) and MDS (8) enrolled, 16 (48%) had >/=5% marrow blasts at transplantation. The most common vaccine toxicity was injection site reactions. One patient developed severe eosinophilia and died of eosinophilic myocarditis. With a median follow-up of 67 months, cumulative incidence of grade 2-4 acute and chronic GVHD were 24% and 33%, respectively. Relapse and nonrelapse mortality were 48% and 9%, respectively. Progression-free survival (PFS) and overall survival (OS) at 5 years were 39% and 39%. Vaccinated patients who were transplanted with active disease (>/=5% marrow blasts) had similar OS and PFS at 5 years compared with vaccinated patients transplanted with <5% marrow blasts (OS, 44% vs 35%, respectively, P = .81; PFS, 44% vs 35%, respectively, P = .34). Postvaccination antibody responses to angiopoietin-2 was associated with superior OS (hazard ratio [HR], 0.43; P = .031) and PFS (HR, 0.5; P = .036). Patients transplanted with active disease had more frequent angiopoeitin-2 antibody responses (62.5% vs 20%, P = .029) than those transplanted in remission. GM-K562/leukemia cell vaccination induces biologic activity, even in patients transplanted with active MDS/AML. This study is registered at www.clinicaltrials.gov as #NCT 00809250.

Author Info: (1) Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School

Author Info: (1) Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. (2) Department of Biostatistics and Computation Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA. (3) Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. (4) Department of Dermatology and. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. (5) Department of Hematopathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; and. (6) Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. Biomedical Research Laboratories, Medicine Faculty, Catholic University of Maule, Talca, Chile. (7) Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. (8) Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. (9) Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. (10) Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. (11) Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. (12) Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. (13) Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. (14) Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. (15) Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. (16) Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

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A phase I clinical trial of RNF43 peptide-related immune cell therapy combined with low-dose cyclophosphamide in patients with advanced solid tumors

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The objective of this study was to investigate the safety and the tolerability of combined cellular immunotherapy with low-dose cyclophosphamide (CPA) in patients with advanced solid tumors. This study targeted a novel tumor-associated antigen, ring finger protein 43 (RNF43). Eligible patients were resistant to standard therapy, HLA-A*24:02- or A*02:01-positive and exhibiting high RNF43 expression in their tumor cells. They were administered 300 mg/m2 CPA followed by autologous lymphocytes, preliminarily cultured with autologous RNF43 peptide-pulsed dendritic cells (DCs), RNF43 peptide-pulsed DCs and systemic low dose interleukin-2. The primary endpoint was safety whereas the secondary endpoint was immunological and clinical response to treatment. Ten patients, in total, were enrolled in this trial. Primarily, no adverse events greater than Grade 3 were observed. Six out of 10 patients showed stable disease (SD) on day 49, while 4 other patients showed progressive disease. In addition, one patient with SD exhibited a partial response after the second trial. The frequency of regulatory T cells (Tregs) in patients with SD significantly decreased after CPA administration. The ratio of interferon-gamma-producing, tumor-reactive CD8+ T cells increased with time in patients with SD. We successfully showed that the combination of immune cell therapy and CPA was safe, might induce tumor-specific immune responses and clinical efficacy, and was accompanied by a decreased ratio of Tregs in patients with RNF43-positive advanced solid tumors.

Author Info: (1) Department of Advanced Cell and Molecular Therapy, Kyushu University Hospital, Fukuoka, Japan. (2) ARO Advanced Medical Center, Kyushu University Hospital, Fukuoka, Japan. (3) ARO

Author Info: (1) Department of Advanced Cell and Molecular Therapy, Kyushu University Hospital, Fukuoka, Japan. (2) ARO Advanced Medical Center, Kyushu University Hospital, Fukuoka, Japan. (3) ARO Advanced Medical Center, Kyushu University Hospital, Fukuoka, Japan. (4) Department of Advanced Cell and Molecular Therapy, Kyushu University Hospital, Fukuoka, Japan. (5) Department of Anatomic Pathology, Pathological Sciences, Kyushu University, Fukuoka, Japan. (6) Department of Advanced Cell and Molecular Therapy, Kyushu University Hospital, Fukuoka, Japan. (7) Department of Advanced Cell and Molecular Therapy, Kyushu University Hospital, Fukuoka, Japan. (8) Department of Advanced Cell and Molecular Therapy, Kyushu University Hospital, Fukuoka, Japan. (9) ARO Advanced Medical Center, Kyushu University Hospital, Fukuoka, Japan. (10) Research Institute of Diseases of Chest, Kyushu University, Fukuoka, Japan. (11) Department of Anatomic Pathology, Pathological Sciences, Kyushu University, Fukuoka, Japan. (12) Human genome center, Institute of medical science, University of Tokyo, Tokyo, Japan. (13) Department of Advanced Cell and Molecular Therapy, Kyushu University Hospital, Fukuoka, Japan. Project Division of ALA Advanced Medical Research, Advanced Medical Science of Internal Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

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Brief Communication; A Heterologous Oncolytic Bacteria-Virus Prime-Boost Approach for Anticancer Vaccination in Mice

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Anticancer vaccination is becoming a popular therapeutic approach for patients with cancers expressing common tumor antigens. One variation on this strategy is a heterologous virus vaccine where 2 viruses encoding the same tumor antigen are administered sequentially to prime and boost antitumor immunity. This approach is currently undergoing clinical investigation using an adenovirus (Ad) and the oncolytic virus Maraba (MRB). In this study, we show that Listeria monocytogenes can be used in place of the Ad to obtain comparable immune priming efficiency before MRB boosting. Importantly, the therapeutic benefits provided by our heterologous L. monocytogenes-MRB prime-boost strategy are superior to those conferred by the Ad-MRB combination. Our study provides proof of concept for the heterologous oncolytic bacteria-virus prime-boost approach for anticancer vaccination and merits its consideration for clinical testing.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/.

Author Info: (1) Centre for Innovative Cancer Research, Ottawa Hospital Research Institute. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada. (2) Centre for Innovative

Author Info: (1) Centre for Innovative Cancer Research, Ottawa Hospital Research Institute. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada. (2) Centre for Innovative Cancer Research, Ottawa Hospital Research Institute. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada. (3) Centre for Innovative Cancer Research, Ottawa Hospital Research Institute. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada. (4) Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada. (5) Centre for Innovative Cancer Research, Ottawa Hospital Research Institute. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada. (6) Centre for Innovative Cancer Research, Ottawa Hospital Research Institute. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada.

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Immunogenicity of a two-dose investigational hepatitis B vaccine, HBsAg-1018, using a toll-like receptor 9 agonist adjuvant compared with a licensed hepatitis B vaccine in adults

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BACKGROUND: Hepatitis B virus infection remains an important public health problem in the United States. Currently approved alum-adjuvanted vaccines require three doses and have reduced immunogenicity in adults, particularly in those who have diabetes mellitus, or are older, male, obese, or who smoke. METHODS: Phase 3 observer-blinded, randomized (2:1 HBsAg-1018 [HEPLISAV-B]:HBsAg-Eng [Engerix-B(R)]), active-controlled trial in adults 18-70years of age. HBsAg-1018 was administered intramuscularly at weeks 0 and 4 and placebo at week 24 and HBsAg-Eng at weeks 0, 4, and 24. The primary immunogenicity endpoint assessed the noninferiority of the seroprotection rate at week 28 in participants with type 2 diabetes mellitus. Secondary endpoints included seroprotection rates in the total trial population and by age, sex, body mass index, and smoking status. RESULTS: Among 8374 participants randomized, 961 participants in the per-protocol population had type 2 diabetes mellitus. In diabetes participants, the seroprotection rate in the HBsAg-1018 group at week 28 was 90.0%, compared with 65.1% in the HBsAg-Eng group, with a difference of 24.9% (95% CI: 19.3%, 30.7%), which met the prospectively-defined criteria for noninferiority and statistical significance. In the total study per-protocol population (N=6826) and each pre-specified subpopulation, the seroprotection rate in the HBsAg-1018 group was statistically significantly higher than in the HBsAg-Eng group. CONCLUSION: Two doses of HBsAg-1018, administered over 4weeks, induced significantly higher seroprotection rates than three doses of HBsAg-Eng, given over 24weeks, in adults with factors known to reduce the immune response to hepatitis B vaccines as well as in those without those factors. With fewer doses in a shorter time, and greater immunogenicity, HBsAg-1018 has the potential to significantly improve protection against hepatitis B in adults at risk for hepatitis B infection. Trial Registration clinicaltrials.gov Identifier: NCT02117934.

Author Info: (1) Dynavax Technologies Corporation, 2929 Seventh Street, Suite 100, Berkeley, CA 94710, United States. Electronic address: sjackson@alkahest.com. (2) Radiant Research, Inc., 515 North State Street

Author Info: (1) Dynavax Technologies Corporation, 2929 Seventh Street, Suite 100, Berkeley, CA 94710, United States. Electronic address: sjackson@alkahest.com. (2) Radiant Research, Inc., 515 North State Street, Suite 2700, Chicago, IL 60654, United States. Electronic address: josephlentino@radiantresearch.com. (3) Radiant Research, Inc., 1657 Greenville Street, Anderson, SC 29621, United States. Electronic address: jameskopp@radiantresearch.com. (4) Radiant Research, Inc., 6010 Park Blvd, Pinellas Park, FL 33781, United States. Electronic address: LindaMurray@radiantresearch.com. (5) Radiant Research, Inc., 322 Memorial Drive, Greer, SC 29650, United States. Electronic address: travisellison@radiantresearch.com. (6) Radiant Research, Inc., 530 South Main Street, Suite 1712, Akron, OH 44311, United States. Electronic address: MargaretRhee@radiantresearch.com. (7) Desert Clinical Research, LLC/Clinical Research Advantage, Inc., 2310 E. Brown Road, Mesa, AZ 85213, United States. Electronic address: gshockey@crastudies.com. (8) Stat Shop Inc., 425 1st street, San Francisco, CA 94105, United States. Electronic address: lalith.akella@statshopinc.com. (9) Dynavax Technologies Corporation, 2929 Seventh Street, Suite 100, Berkeley, CA 94710, United States. Electronic address: kerby@dynavax.com. (10) Dynavax Technologies Corporation, 2929 Seventh Street, Suite 100, Berkeley, CA 94710, United States. Electronic address: william_heyward@yahoo.com. (11) Dynavax Technologies Corporation, 2929 Seventh Street, Suite 100, Berkeley, CA 94710, United States. Electronic address: rjanssen@dynavax.com.

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Synthetic polymeric mixed micelles target to lymph node triggering enhanced cellular and humoral immune responses

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It has been widely accepted that lymph nodes (LNs) are critical targets of cancer vaccines since antigen presentation and initiation of T cell-mediated immune responses occur primarily at these locations. In this study, amphiphilic diblock copolymer PEOz-PLA combined with carboxylterminalted-Pluronic F127 were used to construct mixed micelles (carboxylated-NPs) for co-delivery of antigen OVA and Toll-like receptor-7 agonist CL264 (carboxylated-NPs/OVA/CL264) to the LN resident DCs. The results showed that the small, sub-60nm size of the self-assembled mixed micelles enables them to rapidly penetrate into lymphatic vessels and reach DLNs after subcutaneous injection. Furthermore, the surface modification with carboxylic groups imparted the carboxylated-NPs with endocytic receptor targeting ability, allowing for DCs internalization of carboxylated-NPs/OVA/CL264 via scavenger receptor-mediate pathway. Because stimulation of CL264 in early endosomes will lead to a more effective immune response than that in late endo/lysosomes, the mass ratio of PEOz-PLA to carboxylated-Pluronic F127 in the mixed micelles was adjusted to release the encapsulated CL264 to the early endosome, resulting in increased the expression of co-stimulatory molecules and secretion of stimulated cytokines by DCs. Moreover, the incorporation of PEOz outside micellar shell effectively augmented MHC I antigen presentation through facilitating endosome escape and cytosolic release of antigens. This in turn evoked potent immune responses in vivo, including activation of antigen-specific T cell responses, production of antigen-specific IgG antibodies and the generation of cytotoxic T lymphocytes responses. Finally, immunization with the co-delivery system in E.G7-OVA tumor-bearing mice could not only significantly inhibit tumor growth, but also markedly prolong the survival of tumor-bearing mice. Taken together, carboxylated-NPs/OVA/CL264 has been demonstrated great potential for clinical applications as an effective anti-tumor vaccine for further immunotherapy.

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

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

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