Heterologous human/rat HER2-specific exosome-targeted T cell vaccine stimulates potent humoral and CTL responses leading to enhanced circumvention of HER2 tolerance in double transgenic HLA-A2/HER2 mice |
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| Affiliation: | 1. Cancer Research, Saskatchewan Cancer Agency, Canada;2. Department of Oncology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada;3. Department of Pathology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada;4. Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China;5. Molecular Physiology and Therapeutics Branch, National Institute of Dental Craniofacial Research, National Institute of Health, Bethesda, MD, USA;1. Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea;2. Department of Pediatrics, Gachon University College of Medicine, Incheon, Republic of Korea;3. Departments of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea;4. Department of Pediatrics, School of Medicine, Ewha Womans University, Seoul, Republic of Korea;5. Department of Pediatrics, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Republic of Korea;6. Department of Pediatrics, Inha University College of Medicine, Incheon, Republic of Korea;7. Department of Pediatrics, Korea Cancer Center Hospital, Seoul, Republic of Korea;8. Department of Pediatrics, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea;9. Department of Pediatrics, College of Medicine, Kyunghee University, Seoul, Republic of Korea;1. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, MLC 4000, Cincinnati, OH 45229, United States;2. Cota Enterprises, Inc., 16570 46th Street, McLouth, KS, 66054 , United States;3. Division of Adolescent and Young Adult Health, Vanderbilt University, 719 Thompson Lane Suite 36300, Nashville, TN 37204, United States;4. Division of Pediatric Infectious Diseases, Children’s Mercy Hospital Kansas City, 2401 Gillham Road, Kansas City, MO 64108, United States;5. Division of Infectious Diseases, Allergy and Immunology, Saint Louis University, 1100 S. Grand Boulevard, St. Louis, MO 63104, United States;6. Division of Infectious Diseases and Tropical Pediatrics, Center for Vaccine Development, Institute for Global Health, University of Maryland School of Medicine, 685 W. Baltimore Street, HSF 480, Baltimore, MD 21201, United States;7. Division of Infectious Diseases and Tropical Pediatrics, Center for Vaccine Development, University of Maryland School of Medicine, 685 W. Baltimore Street, HSF 480, Baltimore, MD 21201, United States;8. Division of Pediatric Infectious Diseases, Vanderbilt Vaccine Research Program, D7227 Medical Center North, Vanderbilt University School of Medicine, Nashville, TN, United States;9. The Hope Clinic of the Emory Vaccine Center, Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, 500 Irvin Court, Suite 200, Decatur, GA 30030, United States;10. Kaiser Permanente Georgia, 200 Crescent Centre Parkway, Tucker, GA 30084, United States;11. The Emmes Corporation, 401 North Washington Street, Suite 700, Rockville, MD 20850, United States;1. Department of Biotechnology, University of Turku, Turku, Finland;2. Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland;3. Department of Pediatrics and Adolescent Medicine, Turku University Hospital, Turku, Finland;4. Department of Medical Microbiology, Capital Medical University, Beijing, China;1. Univ. Lille, U1019 – UMR 8204 – CIIL – Centre d''Infection et d''Immunité de Lille, F-59000 Lille, France;2. CNRS, UMR 8204, F-59000 Lille, France;3. Inserm, U1019, F-59000 Lille, France;4. CHU Lille, F-59000 Lille, France;5. Institut Pasteur de Lille, F-59000 Lille, France;6. RIVM, Bilthoven, The Netherlands;7. Public Health England, Porton Down, Salisbury SP4 0JG, United Kingdom;1. Department of Microbiology, Faculty of Science, Federal University, Birnin Kebbi P.M.B. 1157 Kalgo Road, Birnin Kebbi, Kebbi State, Nigeria;2. Immunization, Vaccines and Emergencies, World Health Organization, Kebbi State Field Office, Nigeria;3. Department of Demography and Social Statistics, Faculty of Art, Social and Management Sciences, Federal University, Birnin Kebbi P.M.B. 1157 Kalgo Road, Birnin Kebbi, Kebbi State, Nigeria;1. Kid Risk, Inc., 10524 Moss Park Rd., Ste. 204-364, Orlando, FL 32832, United States;2. University of Central Florida, College of Medicine, Orlando, FL 32827, United States;3. Sabin Vaccine Institute, 2175 K Street, NW, Suite 400, Washington, DC 20037, United States;4. Task Force for Global Health, 325 Swanton Way, Decatur, GA 30030, United States;5. Emory University, 1462 Clifton Rd NE, Rm 446, Atlanta, GA 30322, United States |
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| Abstract: | DNA vaccines composed of heterologous human HER2 and rat neu sequences induce stronger antibody response and protective antitumor immunity than either HER2 or neu DNA vaccines in transgenic mice. We previously developed HER2-specific exosome-targeted T-cell vaccine HER2-TEXO capable of stimulating HER2-specific CD8+ T-cell responses, but only leading to partial protective immunity in double-transgenic HLA-A2/HER2 mice with self-immune tolerance to HER2. Here, we constructed an adenoviral vector AdVHuRt expressing HuRt fusion protein composed of NH2-HER21-407 (Hu) and COOH-neu408-690 (Rt) fragments, and developed a heterologous human/rat HER2-specific exosome-targeted T-cell vaccine HuRt-TEXO using polyclonal CD4+ T-cells uptaking exosomes released by AdVHuRt-transfected dendritic cells. We found that the HuRt-TEXO vaccine stimulates enhanced CD4+ T-cell responses leading to increased induction of HER2-specific antibody (∼70 µg/ml) compared to that (∼40 µg/ml) triggered by the homologous HER2-TEXO vaccine. By using PE-H-2Kd/HER223-71 tetramer, we determined that HuRt-TEXO stimulates stronger HER2-specific CD8+ T-cell responses eradicating 90% of HER2-specific target cells, while HER2-TEXO-induced CD8+ T-cell responses only eliminating 53% targets. Furthermore, HuRt-TEXO, but not HER2-TEXO vaccination, is capable of suppressing early stage-established HER2-expressing 4T1HER2 breast cancer in its lung metastasis or subcutaneous form in BALB/c mice, and of completely protecting transgenic HLA-A2/HER2 mice from growth of HLA-A2/HER2-expressing BL6-10A2/HER2 melanoma. HuRt-TEXO-stimulated HER2-specific CD8+ T-cells not only are cytolytic to trastuzumab-resistant HLA-A2/HER2-expressing BT474/A2 breast tumor cells in vitro but also eradicates pre-established BT474/A2 tumors in athymic nude mice. Therefore, our novel heterologous human/rat HER2-specific T-cell vaccine HuRt-TEXO, circumventing HER2 tolerance, may provide a new therapeutic alternative for patients with trastuzumab-resistant HER2+ breast tumor. |
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| Keywords: | Heterozygous HER2 T cell vaccine Antibody CTL Tolerance Transgenic HER2 mice |
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