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Bermúdez-Abreut E, Bergado Báez G, Martínez Pestano M, Attanasio G, Gonzales Castillo CY, Hernández Fernández DR, Alvarez-Arzola R, Alimonti A, Sánchez-Ramírez B. Antitumor activity of PAbs generated by immunization with a novel HER3-targeting protein-based vaccine candidate in preclinical models. Front Oncol 2024; 14:1472607. [PMID: 39479017 PMCID: PMC11521786 DOI: 10.3389/fonc.2024.1472607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 09/23/2024] [Indexed: 11/02/2024] Open
Abstract
Despite the cumulative evidence supporting HER3 as a target for antitumor therapies, no agents targeting HER3 have been approved for cancer treatment. Most of the agents evaluated in preclinical and clinical trials have been specific monoclonal antibodies (MAbs), with few examples of active immunotherapy directed against this receptor. However, some cancer vaccine formats may generate polyclonal antibodies (PAbs) that replicate the diverse effector mechanisms of MAbs, including ligand neutralization and receptor degradation. In this study, we developed a protein subunit-based monovalent vaccine candidate targeting the extracellular domain (ECD) of HER3. Immunization of mice with a formulation targeting murine ErbB3-ECD successfully overcome tolerance to this self-antigen, inducing high titers of ErbB3-specific PAbs. The antitumor potential of this formulation and the induced PAbs was demonstrated in vivo and in vitro in an ErbB3-overexpressing 3LL-D122-derived tumor model. The immunogenicity of the HER3-ECD-based vaccine candidate was confirmed by the induction of high titers of HER3-specific PAbs. Consistent with the initial results, HER3-ECD-targeting PAbs were cytotoxic in several human epithelial tumor cell lines and exerted antitumor effects in vivo. These results support the value of HER3 as a tumor antigen and the effector mechanisms of HER3-specific therapeutic MAbs, while suggesting the potential of the proposed vaccine candidate for the treatment of HER3-expressing carcinomas.
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Affiliation(s)
| | - Gretchen Bergado Báez
- Immunology and Immunotherapy Division, Center of Molecular Immunology (CIM), Havana, Cuba
| | | | - Giuseppe Attanasio
- Department of Molecular Oncology, Institute of Oncology Research (IOR), Bellinzona, Switzerland
| | | | | | - Rydell Alvarez-Arzola
- Immunology and Immunotherapy Division, Center of Molecular Immunology (CIM), Havana, Cuba
| | - Andrea Alimonti
- Department of Molecular Oncology, Institute of Oncology Research (IOR), Bellinzona, Switzerland
- Faculty of Medicine, Università della Svizzera Italiana, Lugano, Switzerland
- Department of Medicine, University of Padua, Padua, Italy
- Medical Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
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Alvarez-Arzola R, Bancaro N, Lai P, Attanasio G, Pellegrini L, Troiani M, Colucci M, Mosole S, Pasquini E, Alimonti A, Mesa C. VSSP-activated macrophages mediate senescence and tumor inhibition in a preclinical model of advanced prostate cancer. Cell Commun Signal 2023; 21:76. [PMID: 37055829 PMCID: PMC10100133 DOI: 10.1186/s12964-023-01095-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 03/07/2023] [Indexed: 04/15/2023] Open
Abstract
Androgen deprivation therapy (ADT) is a standard therapy for prostate cancer (PCa). Though disseminated disease is initially sensitive to ADT, an important fraction of the patients progresses to castration-resistant prostate cancer (CRPC). For this reason, the identification of novel effective therapies for treating CRPC is needed. Immunotherapeutic strategies focused on macrophages as antitumor effectors, directly enhancing their tumoricidal potential at the tumor microenvironment or their adoptive transfer after ex vivo activation, have arisen as promising therapies in several cancer types. Despite several approaches centered on the activation of tumor-associated macrophages (TAMs) in PCa are under investigation, to date there is no evidence of clinical benefit in patients. In addition, the evidence of the effectiveness of macrophage adoptive transfer on PCa is poor. Here we find that VSSP, an immunomodulator of the myeloid system, decreases TAMs and inhibits prostatic tumor growth when administered to castrated Pten-deficient prostate tumor-bearing mice. In mice bearing castration-resistant Ptenpc-/-; Trp53pc-/- tumors, VSSP administration showed no effect. Nevertheless, adoptive transfer of macrophages activated ex vivo with VSSP inhibited Ptenpc-/-; Trp53pc-/- tumor growth through reduction of angiogenesis and tumor cell proliferation and induction of senescence. Taken together, our results highlight the rationale of exploiting macrophage functional programming as a promising strategy for CRPC therapy, with particular emphasis on ex vivo-activated proinflammatory macrophage adoptive transfer. Video abstract.
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Affiliation(s)
- Rydell Alvarez-Arzola
- Department of Immunoregulation, Immunology and Immunotherapy Direction, Center of Molecular Immunology, Havana, Cuba.
| | - Nicoló Bancaro
- Department of Molecular Oncology, Institute of Oncology Research (IOR), 6500, Bellinzona, Switzerland
| | - Ping Lai
- Department of Molecular Oncology, Institute of Oncology Research (IOR), 6500, Bellinzona, Switzerland
| | - Giuseppe Attanasio
- Department of Molecular Oncology, Institute of Oncology Research (IOR), 6500, Bellinzona, Switzerland
| | - Laura Pellegrini
- Department of Molecular Oncology, Institute of Oncology Research (IOR), 6500, Bellinzona, Switzerland
| | - Martina Troiani
- Department of Molecular Oncology, Institute of Oncology Research (IOR), 6500, Bellinzona, Switzerland
| | - Manuel Colucci
- Department of Molecular Oncology, Institute of Oncology Research (IOR), 6500, Bellinzona, Switzerland
| | - Simone Mosole
- Department of Molecular Oncology, Institute of Oncology Research (IOR), 6500, Bellinzona, Switzerland
| | - Emiliano Pasquini
- Department of Molecular Oncology, Institute of Oncology Research (IOR), 6500, Bellinzona, Switzerland
| | - Andrea Alimonti
- Department of Molecular Oncology, Institute of Oncology Research (IOR), 6500, Bellinzona, Switzerland
- Faculty of Medicine, Università della Svizzera Italiana, 1011, Lugano, Switzerland
- Department of Medicine, University of Padua, 35131, Padua, Italy
- Medical Oncology, Oncology Institute of Southern Switzerland, 6500, Bellinzona, Switzerland
| | - Circe Mesa
- Innovative Immunotherapy Alliance S.A., Mariel, Artemisa, Cuba
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Campal-Espinosa AC, Junco-Barranco JA, Fuentes-Aguilar F, Calzada-Aguilera L, Rivacoba-Betancourt A, Rodríguez-Bueno RH, Bover-Campal AC, Bover-Fuentes EE, González L, de Quesada L, Alvarez A, Garay-Pérez HE. Influence of Humoral Response Against GnRH, Generated by Immunization with a Therapeutic Vaccine Candidate on the Evolution of Patients with Castration-Sensitive Prostate Adenocarcinoma. Technol Cancer Res Treat 2023; 22:15330338231207318. [PMID: 37828833 PMCID: PMC10576932 DOI: 10.1177/15330338231207318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2023] Open
Abstract
BACKGROUND AND AIMS A gonadotropin-releasing hormone (GnRH)-based therapeutic vaccine candidate against hormone-sensitive prostate cancer has demonstrated its safety and signs of efficacy in phase I/II trials. In this study, we characterized the isotype/subclass profiles of the anti-GnRH humoral response generated by the vaccination and analyzed its association with patients' clinical outcomes. METHODS The immunoglobulin isotypes and IgG subclasses of the antibody responses of 34 patients included in a randomized, open, prospective phase I/II clinical trial were characterized. Every patient included in the study had a diagnosis of locally advanced prostate adenocarcinoma at stages 3 and 4 and received immunization with the vaccine candidate. Additionally, serum testosterone and prostate specific antigen (PSA) concentrations, serving as indicators of tumor response, were determined. The type of anti-GnRH antibody response was correlated to the time elapsed until the first biochemical recurrence in patients and the outcome of the disease. RESULTS All patients developed strong and prolonged anti-GnRH antibody responses, resulting in a short- to mid-term decrease in serum testosterone and PSA levels. Following immunizations, anti-GnRH antibodies of the IgM/IgG and IgG1/IgG3 subclasses were observed. Following radiotherapy, the humoral response switched to IgG (IgG1/IgG4). Patients who experienced a short-term biochemical relapse were characterized by significantly higher levels of anti-GnRH IgG titers, particularly IgG1 and IgG4 subclasses. These characteristics, along with a high response of specific IgM antibodies at the end of immunizations and the development of anti-GnRH IgA antibody responses following radiotherapy, were observed in patients whose disease progressed, compared to those with controlled disease. CONCLUSION The nature of the humoral response against anti-GnRH, induced by vaccination may play a key role in activating additional immunological mechanisms. Collectively, these mechanisms could contribute significantly to the regulation of tumor growth.
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Affiliation(s)
| | - Jesús Arturo Junco-Barranco
- Vaccine Research Group, Research Department, Center of Genetic Engineering and Biotechnology, Camagüey, Cuba
| | - Franklin Fuentes-Aguilar
- Vaccine Research Group, Research Department, Center of Genetic Engineering and Biotechnology, Camagüey, Cuba
| | - Lesvia Calzada-Aguilera
- Vaccine Research Group, Research Department, Center of Genetic Engineering and Biotechnology, Camagüey, Cuba
| | | | | | | | - Eddy Emilio Bover-Fuentes
- Vaccine Research Group, Research Department, Center of Genetic Engineering and Biotechnology, Camagüey, Cuba
| | - Lourdes González
- Department of Urology, Oncological Hospital Camagüey, Camagüey, Cuba
| | | | - Allelin Alvarez
- Department of Urology, Oncological Hospital Camagüey, Camagüey, Cuba
| | - Hilda Elisa Garay-Pérez
- Department of Immunology, Eduardo Agramonte Piña Pediatric Hospital Camagüey, Camagüey, Cuba
- Synthetic Peptides Group, Division of Biomedical Research, Center of Genetic Engineering and Biotechnology, Havana, Cuba
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Khan ANH, Emmons TR, Magner WJ, Alqassim E, Singel KL, Ricciuti J, Eng KH, Odunsi K, Tomasi TB, Lee K, Abrams SI, Mesa C, Segal BH. VSSP abrogates murine ovarian tumor-associated myeloid cell-driven immune suppression and induces M1 polarization in tumor-associated macrophages from ovarian cancer patients. Cancer Immunol Immunother 2022; 71:2355-2369. [PMID: 35166871 PMCID: PMC10591410 DOI: 10.1007/s00262-022-03156-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 01/16/2022] [Indexed: 02/07/2023]
Abstract
The ovarian tumor microenvironment (TME) is characterized by the accumulation of immunosuppressive tumor-associated macrophages (TAMs) and granulocytic cells. Very small size particles (VSSP), comprised of the ganglioside NAcGM3 and Neisseria meningitidis derived outer membrane vesicles, is being developed as a nanoparticulated modulator of innate immunity. Prior studies have shown that VSSP enhanced antigen-specific cytotoxic T cell responses and reduced the suppressive phenotype of splenic granulocytic cells in tumor-bearing mice. Here, we hypothesized that intraperitoneal VSSP would modify myeloid cell accumulation and phenotypes in the ovarian TME and abrogate suppressor function of TAMs and tumor-associated granulocytic cells. In the ID8 syngeneic model of epithelial ovarian cancer, VSSP reduced peritoneal TAMs and induced M1-like polarization in TAMs. In addition, VSSP stimulated peritoneal inflammation characterized by increased granulocytes and monocytes, including inflammatory monocytic cells. VSSP treatment resulted in peritoneal TAMs and granulocytic cells being less suppressive of ex vivo stimulated CD8+ T cell responses. VSSP alone and combined with anti-PD-1 modestly but significantly prolonged survival in tumor-bearing mice. In addition, ex vivo treatment with VSSP induced M1-like polarization in TAMs from patients with metastatic ovarian cancer and variably abrogated their suppressor phenotype. VSSP treatment also partially abrogated the induction of suppressor function in healthy donor neutrophils exposed to ascites supernatants from patients with ovarian cancer. Together, these results point to VSSP reprogramming myeloid responses resulting in abrogation of suppressive pathways and raise the potential for administration of VSSP into the TME to enhance anti-tumor immunity.
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Affiliation(s)
- Anm Nazmul H Khan
- Department of Internal Medicine, Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY, USA
| | - Tiffany R Emmons
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY, USA
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - William J Magner
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY, USA
- Department of Microbiology & Immunology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Emad Alqassim
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- Department of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Kelly L Singel
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY, USA
- Office of Evaluation, Performance, and Reporting; Division of Program Coordination, Planning, and Strategic Initiatives; Office of the Director, National Institutes of Health, Bethesda, MD, USA
| | - Jason Ricciuti
- Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Kevin H Eng
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Kunle Odunsi
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY, USA
- Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL, USA
| | - Thomas B Tomasi
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY, USA
- Department of Microbiology & Immunology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
- Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Kelvin Lee
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY, USA
- Department of Medicine, Roswell Park Comprehensive Cancer Center, University at Buffalo, Buffalo, NY, USA
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, USA
| | - Scott I Abrams
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY, USA
| | - Circe Mesa
- Center of Molecular Immunology, Havana, Cuba
- Innovative Immunotherapy Alliance, S. A. Mariel, Artemisa, Cuba
| | - Brahm H Segal
- Department of Internal Medicine, Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY, USA.
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY, USA.
- Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
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Zahedipour F, Zamani P, Jamialahmadi K, Jaafari MR, Sahebkar A. Vaccines targeting angiogenesis in melanoma. Eur J Pharmacol 2021; 912:174565. [PMID: 34656608 DOI: 10.1016/j.ejphar.2021.174565] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 09/28/2021] [Accepted: 10/11/2021] [Indexed: 12/15/2022]
Abstract
Angiogenesis has a significant role in metastasis and progression of melanoma. Even small tumors may be susceptible to metastasis and hence lead to a worse outcome in patients with melanoma. One of the anti-angiogenic treatment approaches that is undergoing comprehensive study is specific immunotherapy. While tumor cells are challenging targets for immunotherapy due to their genetic instability and heterogeneity, endothelial cells (ECs) are genetically stable. Therefore, vaccines targeting angiogenesis in melanoma are appropriate choices that target both tumor cells and ECs while capable of inducing strong, anti-tumor immune responses with limited toxicity. The main targets of angiogenesis are VEGFs and their receptors but other potential targets have also been investigated, especially in preclinical studies. Various types of vaccines that target angiogenesis in melanoma have been studied including DNA, peptide, protein, dendritic cell-based, and endothelial cell vaccines. This review outlines a number of target antigens that are important for potential progress in developing vaccines for targeting angiogenesis in melanoma. We also discuss different types of vaccines that have been investigated, delivery mechanisms and popular adjuvants, and suggest ways to improve future clinical outcomes.
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Affiliation(s)
- Fatemeh Zahedipour
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Parvin Zamani
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Khadijeh Jamialahmadi
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud Reza Jaafari
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Medicine, The University of Western Australia, Perth, Australia; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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Mancebo Rodríguez A, Bergado Báez G, Acosta Lago E, León Goñi A, Blanco Gámez D, Fuentes Morales D, Hernández Fernández DR, Sánchez Ramírez B, Pérez Barreda A, Casacó Parada Á. Immuno-toxicological evaluation of her1 cancer vaccine in non-human primates: a 6-month subcutaneous study. Immunopharmacol Immunotoxicol 2021; 43:283-290. [PMID: 33722157 DOI: 10.1080/08923973.2021.1900232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Purpose: A vaccine composition based on the extracellular domain of the human epidermal growth factor receptor 1 (HER1-ECD) and the combination of VSSP (very small size proteoliposomes) and Montanide ISA 51 adjuvants when used by intramuscular route, demonstrated promising results in preclinical studies. However, in order to avoid potential adverse events due to the use of Montanide, it is proposed to modify the vaccine formulation by using VSSP (very small size proteoliposomes) adjuvant alone, and to evaluate the quality of subcutaneously induced immune response. This study aimed to assess the immunotoxicological effects of HER1 vaccine in Cercopithecus aethiops.Materials and methods: Fifteen monkeys were randomized into four groups: Negative Control (Tris/NaCl, s.c.), Positive Control (200 µg HER1-ECD/VSSP/Montanide ISA-51 VG, i.m), Low Dose (200 µg HER1-ECD/VSSP/Tris NaCl, s.c.) and High Dose (800 µg HER1-ECD/VSSP/Tris NaCl, s.c). All monkeys received 7 doses and were daily inspected for clinical signs. Body weight, rectal temperature, cardiac and respiratory rates were measured during the study, and electrocardiographical and ophthalmological studies were performed. Humoral and cellular immune response and clinical pathology parameters were analyzed.Results: Animal's survival in the study was 100% (n = 15). Administration site reactions were observed in the Positive Control animals (n = 4). HER1 vaccine administered subcutaneously (High Dose Group) achieved good IgG antibody titers although lower than the Positive Control group, but with higher ability to inhibit HER1 phosphorylation. Conclusions: This suggests that the alternative of eliminating the use of Montanide in the HER1 vaccine preparation and the using subcutaneous route is feasible.
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Affiliation(s)
- Axel Mancebo Rodríguez
- Center of Experimental Toxicology, National Center for Laboratory Animals Breeding (CENPALAB), La Habana, Cuba
| | | | - Eric Acosta Lago
- Center of Experimental Toxicology, National Center for Laboratory Animals Breeding (CENPALAB), La Habana, Cuba
| | - Avelina León Goñi
- Center of Experimental Toxicology, National Center for Laboratory Animals Breeding (CENPALAB), La Habana, Cuba
| | - Diuris Blanco Gámez
- Center of Experimental Toxicology, National Center for Laboratory Animals Breeding (CENPALAB), La Habana, Cuba
| | - Dasha Fuentes Morales
- Center of Experimental Toxicology, National Center for Laboratory Animals Breeding (CENPALAB), La Habana, Cuba
| | | | | | | | - Ángel Casacó Parada
- Tumor Immunology Direction, Center of Molecular Immunology (CIM), La Habana, Cuba
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Laborde RJ, Ishimura ME, Abreu-Butin L, Nogueira CV, Grubaugh D, Cruz-Leal Y, Luzardo MC, Fernández A, Mesa C, Pazos F, Álvarez C, Alonso ME, Starnbach MN, Higgins DE, Fernández LE, Longo-Maugéri IM, Lanio ME. Sticholysins, pore-forming proteins from a marine anemone can induce maturation of dendritic cells through a TLR4 dependent-pathway. Mol Immunol 2021; 131:144-154. [PMID: 33422341 DOI: 10.1016/j.molimm.2020.12.032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 11/30/2020] [Accepted: 12/24/2020] [Indexed: 02/06/2023]
Abstract
Sticholysins (Sts) I and II (StI and StII) are pore-forming proteins (PFPs), purified from the Caribbean Sea anemone Stichodactyla helianthus. StII encapsulated into liposomes induces a robust antigen-specific cytotoxic CD8+ T lymphocytes (CTL) response and in its free form the maturation of bone marrow-derived dendritic cells (BM-DCs). It is probable that the latter is partially supporting in part the immunomodulatory effect on the CTL response induced by StII-containing liposomes. In the present work, we demonstrate that the StII's ability of inducing maturation of BM-DCs is also shared by StI, an isoform of StII. Using heat-denatured Sts we observed a significant reduction in the up-regulation of maturation markers indicating that both PFP's ability to promote maturation of BM-DCs is dependent on their conformational characteristics. StII-mediated DC maturation was abrogated in BM-DCs from toll-like receptor (TLR) 4 and myeloid differentiation primary response gene 88 (MyD88)-knockout mice but not in cells from TLR2-knockout mice. Furthermore, the antigen-specific CTL response induced by StII-containing liposomes was reduced in TLR4-knockout mice. These results indicate that StII, and probably by extension StI, has the ability to induce maturation of DCs through a TLR4/MyD88-dependent pathway, and that this activation contributes to the CTL response generated by StII-containing liposomes.
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Affiliation(s)
- Rady J Laborde
- Laboratory of Toxins and Liposomes, Center for Protein Studies, Faculty of Biology, University of Havana (UH), Lab UH-CIM, Havana, 10400, Cuba.
| | - Mayari E Ishimura
- Discipline of Immunology, Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP), 04023-062, São Paulo, Brazil.
| | - Lianne Abreu-Butin
- Discipline of Immunology, Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP), 04023-062, São Paulo, Brazil
| | - Catarina V Nogueira
- Department of Microbiology and Immunobiology of Harvard Medical School, Harvard University, MA, USA.
| | - Daniel Grubaugh
- Department of Microbiology and Immunobiology of Harvard Medical School, Harvard University, MA, USA.
| | - Yoelys Cruz-Leal
- Laboratory of Toxins and Liposomes, Center for Protein Studies, Faculty of Biology, University of Havana (UH), Lab UH-CIM, Havana, 10400, Cuba.
| | - María C Luzardo
- Laboratory of Toxins and Liposomes, Center for Protein Studies, Faculty of Biology, University of Havana (UH), Lab UH-CIM, Havana, 10400, Cuba.
| | - Audry Fernández
- Immunobiology Division, Center of Molecular Immunology (CIM), Havana, 11600, Cuba.
| | - Circe Mesa
- Immunobiology Division, Center of Molecular Immunology (CIM), Havana, 11600, Cuba.
| | - Fabiola Pazos
- Laboratory of Toxins and Liposomes, Center for Protein Studies, Faculty of Biology, University of Havana (UH), Lab UH-CIM, Havana, 10400, Cuba.
| | - Carlos Álvarez
- Laboratory of Toxins and Liposomes, Center for Protein Studies, Faculty of Biology, University of Havana (UH), Lab UH-CIM, Havana, 10400, Cuba.
| | - María E Alonso
- Laboratory of Toxins and Liposomes, Center for Protein Studies, Faculty of Biology, University of Havana (UH), Lab UH-CIM, Havana, 10400, Cuba
| | - Michael N Starnbach
- Department of Microbiology and Immunobiology of Harvard Medical School, Harvard University, MA, USA.
| | - Darren E Higgins
- Department of Microbiology and Immunobiology of Harvard Medical School, Harvard University, MA, USA.
| | - Luis E Fernández
- Immunobiology Division, Center of Molecular Immunology (CIM), Havana, 11600, Cuba.
| | - Ieda M Longo-Maugéri
- Discipline of Immunology, Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP), 04023-062, São Paulo, Brazil.
| | - María E Lanio
- Laboratory of Toxins and Liposomes, Center for Protein Studies, Faculty of Biology, University of Havana (UH), Lab UH-CIM, Havana, 10400, Cuba.
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Tamargo Santos B, Fleitas Pérez C, Infante Bourzac JF, Márquez Nápoles Y, Ramírez González W, Bourg V, Torralba D, Pérez V, Mouriño A, Ayala J, Labrada Rosado A, Aleya L, Bungau S, Sierra González VG. Remote induction of cellular immune response in mice by anti-meningococcal nanocochleates - nanoproteoliposomes. THE SCIENCE OF THE TOTAL ENVIRONMENT 2019; 668:1055-1063. [PMID: 31018447 DOI: 10.1016/j.scitotenv.2019.03.075] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 03/05/2019] [Accepted: 03/05/2019] [Indexed: 06/09/2023]
Abstract
New adjuvant formulations, based on proteoliposomes <40 nm and cochleates <100 nm, without Al(OH)3 adjuvant, were evaluated regarding their ability to generate Th1 immune response through a Delayed -Type Hypersensitivity Test, at the mouse model, by using a Neisseria meningitidis B protein complex as antigen. The formulations were administered by intramuscular (IM) (2 inoculations - at baseline and after 14 days) and intranasal (IN) (3 inoculations at 7 days) immunization pathways. All IM immunized groups were able to induce similar response to these formulations as well as to VA-MENGOC-BC® vaccine - containing Al(OH)3 adjuvant (used as positive control of the trial). In all groups, the induced inflammation (IP) rate was statistically higher than in the negative control group (CN) (p < 0.05). Immunogenicity, measured by HSR and CD4+ lymphocyte increase was equivalent to the control vaccine and most important, granuloma reactogenicity at the site of injection was eliminated, fact demonstrated by histological study. All groups of animals immunized by IN route showed HSR reactions and statistically significant differences with respect to the CN group. However, IP values were lower, with statistical differences (p < 0.05) for the same adjuvant formulation IM administered, except the AIF2-nCh formulation that generated statistically similar induction (p > 0.05) by both immunization pathways, suggesting it to be the best candidate for the next IN trial. Proteoliposome and cochleate formulations tested were able to mount potent Th-1 immune response, equivalent to the original vaccine formulation, with the advantage of less reactogenicity in the site of the injection, caused by the toxicity of Al(OH)3 adjuvant gel.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Antonio Mouriño
- Santiago de Compostela University, Santiago de Compostela, Spain
| | - Juan Ayala
- Center for Molecular Biology "Severo Ochoa", Madrid, Spain
| | | | - Lotfi Aleya
- Laboratoire Chrono-environnement, Université de Franche-Comté, Besançon, France.
| | - Simona Bungau
- Faculty of Medicine and Pharmacy, University of Oradea, Romania
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Farjadian F, Moghoofei M, Mirkiani S, Ghasemi A, Rabiee N, Hadifar S, Beyzavi A, Karimi M, Hamblin MR. Bacterial components as naturally inspired nano-carriers for drug/gene delivery and immunization: Set the bugs to work? Biotechnol Adv 2018; 36:968-985. [PMID: 29499341 PMCID: PMC5971145 DOI: 10.1016/j.biotechadv.2018.02.016] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 02/20/2018] [Accepted: 02/26/2018] [Indexed: 12/28/2022]
Abstract
Drug delivery is a rapidly growing area of research motivated by the nanotechnology revolution, the ideal of personalized medicine, and the desire to reduce the side effects of toxic anti-cancer drugs. Amongst a bewildering array of different nanostructures and nanocarriers, those examples that are fundamentally bio-inspired and derived from natural sources are particularly preferred. Delivery of vaccines is also an active area of research in this field. Bacterial cells and their components that have been used for drug delivery, include the crystalline cell-surface layer known as "S-layer", bacterial ghosts, bacterial outer membrane vesicles, and bacterial products or derivatives (e.g. spores, polymers, and magnetic nanoparticles). Considering the origin of these components from potentially pathogenic microorganisms, it is not surprising that they have been applied for vaccines and immunization. The present review critically summarizes their applications focusing on their advantages for delivery of drugs, genes, and vaccines.
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Affiliation(s)
- Fatemeh Farjadian
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohsen Moghoofei
- Department of Microbiology, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Soroush Mirkiani
- Biomaterials Laboratory, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran
| | - Amir Ghasemi
- Department of Materials Science and Engineering, Sharif University of Technology, Tehran, Iran
| | - Navid Rabiee
- Department of Chemistry, Shahid Beheshti University, Tehran, Iran
| | - Shima Hadifar
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran
| | - Ali Beyzavi
- Koch institute of MIT, 500 Main Street, Cambridge, MA, USA
| | - Mahdi Karimi
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran; Department of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran; Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
| | - Michael R Hamblin
- Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Department of Dermatology, Harvard Medical School, Boston, MA 02115, USA; Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA.
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10
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Liang X, Li X, Duan J, Chen Y, Wang X, Pang L, Kong D, Song B, Li C, Yang J. Nanoparticles with CD44 Targeting and ROS Triggering Properties as Effective in Vivo Antigen Delivery System. Mol Pharm 2018; 15:508-518. [DOI: 10.1021/acs.molpharmaceut.7b00890] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Affiliation(s)
- Xiaoyu Liang
- Tianjin
Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China
| | - Xuanling Li
- Tianjin
Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China
| | - Jianwei Duan
- Tianjin
Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China
| | - Youlu Chen
- Tianjin
Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China
| | - Xiaoli Wang
- Tianjin
Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China
| | - Liyun Pang
- Tianjin
Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China
| | - Deling Kong
- Tianjin
Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China
- Key
Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin 300071, China
| | - Bing Song
- School of Dentistry, College of Biomedical & Life Sciences, Cardiff University, Heath Park, Cardiff CF14 4XY, U.K
| | - Chen Li
- Tianjin
Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China
| | - Jing Yang
- Tianjin
Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China
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11
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Morera-Díaz Y, Gavilondo JV, Bequet-Romero M, Sánchez Ramírez J, Hernández-Bernal F, Selman-Housein KH, Perez L, Ayala-Ávila M. Specific active immunotherapy with the HEBERSaVax VEGF-based cancer vaccine: From bench to bedside. Semin Oncol 2018; 45:68-74. [DOI: 10.1053/j.seminoncol.2018.03.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2018] [Revised: 03/12/2018] [Accepted: 03/18/2018] [Indexed: 12/31/2022]
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12
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Castro J, Puente P, Martínez R, Hernández A, Morera Y, Martínez L, Aldana L, Valdés I, Ayala M, Cosme K. Vaccine CIGB 247 is potentially safe for use as a novel therapeutic vaccine against cancer in Chlorocebus aethiops monkeys. Int Immunopharmacol 2017; 48:55-60. [PMID: 28463787 DOI: 10.1016/j.intimp.2017.04.023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Revised: 03/31/2017] [Accepted: 04/22/2017] [Indexed: 01/22/2023]
Abstract
CIGB 247 is a novel cancer therapeutic vaccine based on human vascular endothelial growth factor (VEGF) variant molecule as antigen, in combination with a bacterial adjuvant. This vaccine candidate has previously demonstrated efficacy and safety in mice, rats, rabbits and non-human primates. In the present study we evaluated the effects on the clinical, hematological and biochemical parameters of CIGB 247 vaccine in Chlorocebus aethiops monkeys. Three groups of monkeys were immunized with three doses of vaccine formulation to measure physiological values of clinical, hematological and serum biochemical parameters. Monkeys' body weight and temperature were kept stable and close to standard values throughout the study. Variations in the levels of red blood cells and hemoglobin were observed among the different groups for all injected doses, but these hematological parameters recovered normal values at the end of the study. On the other hand, biochemical parameters such as the total bilirubin and total protein counts showed variations along the study, while they were not associated with the test substance. In summary, no negative effects on clinical, hematological and biochemical parameters were detected. Together, our results put forward the potential and support the safety of the CIGB 247 vaccine candidate for use in clinical applications. The data presented here can be used to estimate a human dosing regimen from preclinical data.
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Affiliation(s)
- Jorge Castro
- Center for Genetic Engineering and Biotechnology (CIGB), Avenue 31, PO. Box 6162, Havana 6 10600, Cuba.
| | - Pedro Puente
- Center for Genetic Engineering and Biotechnology (CIGB), Avenue 31, PO. Box 6162, Havana 6 10600, Cuba
| | - Rafael Martínez
- Center for Genetic Engineering and Biotechnology (CIGB), Avenue 31, PO. Box 6162, Havana 6 10600, Cuba
| | - Alexander Hernández
- Center for Genetic Engineering and Biotechnology (CIGB), Avenue 31, PO. Box 6162, Havana 6 10600, Cuba
| | - Yanelys Morera
- Center for Genetic Engineering and Biotechnology (CIGB), Avenue 31, PO. Box 6162, Havana 6 10600, Cuba
| | - Leticia Martínez
- Center for Genetic Engineering and Biotechnology (CIGB), Avenue 31, PO. Box 6162, Havana 6 10600, Cuba
| | - Lizet Aldana
- Center for Genetic Engineering and Biotechnology (CIGB), Avenue 31, PO. Box 6162, Havana 6 10600, Cuba
| | - Iris Valdés
- Center for Genetic Engineering and Biotechnology (CIGB), Avenue 31, PO. Box 6162, Havana 6 10600, Cuba
| | - Marta Ayala
- Center for Genetic Engineering and Biotechnology (CIGB), Avenue 31, PO. Box 6162, Havana 6 10600, Cuba
| | - Karelia Cosme
- Center for Genetic Engineering and Biotechnology (CIGB), Avenue 31, PO. Box 6162, Havana 6 10600, Cuba
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13
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Laborde RJ, Sanchez-Ferras O, Luzardo MC, Cruz-Leal Y, Fernández A, Mesa C, Oliver L, Canet L, Abreu-Butin L, Nogueira CV, Tejuca M, Pazos F, Álvarez C, Alonso ME, Longo-Maugéri IM, Starnbach MN, Higgins DE, Fernández LE, Lanio ME. Novel Adjuvant Based on the Pore-Forming Protein Sticholysin II Encapsulated into Liposomes Effectively Enhances the Antigen-Specific CTL-Mediated Immune Response. THE JOURNAL OF IMMUNOLOGY 2017; 198:2772-2784. [PMID: 28258198 DOI: 10.4049/jimmunol.1600310] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Accepted: 01/18/2017] [Indexed: 12/21/2022]
Abstract
Vaccine strategies to enhance CD8+ CTL responses remain a current challenge because they should overcome the plasmatic and endosomal membranes for favoring exogenous Ag access to the cytosol of APCs. As a way to avoid this hurdle, sticholysin (St) II, a pore-forming protein from the Caribbean Sea anemone Stichodactyla helianthus, was encapsulated with OVA into liposomes (Lp/OVA/StII) to assess their efficacy to induce a CTL response. OVA-specific CD8+ T cells transferred to mice immunized with Lp/OVA/StII experienced a greater expansion than when the recipients were injected with the vesicles without St, mostly exhibiting a memory phenotype. Consequently, Lp/OVA/StII induced a more potent effector function, as shown by CTLs, in vivo assays. Furthermore, treatment of E.G7-OVA tumor-bearing mice with Lp/OVA/StII significantly reduced tumor growth being more noticeable in the preventive assay. The contribution of CD4+ and CD8+ T cells to CTL and antitumor activity, respectively, was elucidated. Interestingly, the irreversibly inactive variant of the StI mutant StI W111C, encapsulated with OVA into Lp, elicited a similar OVA-specific CTL response to that observed with Lp/OVA/StII or vesicles encapsulating recombinant StI or the reversibly inactive StI W111C dimer. These findings suggest the relative independence between StII pore-forming activity and its immunomodulatory properties. In addition, StII-induced in vitro maturation of dendritic cells might be supporting these properties. These results are the first evidence, to our knowledge, that StII, a pore-forming protein from a marine eukaryotic organism, encapsulated into Lp functions as an adjuvant to induce a robust specific CTL response.
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Affiliation(s)
- Rady J Laborde
- Center for Protein Studies, Faculty of Biology, University of Havana, Havana 10400, Cuba
| | - Oraly Sanchez-Ferras
- Center for Protein Studies, Faculty of Biology, University of Havana, Havana 10400, Cuba
| | - María C Luzardo
- Center for Protein Studies, Faculty of Biology, University of Havana, Havana 10400, Cuba
| | - Yoelys Cruz-Leal
- Center for Protein Studies, Faculty of Biology, University of Havana, Havana 10400, Cuba
| | - Audry Fernández
- Immunobiology Division, Center of Molecular Immunology, Havana 11600, Cuba
| | - Circe Mesa
- Immunobiology Division, Center of Molecular Immunology, Havana 11600, Cuba
| | - Liliana Oliver
- Immunobiology Division, Center of Molecular Immunology, Havana 11600, Cuba
| | - Liem Canet
- Center for Protein Studies, Faculty of Biology, University of Havana, Havana 10400, Cuba
| | - Liane Abreu-Butin
- Discipline of Immunology, Department of Microbiology, Immunology, and Parasitology, Paulista Medical School, Federal University of São Paulo, São Paulo 04023-900, Brazil; and
| | - Catarina V Nogueira
- Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115
| | - Mayra Tejuca
- Center for Protein Studies, Faculty of Biology, University of Havana, Havana 10400, Cuba
| | - Fabiola Pazos
- Center for Protein Studies, Faculty of Biology, University of Havana, Havana 10400, Cuba
| | - Carlos Álvarez
- Center for Protein Studies, Faculty of Biology, University of Havana, Havana 10400, Cuba
| | - María E Alonso
- Center for Protein Studies, Faculty of Biology, University of Havana, Havana 10400, Cuba
| | - Ieda M Longo-Maugéri
- Discipline of Immunology, Department of Microbiology, Immunology, and Parasitology, Paulista Medical School, Federal University of São Paulo, São Paulo 04023-900, Brazil; and
| | - Michael N Starnbach
- Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115
| | - Darren E Higgins
- Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115
| | - Luis E Fernández
- Immunobiology Division, Center of Molecular Immunology, Havana 11600, Cuba;
| | - María E Lanio
- Center for Protein Studies, Faculty of Biology, University of Havana, Havana 10400, Cuba;
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14
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Anani W, Shurin MR. Targeting Myeloid-Derived Suppressor Cells in Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1036:105-128. [PMID: 29275468 DOI: 10.1007/978-3-319-67577-0_8] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Myeloid derived suppressor cells (MDSC) represent only a minor fraction of circulating blood cells but play an important role in tumor formation and progression. They are a heterogeneous group of cells that influence the tumor microenvironment by depletion of amino acids, oxidative stress, decreased trafficking of antitumor effector cells, and increased regulatory T and regulatory dendritic cell responses. Investigational treatment strategies targeting MDSCs have attempted to inhibit MDSC development and expansion (stem cell factor blockade, modulate of cell signaling, and target MDSC migration and recruitment), inhibit MDSC function (nitric oxide inhibition and reactive oxygen and nitrogen species inhibition), differentiate MDSCs into more mature cells (Vitamins A and D, all-trans retinoic acid, interleukin-2, toll-like receptor 9 inhibitors, taxanes, beta-glucan particles, tumor-derived exosome inhibition, and very small size proteoliposomes), and destroy MDSCs (cytotoxic agents, ephrin A2 degradation, anti-interleukin 13, and histamine blockers). To date, there are no Food and Drug Administration approved therapies selectively targeting MDSCs, but such therapies are likely to be implemented in the future, due to the key role of MDSCs in antitumor immunity.
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Affiliation(s)
- Waseem Anani
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
| | - Michael R Shurin
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
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15
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Pérez Sánchez L, Morera Díaz Y, Bequet-Romero M, Ramses Hernández G, Rodríguez Y, Castro Velazco J, Puente Pérez P, Ayala Avila M, Gavilondo JV. Experimental studies of a vaccine formulation of recombinant human VEGF antigen with aluminum phosphate. Hum Vaccin Immunother 2016; 11:2030-7. [PMID: 25891359 DOI: 10.1080/21645515.2015.1029213] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
CIGB-247 is a cancer vaccine that is a formulation of a recombinant protein antigen representative of the human vascular endothelial growth factor (VEGF) with a bacterially-derived adjuvant (VSSP). The vaccine has shown an excellent safety profile in mice, rats, rabbits, not-human primates and in recent clinical trials in cancer patients. Response to the vaccine is characterized by specific antibody titers that neutralize VEGF/VEGFR2 binding and a cytotoxic tumor-specific response. To expand our present anti-VEGF active immunotherapy strategies, we have now studied in mice and non-human primates the effects of vaccination with a formulation of our recombinant VEGF antigen and aluminum phosphate adjuvant (hereafter denominated CIGB-247-A). Administered bi-weekly, CIGB-247-A produces high titers of anti-VEGF IgG blocking antibodies in 2 mice strains. Particularly in BALB/c, the treatment impaired subcutaneous F3II mammary tumor growth and reduced the number of spontaneous lung macro metastases, increasing animals' survival. Spleen cells from specifically immunized mice directly killed F3II tumor cells in vitro. CIGB-247-A also showed to be immunogenic in non-human primates, which developed anti-VEGF blocking antibodies and the ability for specific direct cell cytotoxic responses, all without impairing the healing of deep skin wounds or other side effect. Our results support consideration of aluminum phosphate as a suitable adjuvant for the development of new vaccine formulations using VEGF as antigen.
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Key Words
- ANOVA, Analysis of Variance
- Aluminum phosphate
- CFSE, Carboxyfluorescein succinimidyl ester
- CTL, Cytotoxic T lymphocyte
- ELISA, Enzyme-linked immune-sorbent assay
- FACS, Fluorescence-activated cell sorting
- GST, Glutathione S-transferase
- HPLC, High-performance liquid chromatography
- KDR, kinase domain receptor
- Ni-NTA, nickel-nitrilotriacetic acid
- PBMC, Peripheral blood mononuclear cells
- VEGF
- VEGF, vascular endothelial growth factor
- VEGFR2, vascular endothelial growth factor receptor 2
- VSSP, very small sized proteoliposomes
- adjuvant
- antibodies
- cancer therapeutic vaccine
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Affiliation(s)
- Lincidio Pérez Sánchez
- a Cancer Immunotherapy Laboratory; Department of Pharmaceuticals; Center for Genetic Engineering and Biotechnology (CIGB) ; Playa Cubanacan , Havana , Cuba
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16
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The LALF32-51 peptide as component of HPV therapeutic vaccine circumvents the alum-mediated inhibition of IL-12 and promotes a Th1 response. ACTA ACUST UNITED AC 2016. [DOI: 10.1016/j.jocit.2015.01.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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17
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Fernández A, Oliver L, Alvarez R, Fernández LE, Lee KP, Mesa C. Adjuvants and myeloid-derived suppressor cells: enemies or allies in therapeutic cancer vaccination. Hum Vaccin Immunother 2015; 10:3251-60. [PMID: 25483674 DOI: 10.4161/hv.29847] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Adjuvants are a critical but largely overlooked and poorly understood component included in vaccine formulations to stimulate and modulate the desired immune responses to an antigen. However, unlike in the protective infectious disease vaccines, adjuvants for cancer vaccines also need to overcome the effect of tumor-induced suppressive immune populations circulating in tumor-bearing individuals. Myeloid-derived suppressor cells (MDSC) are considered to be one of the key immunosuppressive populations that inhibit tumor-specific T cell responses in cancer patients. This review focuses on the different signals for the activation of the immune system induced by adjuvants, and the close relationship to the mechanisms of recruitment and activation of MDSC. This work explores the possibility that a cancer vaccine adjuvant may either strengthen or weaken the effect of tumor-induced MDSC, and the crucial need to address this in present and future cancer vaccines.
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Key Words
- APC, antigen-presenting cells
- ARG1, arginase 1
- CTL, cytotoxic T lymphocytes
- DC, dendritic cells
- G-MDSC, granulocytic MDSC
- GM-CSF, granulocyte macrophage colony-stimulating factor
- MDSC
- MDSC, myeloid-derived suppressor cells
- Mo-MDSC, monocytic MDSC
- NK, natural killer
- NOS2, inducible nitric oxide synthase
- TAM, tumor-associated macrophages
- TLR ligands
- TLR, Toll-like receptors
- Treg, regulatory T cells
- adjuvants
- cancer
- cytokines
- immunotherapy
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Affiliation(s)
- Audry Fernández
- a Immunobiology Division; Center of Molecular Immunology ; Havana , Cuba
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18
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Labrada M, Pablos I, Prete F, Hevia G, Clavell M, Benvenuti F, Fernández LE. Induction of leukocyte infiltration at metastatic site mediates the protective effect of NGcGM3-based vaccine. Hum Vaccin Immunother 2015; 10:2312-20. [PMID: 25424937 DOI: 10.4161/hv.29161] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
While the NGcGM3/VSSP vaccine, a preparation consisting in very small sized proteoliposomes (VSSP) obtained by the incorporation of the NGcGM3 ganglioside into the outer membrane protein (OMP) complex of Neisseria meningitides, is currently studied in late stage clinical trials in breast cancer and melanoma patients, mechanisms involved in the vaccine's antitumor effect are insufficiently understood. Here we have addressed the role of adaptive and innate immune cells in mediating the protective effect of the vaccine. To this aim we selected the 3LL-D122 Lewis lung spontaneous metastasis model. Unexpectedly, inoculation of the vaccine in tumor bearing C57BL/6 mice, either by subcutaneous (sc) or intraperitoneal (ip) routes, induced similar anti-metastatic effect. Regardless the T-independent nature of NGcGM3 ganglioside as antigen, the antimetastatic effect of NGcGM3/VSSP is dependent on CD4(+) T cells. In a further step we found that the vaccine was able to promote the increase, maturation, and cytokine secretion of conventional DCs and the maturation of Bone Marrow-derived plasmacytoid DCs. In line with this result the in vivo IFNα serum level in ip vaccinated mice increased as soon as 2h after treatment. On the other hand the infiltration of NK1.1(+)CD3(-) and NK1.1(+)CD3(+) cells in lungs of vaccinated mice was significantly increased, compared with the presence of these cells in control animal lungs. In the same way NGcGM3/VSSP mobilized acquired immunity effector cells into the lungs of vaccinated tumor bearing mice. Finally and not less noteworthy, leukocyte infiltration in lungs of tumor bearing mice correlates with vaccine induced inhibition of lung metastization.
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Affiliation(s)
- Mayrel Labrada
- a Center of Molecular Immunology (CIM); Immunobiology Division; Atabey; Havana Cuba
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19
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Fernández A, Oliver L, Alvarez R, Fernández LE, Mesa C. GM3-containing nanoparticles in immunosuppressed hosts: Effect on myeloid-derived suppressor cells. World J Immunol 2014; 4:98-106. [DOI: 10.5411/wji.v4.i2.98] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2014] [Revised: 05/27/2014] [Accepted: 06/27/2014] [Indexed: 02/05/2023] Open
Abstract
Cancer vaccines to date have not broadly achieved a significant impact on the overall survival of patients. The negative effect on the immune system of the tumor itself and conventional anti-tumor treatments such as chemotherapy is, undoubtedly, a key reason for these disappointing results. Myeloid-derived suppressor cells (MDSCs) are considered a central node of the immunosuppressive network associated with tumors. These cells inhibit the effector function of natural killer and CD8+ T cells, expand regulatory T cells and can differentiate into tumor-associated macrophages within the tumor microenvironment. Thus, overcoming the suppressive effects of MDSCs is likely to be critical for cancer immunotherapy to generate effective anti-tumor immune responses. However, the capacity of cancer vaccines and particularly their adjuvants to overcome this inhibitory population has not been well characterized. Very small size proteoliposomes (VSSP) is a nanoparticulated adjuvant specifically designed to be formulated with vaccines used in the treatment of immunocompromised patients. This adjuvant contains immunostimulatory bacterial signals together with GM3 ganglioside. VSSP promotes dendritic cell maturation, antigen cross-presentation to CD8+ T cells, Th1 polarization, and enhances CD8+ T cell response in tumor-free mice. Currently, four cancer vaccines using VSSP as the adjuvant are in Phase I and II clinical trials. In this review, we summarize our work characterizing the unique ability of VSSP to stimulate antigen-specific CD8+ T cell responses in two immunocompromised scenarios; in tumor-bearing mice and during chemotherapy-induced leukopenia. Particular emphasis has been placed on the interaction of these nanoparticles with MDSCs, as well as comparison with other cancer vaccine adjuvants currently in preclinical or clinical studies.
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20
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Acevedo R, Fernández S, Zayas C, Acosta A, Sarmiento ME, Ferro VA, Rosenqvist E, Campa C, Cardoso D, Garcia L, Perez JL. Bacterial outer membrane vesicles and vaccine applications. Front Immunol 2014; 5:121. [PMID: 24715891 PMCID: PMC3970029 DOI: 10.3389/fimmu.2014.00121] [Citation(s) in RCA: 184] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 03/09/2014] [Indexed: 11/13/2022] Open
Abstract
Vaccines based on outer membrane vesicles (OMV) were developed more than 20 years ago against Neisseria meningitidis serogroup B. These nano-sized structures exhibit remarkable potential for immunomodulation of immune responses and delivery of meningococcal antigens or unrelated antigens incorporated into the vesicle structure. This paper reviews different applications in OMV Research and Development (R&D) and provides examples of OMV developed and evaluated at the Finlay Institute in Cuba. A Good Manufacturing Practice (GMP) process was developed at the Finlay Institute to produce OMV from N. meningitidis serogroup B (dOMVB) using detergent extraction. Subsequently, OMV from N. meningitidis, serogroup A (dOMVA), serogroup W (dOMVW), and serogroup X (dOMVX) were obtained using this process. More recently, the extraction process has also been applied effectively for obtaining OMV on a research scale from Vibrio cholerae (dOMVC), Bordetella pertussis (dOMVBP), Mycobacterium smegmatis (dOMVSM), and BCG (dOMVBCG). The immunogenicity of the OMV has been evaluated for specific antibody induction, and together with functional bactericidal and challenge assays in mice has shown their protective potential. dOMVB has been evaluated with non-neisserial antigens, including with a herpes virus type 2 glycoprotein, ovalbumin, and allergens. In conclusion, OMV are proving to be more versatile than first conceived and remain an important technology for development of vaccine candidates.
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Affiliation(s)
| | | | | | | | | | - Valerie A Ferro
- Strathclyde Institute of Pharmacy and Biomedical Science, Strathclyde University , Glasgow , UK
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21
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Fernández A, Oliver L, Alvarez R, Hernández A, Raymond J, Fernández LE, Mesa C. Very small size proteoliposomes abrogate cross-presentation of tumor antigens by myeloid-derived suppressor cells and induce their differentiation to dendritic cells. J Immunother Cancer 2014; 2:5. [PMID: 24829762 PMCID: PMC4019907 DOI: 10.1186/2051-1426-2-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2013] [Accepted: 03/04/2014] [Indexed: 12/22/2022] Open
Abstract
Background Myeloid-derived suppressor cells (MDSCs) are among the major obstacles that adjuvants for cancer vaccines have to overcome. These cells cross-present tumor-associated antigens (TAA) to naive T lymphocytes with a tolerogenic outcome. Very Small Size Proteoliposomes (VSSP) is used as adjuvant by four therapeutic cancer vaccines currently in Phase I and II clinical trials. We previously found that VSSP reduces the suppressive function of MDSCs, then activating antigen-specific CTL responses in tumor-bearing (TB) mice, with the consequent reduction of tumor growth. However the mechanistic explanation for the immunomodulatory effect of this adjuvant in TB hosts has not been addressed before. Methods TB mice were inoculated with VSSP and MDSCs isolated and characterized by their expression of Arg1 and Nos2 genes by RT-PCR. The effect of VSSP on antigen cross-presentation by MDSCs, regulatory T cells (Tregs) expansion and MDSCs differentiation towards dendritic cells (DCs) was analyzed by FACS. Student’s t test or ANOVA and Tukey’s tests were used for statistical analyses. Results After inoculating VSSP into TB mice, a significant reduction of Arg1 and Nos2 gene expression was observed in recovered MDSCs. Concurrently the ability of these cells to induce down-regulation of CD3ζ chain on T cells was lost. Likewise in mice inoculated with the adjuvant lower percentages of Tregs were detected. In vitro, VSSP treatment was enough to differentiate MDSCs into phenotypically mature DCs, eliminating the former suppressive effect. Noteworthy, in vivo administration of VSSP to OVA-expressing (EG.7) TB mice abrogated this model antigen cross-presentation by splenic MDSCs. Similar results were obtained even when OVA antigen was administered into these TB mice formulated in VSSP. On the contrary, immunization with the same protein in polyI:C did not change the percentage of MDSCs expressing SIINFEKL/H-2Kb complexes, whereas a concomitant injection of VSSP aborted the limitations of polyI:C in this setting. Conclusions Altogether, these results indicate that VSSP has the peculiar capacity of inhibiting TAA cross-presentation and certain suppressive mechanisms on MDSCs which in turn, combined with the ability to induce differentiation of these cells into antigen-presenting cells (APCs), sustains this adjuvant as an ideal immunomodulator for cancer immunotherapy.
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Affiliation(s)
- Audry Fernández
- Immunobiology Division, Center of Molecular Immunology, 216 St and 15th Ave., Atabey, Playa, P.O. Box 16040, Havana 11600, Cuba
| | - Liliana Oliver
- Immunobiology Division, Center of Molecular Immunology, 216 St and 15th Ave., Atabey, Playa, P.O. Box 16040, Havana 11600, Cuba
| | - Rydell Alvarez
- Immunobiology Division, Center of Molecular Immunology, 216 St and 15th Ave., Atabey, Playa, P.O. Box 16040, Havana 11600, Cuba
| | - Arletty Hernández
- Immunobiology Division, Center of Molecular Immunology, 216 St and 15th Ave., Atabey, Playa, P.O. Box 16040, Havana 11600, Cuba
| | - Judith Raymond
- Systems Biology Division, Center of Molecular Immunology, 216 St and 15th Ave., Atabey, Playa, P.O. Box 16040, Havana 11600, Cuba
| | - Luis E Fernández
- Innovation Division, Center of Molecular Immunology, 216 St and 15th Ave., Atabey, Playa, P.O. Box 16040, Havana 11600, Cuba
| | - Circe Mesa
- Immunobiology Division, Center of Molecular Immunology, 216 St and 15th Ave., Atabey, Playa, P.O. Box 16040, Havana 11600, Cuba
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Non-clinical immuno-toxicological evaluation of HER1 cancer vaccine in non-human primates: a 12-month study. Vaccine 2012; 31:89-95. [DOI: 10.1016/j.vaccine.2012.10.098] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2012] [Revised: 10/25/2012] [Accepted: 10/28/2012] [Indexed: 11/22/2022]
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23
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Mancebo A, Casacó A, Sánchez B, González B, Gómez D, León A, Bada A, Arteaga M, González Y, González C, Pupo M, Fuentes D. Repeated dose (14days) rat intramuscular toxicology study of Her1 vaccine. Regul Toxicol Pharmacol 2012; 64:425-34. [DOI: 10.1016/j.yrtph.2012.10.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2012] [Revised: 10/01/2012] [Accepted: 10/04/2012] [Indexed: 01/27/2023]
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24
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25
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Oliver L, Fernández A, Raymond J, López-Requena A, Fernández LE, Mesa C. Very small size proteoliposomes derived from Neisseria meningitidis: an effective adjuvant for antigen-specific cytotoxic T lymphocyte response stimulation under leukopenic conditions. Vaccine 2012; 30:2963-72. [PMID: 22391399 DOI: 10.1016/j.vaccine.2012.02.054] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2011] [Revised: 02/16/2012] [Accepted: 02/19/2012] [Indexed: 10/28/2022]
Abstract
Leukopenia is a severe condition resulting from both pathological processes and some treatments, like chemotherapy in cancer patients. However, the activation of the patient immune system is required for the success of immunotherapeutic strategies, as cancer vaccines. In this regard, leukopenia constitutes a major hurdle to overcome, mainly due to the impairment of cytotoxic T lymphocyte (CTL) responses. Adjuvants are basic components of vaccine formulations, which might be useful to stimulate immunity under this immunosuppressed condition. To this aim, we tested the capacity of a novel nanoparticulated complex, very small size proteoliposomes (VSSP), to promote CTL even in a leukopenic scenario. Noteworthy, we observed that a VSSP-based OVA vaccine induced a normal antigen-specific CTL response in mice rendered leukopenia by the administration of high doses of the chemotherapeutic agent cyclophosphamide (CY), while under the same conditions the OVA antigen formulated in the TLR-3 agonist polyinosinic-polycytidylic acid (P(I:C)) was ineffective. Moreover, an appropriate combination of VSSP with the P(I:C) vaccine was able to restore the CD8(+) T cell effector function in leukopenic mice. VSSP induced not only a faster repopulation of immune cells in CY-receiving animals, but also enhanced the recovery of memory T lymphocytes and myeloid dendritic cells (DCs) while simultaneously abrogated the immunosuppressive capacity of myeloid-derived suppressor cells (MDSCs). Our results suggest that VSSP could be a particularly suitable immunomodulator to be used in CTL-promoting active immunotherapy strategies operating in severe immune compromised scenarios.
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Affiliation(s)
- Liliana Oliver
- Center of Molecular Immunology, Atabey, Playa, Havana 11600, Cuba
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26
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Antigen dose escalation study of a VEGF-based therapeutic cancer vaccine in non human primates. Vaccine 2011; 30:368-77. [PMID: 22075086 DOI: 10.1016/j.vaccine.2011.10.082] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2011] [Revised: 09/14/2011] [Accepted: 10/28/2011] [Indexed: 01/27/2023]
Abstract
CIGB-247 is a cancer therapeutic, based on recombinant modified human vascular endothelial growth factor (VEGF) as antigen, in combination with the oil free adjuvant VSSP (very small sized proteoliposomes of Neisseria meningitidis outer membrane). Our previous experimental studies in mice with CIGB-247 have shown that the vaccine has both anti-tumoral and anti-metastatic activity, and produces both antibodies that block VEGF-VEGF receptor interaction, and a specific T-cell cytotoxic response against tumor cells. CIGB-247, with an antigen dose of 100 μg, has been characterized by an excellent safety profile in mice, rats, rabbits, and non human primates. In this article we extend the immunogenicity and safety studies of CIGB-247 in non human primates, scaling the antigen dose from 100 μg to 200 and 400 μg/vaccination. Our results indicate that such dose escalation did not affect animal behavior, clinical status, and blood parameters and biochemistry. Also, vaccination did not interfere with skin deep skin wound healing. Anti-VEGF IgG antibodies and specific T-cell mediated responses were documented at all three studied doses. Antigen dose apparently did not determine differences in maximum antibody titer during the 8 weekly immunization induction phase, or the subsequent increase in antibodies seen for monthly boosters delivered afterwards. Higher antigen doses had a positive influence in antibody titer maintenance, after cessation of immunizations. Boosters were important to achieve maximum antibody VEGF blocking activity, and specific T-cell responses in all individuals. Purified IgG from CIGB-247 immunized monkey sera was able to impair proliferation and formation of capillary-like structures in Matrigel, for HMEC cells in culture. Altogether, these results support the further clinical development of the CIGB-247 therapeutic cancer vaccine, and inform on the potential mechanisms involved in its effect.
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27
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Fernández A, Mesa C, Marigo I, Dolcetti L, Clavell M, Oliver L, Fernández LE, Bronte V. Inhibition of tumor-induced myeloid-derived suppressor cell function by a nanoparticulated adjuvant. THE JOURNAL OF IMMUNOLOGY 2010; 186:264-74. [PMID: 21135171 DOI: 10.4049/jimmunol.1001465] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The interaction between cancer vaccine adjuvants and myeloid-derived suppressor cells (MDSCs) is currently poorly understood. Very small size proteoliposomes (VSSP) are a nanoparticulated adjuvant under investigation in clinical trials in patients with renal carcinoma, breast cancer, prostate cancer, and cervical intraepithelial neoplasia grade III. We found that VSSP adjuvant induced a significant splenomegaly due to accumulation of CD11b(+)Gr-1(+) cells. However, VSSP-derived MDSCs showed a reduced capacity to suppress both allogeneic and Ag-specific CTL response compared with that of tumor-induced MDSCs. Moreover, splenic MDSCs isolated from tumor-bearing mice treated with VSSP were phenotypically more similar to those isolated from VSSP-treated tumor-free mice and much less suppressive than tumor-induced MDSCs, both in vitro and in vivo. Furthermore, different from dendritic cell vaccination, inoculation of VSSP-based vaccine in EG.7-OVA tumor-bearing mice was sufficient to avoid tumor-induced tolerance and stimulate an immune response against OVA Ag, similar to that observed in tumor-free mice. This effect correlated with an accelerated differentiation of MDSCs into mature APCs that was promoted by VSSP. VSSP used as a cancer vaccine adjuvant might thus improve antitumor efficacy not only by stimulating a potent immune response against tumor Ags but also by reducing tumor-induced immunosuppression.
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28
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Han R, Zhu J, Yang X, Xu H. Surface modification of poly(D,L-lactic-co-glycolic acid) nanoparticles with protamine enhanced cross-presentation of encapsulated ovalbumin by bone marrow-derived dendritic cells. J Biomed Mater Res A 2010; 96:142-9. [PMID: 21105162 DOI: 10.1002/jbm.a.32860] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2010] [Accepted: 04/26/2010] [Indexed: 11/09/2022]
Abstract
Cross-presentation is the key process in stimulation of cytotoxic T lymphocyte (CTL) immune response in eliminating many infectious diseases and tumors. Previous studies have shown that surface modification of poly(D,L-lactic-co-glycolic acid) (PLGA) particles with polycations enhanced their adjuvant ability resulting in a strong antibody response to the encapsulated antigen. However, the in vitro cross-presentation by protamine-coated PLGA nanoparticles (NPs) has not been addressed yet. In this study, a model antigen ovalbumin (OVA) was encapsulated into PLGA nanoparticles, with (OVA-NPs/protamine) or without protamine coating (OVA-NPs). These nanoparticles were then used to stimulate murine bone marrow-derived dendritic cells (BMDCs). Flow cytometry analysis revealed an increase in endocytosis of protamine-coated PLGA nanoparticles by BMDCs at 37°C. Compared with OVA-NPs-treated BMDCs, stimulation with OVA-NPs/protamine led to significantly upregulation of CD80, CD86, and CD83, increased secretion of IL-12p70, and decreased production of IL-4 by BMDCs. Furthermore, OVA-NPs/protamine-treated BMDCs also showed an enhanced cross-presentation to B3Z T cell hybridoma in vitro. Transmission electron microscopy (TEM) study showed that protamine-coated PLGA nanoparticles escaped from lysosomes through the interaction with lysosomal membrane. These results demonstrated that protamine-coated PLGA nanoparticles could enhance the cross-presentation of encapsulated exogenous antigen by facilitating antigen uptake and lysosomal escape, suggesting the feasibility to be a potent adjuvant for cellular vaccines.
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Affiliation(s)
- Ruiling Han
- College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
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29
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Gupta SK, Smita S, Sarangi AN, Srivastava M, Akhoon BA, Rahman Q, Gupta SK. In silico CD4+ T-cell epitope prediction and HLA distribution analysis for the potential proteins of Neisseria meningitidis Serogroup B—A clue for vaccine development. Vaccine 2010; 28:7092-7. [DOI: 10.1016/j.vaccine.2010.08.005] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2010] [Revised: 07/22/2010] [Accepted: 08/02/2010] [Indexed: 01/11/2023]
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30
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Morera Y, Bequet-Romero M, Ayala M, Velazco JC, Pérez PP, Alba JS, Ancizar J, Rodríguez M, Cosme K, Gavilondo JV. Immunogenicity and some safety features of a VEGF-based cancer therapeutic vaccine in rats, rabbits and non-human primates. Vaccine 2010; 28:3453-61. [PMID: 20197134 DOI: 10.1016/j.vaccine.2010.02.069] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2009] [Revised: 02/12/2010] [Accepted: 02/15/2010] [Indexed: 11/16/2022]
Abstract
We have developed a cancer vaccine candidate (hereafter denominated CIGB-247), based on recombinant modified human vascular endothelial growth factor (VEGF) as antigen, and the adjuvant VSSP (very small sized proteoliposomes of Neisseria meningitidis outer membrane). In mice, previous work of our group had shown that vaccination with CIGB-247 extended tumor-take time, slowed tumor growth, and increased animal survival. Immunization elicited anti-human and murine VEGF-neutralizing antibodies, and spleen cells of vaccinated mice are cytotoxic in vitro to tumor cells that produce VEGF. We have now tested the immunogenicity of CIGB-247 in Wistar rats, New Zealand White rabbits and the non-human primate Chlorocebus aethiops sabaeus. Using weekly, biweekly and biweekly plus montanide immunization schemes, all three species develop antigen-specific IgG antibodies that can block the interaction of VEGF and VEGF receptor 2 in an ELISA assay. Antibody titers decline after vaccination stops, but can be boosted with new immunizations. In monkeys, DTH and direct cell cytotoxicity experiments suggest that specific T-cell responses are elicited by vaccination. Immunization with CIGB-247 had no effect on normal behavior, hematology, blood biochemistry and histology of critical organs, in the tested animals. Skin deep wound healing was not affected in vaccinated rats and monkeys.
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Affiliation(s)
- Yanelys Morera
- Recombinant Antibodies Laboratory, Dept. of Pharmaceuticals, Center for Genetic Engineering and Biotechnology, P.O. Box 6162, Cubanacán, Playa Havana 10600, Cuba.
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31
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Bhagawati-Prasad VN, De Leenheer E, Keefe NP, Ryan LA, Carlring J, Heath AW. CD40mAb adjuvant induces a rapid antibody response that may be beneficial in post-exposure prophylaxis. JOURNAL OF IMMUNE BASED THERAPIES AND VACCINES 2010; 8:1. [PMID: 20205811 PMCID: PMC2824643 DOI: 10.1186/1476-8518-8-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/21/2009] [Accepted: 02/04/2010] [Indexed: 11/10/2022]
Abstract
Active vaccination can be effective as a post-exposure prophylaxis, but the rapidity of the immune response induced, relative to the incubation time of the pathogen, is critical. We show here that CD40mAb conjugated to antigen induces a more rapid specific antibody response than currently used immunological adjuvants, alum and monophosphoryl lipid A.
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Affiliation(s)
- Vijay Ns Bhagawati-Prasad
- Department of Infection and Immunity, University of Sheffield Medical School, Beech Hill Rd, Sheffield S10 2RX, UK
| | - Evy De Leenheer
- Department of Infection and Immunity, University of Sheffield Medical School, Beech Hill Rd, Sheffield S10 2RX, UK
| | - Nadine P Keefe
- Department of Infection and Immunity, University of Sheffield Medical School, Beech Hill Rd, Sheffield S10 2RX, UK
| | - Lorna A Ryan
- Department of Infection and Immunity, University of Sheffield Medical School, Beech Hill Rd, Sheffield S10 2RX, UK
| | - Jennifer Carlring
- Department of Infection and Immunity, University of Sheffield Medical School, Beech Hill Rd, Sheffield S10 2RX, UK
| | - Andrew W Heath
- Department of Infection and Immunity, University of Sheffield Medical School, Beech Hill Rd, Sheffield S10 2RX, UK.,Adjuvantix Ltd, c/o Fusion plc, Sheffield Bioincubator, Leavygreave Rd, Sheffield, UK
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32
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Virus-Like Particles as vaccine antigens and adjuvants: application to chronic disease, cancer immunotherapy and infectious disease preventive strategies. ACTA ACUST UNITED AC 2010. [DOI: 10.1016/j.provac.2010.07.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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33
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Durand V, MacKenzie J, de Leon J, Mesa C, Quesniaux V, Montoya M, Le Bon A, Wong SY. Role of lipopolysaccharide in the induction of type I interferon-dependent cross-priming and IL-10 production in mice by meningococcal outer membrane vesicles. Vaccine 2009; 27:1912-22. [DOI: 10.1016/j.vaccine.2009.01.109] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2008] [Revised: 01/17/2009] [Accepted: 01/22/2009] [Indexed: 02/06/2023]
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34
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Morera Y, Bequet-Romero M, Ayala M, Lamdán H, Agger EM, Andersen P, Gavilondo JV. Anti-tumoral effect of active immunotherapy in C57BL/6 mice using a recombinant human VEGF protein as antigen and three chemically unrelated adjuvants. Angiogenesis 2008; 11:381-93. [PMID: 19034678 DOI: 10.1007/s10456-008-9121-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2008] [Accepted: 10/01/2008] [Indexed: 11/30/2022]
Abstract
Following the clinical success of Bevacizumab, a humanized monoclonal antibody that affects the interaction between vascular endothelial growth factor (VEGF) and its receptors, blocking tumor-induced angiogenesis has become one of the most important targets for the development of new cancer therapeutic drugs and procedures. Among the latter, therapeutic vaccination using VEGF as antigen presents itself as very attractive, with the potential of generating not only a growth factor blocking antibody response but also a cellular response against tumor cells and stromal elements, which appear to be a major source of tumor VEGF. In this paper, we report the development of a protein vaccine candidate, based on a human modified VEGF antigen that is expressed at high levels in E. coli. With respect to controls, immunization experiments in C57BL/6 mice using weekly doses of this antigen and three adjuvants of different chemical natures show that time for tumor development after subcutaneous injection of Melanoma B16-F10 cells increases, tumors that develop grow slower, and overall animal survival is higher. Immunization also prevents tumor development in some mice, making them resistant to second tumor challenges. Vaccination of mice with the human modified VEGF recombinant antigen produces antibodies against the human antigen and the homologous mouse VEGF molecule. We also show that sera from immunized mice block human VEGF-induced HUVEC proliferation. Finally, a possible contribution of T cell cytotoxicity to the overall anti-tumor effect is suggested from the results of vaccination experiments where CD8+ lymphocytes were impaired using neutralizing rat antibodies.
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Affiliation(s)
- Yanelys Morera
- Recombinant Antibody Group, Cancer Research Department, Center for Genetic Engineering and Biotechnology, P.O. Box 6162, Ave 31 and 190 Cubanacán, 10600, Playa, Havana, Cuba
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35
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Ramírez BS, Alpízar YA, Fernández DRH, Hidalgo GG, Capote AR, Rodríguez RP, Fernández LE. Anti-EGFR activation, anti-proliferative and pro-apoptotic effects of polyclonal antibodies induced by EGFR-based cancer vaccine. Vaccine 2008; 26:4918-26. [DOI: 10.1016/j.vaccine.2008.07.018] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2008] [Revised: 07/03/2008] [Accepted: 07/10/2008] [Indexed: 11/30/2022]
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36
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Baz A, Buttigieg K, Zeng W, Rizkalla M, Jackson DC, Groves P, Kelso A. Branched and linear lipopeptide vaccines have different effects on primary CD4+ and CD8+ T-cell activation but induce similar tumor-protective memory CD8+ T-cell responses. Vaccine 2008; 26:2570-9. [PMID: 18420312 DOI: 10.1016/j.vaccine.2008.03.022] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2007] [Revised: 03/11/2008] [Accepted: 03/12/2008] [Indexed: 11/18/2022]
Abstract
We compared murine T-cell responses to synthetic lipopeptide vaccines in which the TLR2 ligand Pam(2)Cys was attached to co-linear CD4+ and CD8+ T-cell epitopes of ovalbumin (OVA) in a linear or branched configuration. Mice received OVA-specific transgenic CD8+ and CD4+ T-cells followed by one injection of vaccine. Although the branched lipopeptide was more potent in activating OVA-specific CD4+ and CD8+ T-cells in the primary response, both vaccines induced cytolytic T lymphocytes (CTL) that expressed perforin, granzyme A-C, and IFN-gamma mRNAs and conferred long-term protection of most mice against challenge with OVA-expressing tumor cells. OVA epitope display was reduced in tumors that developed in some mice, suggesting CD8+ T-cell dependent selection.
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Affiliation(s)
- Adriana Baz
- Cooperative Research Centre for Vaccine Technology, Queensland Institute of Medical Research, Queensland 4029, Australia
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37
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Venier C, Guthmann MD, Fernández LE, Fainboim L. Innate-immunity cytokines induced by very small size proteoliposomes, a Neisseria-derived immunological adjuvant. Clin Exp Immunol 2007; 147:379-88. [PMID: 17223981 PMCID: PMC1810462 DOI: 10.1111/j.1365-2249.2006.03297.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Neisserial outer membrane proteins have been combined with monosialoganglioside GM3 to form very small size proteoliposomes (VSSP), a nanoparticulated formulation used as a cancer vaccine for the treatment of cancer patients with GM3-positive tumours. VSSP were shown to elicit anti-GM3 and anti-tumour immune responses. VSSP have also been shown to be an efficient adjuvant for tumour-cell and peptide-antigen vaccines in mice. In vitro studies showed that VSSP promote maturation of both murine and human dendritic cells, suggesting that VSSP could be used as efficient adjuvants. In order to study further the capacity of VSSP to elicit innate immune responses, human peripheral blood mononuclear cells and monocytes derived thereof were assessed for in vitro secretion of interleukin (IL)-10, IL-6, IL-12 and interferon (IFN)-gamma. VSSP most prominently induced the secretion of IL-6. IL-10 was secreted at a lower level. IL-12 p40 (but no p70) was also detected. IFN-gamma response was observed in 56% of the tested samples. Cytokine secretion was not related to lipopolysaccharide (LPS) content and involved Toll-like receptor 2 (TLR2)-mediated signal transduction. VSSP also induced DC maturation and a cytokine secretion pattern (high IL-6/low IL-10) which differs from that induced by LPS. The observed proinflammatory cytokine secretion pattern and the capacity of VSSP to drive DC maturation are examined in the light of the properties of other bacterial derivatives currently being user for immunotherapy purposes. Our results suggest that VSSP could be tested in clinical settings where T helper 1-type immune responses would be beneficial.
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Affiliation(s)
- C Venier
- Hospital de Clínicas José de San Martín, University of Buenos Aires, Buenos Aires, Argentina
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