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Bhagat A, Lyerly HK, Morse MA, Hartman ZC. CEA vaccines. Hum Vaccin Immunother 2023; 19:2291857. [PMID: 38087989 PMCID: PMC10732609 DOI: 10.1080/21645515.2023.2291857] [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] [Received: 09/13/2023] [Accepted: 12/02/2023] [Indexed: 12/18/2023] Open
Abstract
Carcinoembryonic antigen (CEA) is a glycosylated cell surface oncofetal protein involved in adhesion, proliferation, and migration that is highly upregulated in multiple carcinomas and has long been a promising target for cancer vaccination. This review summarizes the progress to date in the development of CEA vaccines, examining both pre-clinical and clinical studies across a variety of vaccine platforms that in aggregate, begin to reveal some critical insights. These studies demonstrate the ability of CEA vaccines to break immunologic tolerance and elicit CEA-specific immunity, which associates with improved clinical outcomes in select individuals. Approaches that have combined replicating viral vectors, with heterologous boosting and different adjuvant strategies have been particularly promising but, these early clinical trial results will require confirmatory studies. Collectively, these studies suggest that clinical efficacy likely depends upon harnessing a potent vaccine combination in an appropriate clinical setting to fully realize the potential of CEA vaccination.
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Affiliation(s)
- Anchit Bhagat
- Department of Surgery, Division of Surgical Sciences, Duke University, Durham, NC, USA
| | - Herbert K. Lyerly
- Department of Surgery, Division of Surgical Sciences, Duke University, Durham, NC, USA
- Department of Pathology, Duke University, Durham, NC, USA
- Department of Integrative Immunobiology, Duke University, Durham, NC, USA
| | - Michael A. Morse
- Department of Surgery, Division of Surgical Sciences, Duke University, Durham, NC, USA
- Department of Medicine, Duke University, Durham, NC, USA
| | - Zachary C. Hartman
- Department of Surgery, Division of Surgical Sciences, Duke University, Durham, NC, USA
- Department of Pathology, Duke University, Durham, NC, USA
- Department of Integrative Immunobiology, Duke University, Durham, NC, USA
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朱 晓, 孔 桂, 万 丹, 孙 国, 焦 红, 阴 银, 李 国. 减毒沙门氏菌在消化系肿瘤中的研究进展. Shijie Huaren Xiaohua Zazhi 2017; 25:1480-1485. [DOI: 10.11569/wcjd.v25.i16.1480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
消化系肿瘤在我国是最常见的恶性肿瘤, 随着现代生活节奏的加快, 消化系肿瘤的发病率有增高趋势, 年轻化的趋势也愈加明显. 减毒沙门氏菌作为一个胞内寄生菌, 本省具有抗肿瘤特性, 同时可以作为肿瘤基因治疗的载体进行抗肿瘤治疗. 本文就减毒沙门氏菌及作为治疗载体在肝癌、胃癌、大肠癌的体内外应用进展进行综述.
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Toussaint B, Chauchet X, Wang Y, Polack B, Le Gouëllec A. Live-attenuated bacteria as a cancer vaccine vector. Expert Rev Vaccines 2014; 12:1139-54. [PMID: 24124876 DOI: 10.1586/14760584.2013.836914] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
In the emerging field of active and specific cancer immunotherapy, strategies using live-attenuated bacterial vectors have matured in terms of academic and industrial development. Different bacterial species can be genetically engineered to deliver antigen to APCs with strong adjuvant effects due to their microbial origin. Proteic or DNA-encoding antigen delivery routes and natural bacterial tropisms might differ among species, permitting different applications. After many academic efforts to resolve safety and efficacy issues, some firms have recently engaged clinical trials with live Listeria or Salmonella spp. We describe here the main technological advances that allowed bacteria to become one of the most promising vectors in cancer immunotherapy.
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Affiliation(s)
- Bertrand Toussaint
- Laboratoire TIMC-IMAG/TheREx (UMR 5525 CNRS-UJF), UFR de médecine, Université Joseph Fourier Grenoble I, 38700 La Tronche Cedex, France
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Daudel D, Weidinger G, Spreng S. Use of attenuated bacteria as delivery vectors for DNA vaccines. Expert Rev Vaccines 2014; 6:97-110. [PMID: 17280482 DOI: 10.1586/14760584.6.1.97] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Live, attenuated bacterial vaccines (LBV) are promising candidates for the induction of a broad-based immune response directed at recombinant heterologous antigens and the corresponding pathogen. LBVs allow vaccination through the mucosal surfaces and specific targeting of professional antigen-presenting cells located at the inductive sites of the immune system. A novel approach exploits attenuated intracellular bacteria as delivery vectors for eukaryotic antigen-expression plasmids (so-called DNA vaccines). Candidate carrier bacteria include attenuated strains of Gram-positive and Gram-negative bacteria. These bacteria have been shown to deliver DNA vaccines to human cells in vitro and have also proven their in vivo efficacy in several experimental animal models of infectious diseases and different cancers. The clinical assessment of the safety, immunogenicity and efficacy of these candidate strains will be the next challenging step towards live bacterial DNA vaccines.
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Affiliation(s)
- Damini Daudel
- Berna Biotech AG, Rehhagstrasse 79, CH-3018 Berne, Switzerland.
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Chin'ombe N, Ruhanya V. Recombinant Salmonella Bacteria Vectoring HIV/AIDS Vaccines. Open Virol J 2013; 7:121-6. [PMID: 24478808 PMCID: PMC3905348 DOI: 10.2174/1874357901307010121] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2013] [Revised: 11/13/2013] [Accepted: 11/18/2013] [Indexed: 11/29/2022] Open
Abstract
HIV/AIDS is an important public health problem globally. An affordable, easy-to-deliver and protective HIV
vaccine is therefore required to curb the pandemic from spreading further. Recombinant Salmonella bacteria can be
harnessed to vector HIV antigens or DNA vaccines to the immune system for induction of specific protective immunity.
These are capable of activating the innate, humoral and cellular immune responses at both mucosal and systemic
compartments. Several studies have already demonstrated the utility of live recombinant Salmonella in delivering
expressed foreign antigens as well as DNA vaccines to the host immune system. This review gives an overview of the
studies in which recombinant Salmonella bacteria were used to vector HIV/AIDS antigens and DNA vaccines. Most of
the recombinant Salmonella-based HIV/AIDS vaccines developed so far have only been tested in animals (mainly mice)
and are yet to reach human trials.
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Affiliation(s)
- Nyasha Chin'ombe
- Department of Medical Microbiology, University of Zimbabwe, Harare, Zimbabwe ; Division of Medical Virology, University of Cape Town, Cape Town, South Africa
| | - Vurayai Ruhanya
- Department of Medical Microbiology, University of Zimbabwe, Harare, Zimbabwe
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Rao US, Hoerster NS, Thirumala S, Rao PS. The influence of metastatic site on the expression of CEA and cellular localization of β-catenin in colorectal cancer. J Gastroenterol Hepatol 2013; 28:505-12. [PMID: 23216017 DOI: 10.1111/jgh.12083] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/21/2012] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND AIM The usefulness of carcinoembryonic antigen (CEA) in the diagnosis and prognosis of colorectal cancer (CRC) is unclear. The aim was to analyze changes in the expression of CEA during CRC progression and metastasis, so as to determine the influence of tumor metastatic organ on the CEA expression by CRC cells. METHODS The human biopsies of adenocarcinomas in colon and CRC liver and lung metastases were analyzed by immunohistochemistry for the expression of CEA. Expression of E-cadherin and β-catenin was also analyzed to localize the CRC neoplastic glands in metastatic tissues. RESULTS The CRC neoplastic glands in colon and liver expressed significantly higher amount of CEA compared with crypts in normal colon. In contrast, CRC neoplastic glands formed in lung expressed low CEA level. However, CEA expression was high in areas of tumor necrosis in lung. E-cadherin and β-catenin were cell membrane-bound in normal crypts and CRC neoplastic glands in colon and liver. Although these two proteins were also cell membrane-bound in a majority of CRC neoplastic glands in lungs, a significant proportion of these expressed β-catenin in the nucleus, which lacked either E-cadherin or β-catenin at the cell membrane. CONCLUSION Our findings indicate that lung microenvironment is unique in that it suppresses the expression of CEA by CRC cells forming neoplastic glands. In addition, lung microenvironment promotes nuclear localization of β-catenin, suggesting that the Wnt signaling pathway is relatively active highly in CRC metastasized to lung, when compared with liver or colon.
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Affiliation(s)
- U Subrahmanyeswara Rao
- Department of Biomedical Sciences, Texas Tech University Health Sciences Center, Amarillo, USA
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Lee YJ, Han SR, Kim NY, Lee SH, Jeong JS, Lee SW. An RNA aptamer that binds carcinoembryonic antigen inhibits hepatic metastasis of colon cancer cells in mice. Gastroenterology 2012; 143:155-65.e8. [PMID: 22465431 DOI: 10.1053/j.gastro.2012.03.039] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2011] [Revised: 02/29/2012] [Accepted: 03/21/2012] [Indexed: 12/29/2022]
Abstract
BACKGROUND & AIMS Carcinoembryonic antigen (CEA) is expressed by many types of cancer cells; its overexpression induces cell adhesion, increases resistance to anoikis, and promotes hepatic metastasis of colon cancer cells. The amino acid sequence PELPK in its hinge region, between the N and A1 domains, is required for migration of cancer cells to the liver. We sought to identify ligands of this domain for use in diagnosis and therapy. METHODS We screened for RNA aptamers against the domain of CEA required for metastasis using systematic evolution of ligands by exponential enrichment. The specificity and affinity of the aptamer for CEA protein were characterized by mobility shift, uptake, and surface plasmon resonance assays. We analyzed the effects of the aptamer on metastatic properties of cells, as well as metastasis of colon cancer cells in mice. RESULTS Using systematic evolution of ligands by exponential enrichment, we identified an RNA aptamer that bound to the PELPK sequence in CEA with high affinity and specificity. The isolated aptamer bound specifically to CEA-positive cells and inhibited interactions between CEA and heterogeneous nuclear ribonucleoprotein M4. The aptamer inhibited homotypic aggregation, migration, and invasion by CEA-positive cancer cells, but did not affect adhesion of endothelial cells. The aptamer induced colon cancer cell anoikis by interrupting the interaction between death receptor 5 and CEA. The aptamer prevented metastasis of human colon cancer cells to the livers of mice. CONCLUSIONS An RNA aptamer that binds to the PELPK sequence in CEA inhibits its interactions with heterogeneous nuclear ribonucleoprotein M4 and death receptor 5, migration and invasion by colon cancer cells, and hepatic metastasis of colon cancer cells in mice. It promoted cancer cell anoikis and might be used to identify CEA-positive tumors in patients or be developed as an anti-cancer reagent.
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Affiliation(s)
- Young Ju Lee
- Department of Molecular Biology, Institute of Nanosensor and Biotechnology, Dankook University, Yongin, Republic of Korea
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8
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Dodson LF, Hawkins WG, Goedegebuure P. Potential targets for pancreatic cancer immunotherapeutics. Immunotherapy 2011; 3:517-37. [PMID: 21463193 DOI: 10.2217/imt.11.10] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Pancreatic adenocarcinoma is the fourth leading cause of cancer death with an overall 5-year survival of less than 5%. As there is ample evidence that pancreatic adenocarcinomas elicit antitumor immune responses, identification of pancreatic cancer-associated antigens has spurred the development of vaccination-based strategies for treatment. While promising results have been observed in animal tumor models, most clinical studies have found only limited success. As most trials were performed in patients with advanced pancreatic cancer, the contribution of immune suppressor mechanisms should be taken into account. In this article, we detail recent work in tumor antigen vaccination and the recently identified mechanisms of immune suppression in pancreatic cancer. We offer our perspective on how to increase the clinical efficacy of vaccines for pancreatic cancer.
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Affiliation(s)
- Lindzy F Dodson
- Washington University School of Medicine, Department of Surgery, Saint Louis, MO 63110, USA.
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Immunotherapy of Angiogenesis with DNA Vaccines. Angiogenesis 2008. [DOI: 10.1007/978-0-387-71518-6_39] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Abstract
Mesothelin has been implicated as a potential ideal target antigen for the development of antigen-specific cancer immunotherapy for the control of mesothelin-expressing cancers such as ovarian cancer, mesothelioma and pancreatic adenocarcinoma. In the current study, we utilized a DNA vaccine encoding human mesothelin (pcDNA3-Hmeso) to treat C57BL/6 mice challenged with luciferase-expressing, Hmeso-expressing ovarian cancer cell line, Defb29 Vegf-luc/Hmeso. The therapeutic effect of the tumor-challenged mice was followed by noninvasive bioluminescence imaging systems. The mechanism of the antitumor effect was characterized by depletion of subsets of lymphocytes as well as adopted transfer of serum from pcDNA3-Hmeso-vaccinated mice. We found that vaccination with pcDNA3-Hmeso DNA vaccine generates a significant antitumor effect and promotes survival in mice challenged with Defb29 Vegf-luc/Hmeso. Furthermore, we found CD4+ and CD8+ T-cell immune responses as well as the humoral immune responses are important for the observed antitumor effects in vaccinated mice. Our data indicated that vaccination with DNA vaccine targeting Hmeso could generate potent antitumor effects against mesothelin-expressing tumors through both T cell-mediated immunity as well as antibody-mediated immunity.
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Affiliation(s)
- C-L Chang
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA
- Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan
| | - T-C Wu
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA
- Department of Obstetrics and Gynecology, Johns Hopkins Medical Institutions, Baltimore, MD, USA
- Department of Molecular Microbiology and Immunology, Johns Hopkins Medical Institutions, Baltimore, MD, USA
- Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - C-F Hung
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA
- Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, USA
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Lee SH, Mizutani N, Mizutani M, Luo Y, Zhou H, Kaplan C, Kim SW, Xiang R, Reisfeld RA. Endoglin (CD105) is a target for an oral DNA vaccine against breast cancer. Cancer Immunol Immunother 2006; 55:1565-74. [PMID: 16565828 PMCID: PMC11030801 DOI: 10.1007/s00262-006-0155-5] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2005] [Accepted: 03/06/2006] [Indexed: 10/24/2022]
Abstract
Endoglin (CD105), a co-receptor in the TGF-beta receptor complex, is over-expressed on proliferating endothelial cells in the breast tumor neovasculature and thus offers an attractive target for anti-angiogenic therapy. Here we report the anti-angiogenic/anti-tumor effects achieved in a prophylactic setting with an oral DNA vaccine encoding murine endoglin, carried by double attenuated Salmonella typhimurium (dam-, AroA-) to a secondary lymphoid organ, i.e., Peyer's patches . We demonstrate that an endoglin vaccine elicited activation of antigen-presenting dendritic cells, coupled with immune responses mediated by CD8+ T cells against endoglin-positive target cells. Moreover, we observed suppression of angiogenesis only in mice administered with the endoglin vaccine as compared to controls. These data suggest that a CD8+ T cell-mediated immune response induced by this vaccine effectively suppressed dissemination of pulmonary metastases of D2F2 breast carcinoma cells presumably by eliminating proliferating endothelial cells in the tumor vasculature. It is anticipated that vaccine strategies such as this may contribute to future therapies for breast cancer.
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Affiliation(s)
- Sung-Hyung Lee
- Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 USA
| | - Noriko Mizutani
- Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 USA
| | - Masato Mizutani
- Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 USA
| | - Yunping Luo
- Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 USA
| | - He Zhou
- Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 USA
| | - Charles Kaplan
- Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 USA
| | - Sung-Woo Kim
- Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 USA
| | - Rong Xiang
- Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 USA
| | - Ralph A. Reisfeld
- Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 USA
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Abstract
Significant progress made in the field of tumor immunology by the characterization of a large number of tumor antigens, and the better understanding of the mechanisms preventing immune responses to malignancies has led to the extensive study of cancer immunization approaches such as DNA vaccines encoding tumor antigens. This article reviews major aspects of DNA immunization in cancer. It gives a brief history and then discusses the proposed mechanism of action, preclinical and clinical studies, and methods of enhancing the immune responses induced by DNA vaccines.
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Affiliation(s)
- Rodica Stan
- Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
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Kim B, Suvas S, Sarangi PP, Lee S, Reisfeld RA, Rouse BT. Vascular Endothelial Growth Factor Receptor 2-Based DNA Immunization Delays Development of Herpetic Stromal Keratitis by Antiangiogenic Effects. THE JOURNAL OF IMMUNOLOGY 2006; 177:4122-31. [PMID: 16951377 DOI: 10.4049/jimmunol.177.6.4122] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Stromal keratitis (SK) is an immunoinflammatory eye lesion caused by HSV-1 infection. One essential step in the pathogenesis is neovascularization of the normally avascular cornea, a process that involves the vascular endothelial growth factor (VEGF) family of proteins. In this report, we targeted the proliferating vascular endothelial cells expressing VEGFR-2 in the SK cornea by immunization with recombinant Salmonella typhimurium containing a plasmid encoding murine VEGFR-2. This form of DNA immunization resulted in diminished angiogenesis and delayed development of SK caused by HSV-1 infection and also reduced angiogenesis resulting from corneal implantation with rVEGF. CTL responses against endothelial cells expressing VEGFR-2 were evident in the VEGFR-2-immunized group and in vivo CD8+ T cell depletion resulted in the marked reduction of the antiangiogenic immune response. These results indicate a role for CD8+ T cells in the antiangiogenic effects. Our results may also imply that the anti-VEGFR-2 vaccination approach might prove useful to control pathological ocular angiogenesis and its consequences.
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MESH Headings
- Angiogenesis Inhibitors/administration & dosage
- Angiogenesis Inhibitors/genetics
- Angiogenesis Inhibitors/immunology
- Animals
- Cells, Cultured
- Cornea/blood supply
- Cornea/pathology
- Cornea/virology
- Female
- Genetic Vectors
- Herpesvirus 1, Human/immunology
- Keratitis, Herpetic/immunology
- Keratitis, Herpetic/prevention & control
- Keratitis, Herpetic/virology
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Neovascularization, Pathologic/immunology
- Neovascularization, Pathologic/prevention & control
- Neovascularization, Pathologic/virology
- Salmonella typhimurium/genetics
- Salmonella typhimurium/immunology
- Stromal Cells/immunology
- Stromal Cells/pathology
- Stromal Cells/virology
- Vaccines, DNA/administration & dosage
- Vaccines, DNA/genetics
- Vaccines, DNA/immunology
- Vaccines, Synthetic/administration & dosage
- Vaccines, Synthetic/immunology
- Vascular Endothelial Growth Factor Receptor-2/administration & dosage
- Vascular Endothelial Growth Factor Receptor-2/biosynthesis
- Vascular Endothelial Growth Factor Receptor-2/genetics
- Vascular Endothelial Growth Factor Receptor-2/immunology
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Affiliation(s)
- Bumseok Kim
- Department of Microbiology and Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA
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Saha A, Baral RN, Chatterjee SK, Mohanty K, Pal S, Foon KA, Primus FJ, Krieg AM, Weiner GJ, Bhattacharya-Chatterjee M. CpG oligonucleotides enhance the tumor antigen-specific immune response of an anti-idiotype antibody-based vaccine strategy in CEA transgenic mice. Cancer Immunol Immunother 2006; 55:515-27. [PMID: 16044253 PMCID: PMC11030093 DOI: 10.1007/s00262-005-0009-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2005] [Accepted: 04/01/2005] [Indexed: 11/28/2022]
Abstract
A murine monoclonal anti-idiotype (Id) antibody, 3H1 has been developed and characterized previously. Anti-Id 3H1 mimics a specific epitope of carcinoembryonic antigen (CEA) and can be used as a surrogate antigen for CEA. 3H1 induced anti-CEA immunity in different species of animals as well as humans and showed promise as a potential vaccine candidate in phase I/II clinical trials for colon cancer patients. One area of interest to us has been the development of new immune adjuvants that may augment the potency of 3H1 as a tumor vaccine. Oligodeoxynucleotides containing unmethylated CpG motifs (CpG ODN) are potent immunostimulatory agents capable of enhancing the Ag-specific Th1 response when used as immune adjuvants. In this study, we have evaluated the efficacy of 3H1 as a tumor vaccine when admixed with a select CpG ODN 1826 in transgenic mice that express human CEA. The vaccine potential of 3H1 was also assessed in the presence of another widely used adjuvant, QS-21. 3H1 coupled to keyhole limpet hemocyanin (KLH) and mixed with Freund's adjuvant (FA) was used as a gold standard in this system. 3H1 vaccination with different adjuvants induced both humoral and cellular anti-3H1, as well as anti-CEA immunity in CEA transgenic mice. The immune sera could lyse CEA-transfected murine colon carcinoma cells, C15 effectively in an antibody-dependent cellular cytotoxicity assay. The anti-CEA antibody responses were somewhat comparable in each adjuvant-treated group of mice, whereas cellular immune responses were significantly greater when CpG was used as an adjuvant. Splenocytes obtained from 3H1-CpG-immunized mice showed an increased proliferative CD4(+) Th1-type T-cell response when stimulated in vitro with 3H1 or CEA and secreted elevated levels of Th1 cytokines (IL-2, IFN-gamma). This vaccine also induced MHC class I antigen-restricted CD8(+) T-cell responses. In a solid tumor model, C15 tumor growth was significantly inhibited by 3H1 vaccinations. In 3H1-CpG-vaccinated mice, the duration of survival was, however, longer compared to the 3H1-QS21-vaccinated mice. These findings suggest that 3H1-CpG vaccinations can break peripheral tolerance to CEA and induce protective antitumor immunity in this murine model transgenic for human CEA.
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Affiliation(s)
- Asim Saha
- Department of Internal Medicine and the Barrett Cancer Center, University of Cincinnati, Cincinnati, OH USA
| | - Rathindra Nath Baral
- Department of Internal Medicine and the Barrett Cancer Center, University of Cincinnati, Cincinnati, OH USA
| | - Sunil K. Chatterjee
- Department of Internal Medicine and the Barrett Cancer Center, University of Cincinnati, Cincinnati, OH USA
| | - Kartik Mohanty
- Department of Internal Medicine and the Barrett Cancer Center, University of Cincinnati, Cincinnati, OH USA
| | - Smarajit Pal
- Department of Internal Medicine and the Barrett Cancer Center, University of Cincinnati, Cincinnati, OH USA
| | | | - F. James Primus
- Department of Pathology, Vanderbilt University Medical Center, Nashville, TN USA
| | | | - George J. Weiner
- Department of Internal Medicine, University of Iowa, Iowa City, IA USA
| | - Malaya Bhattacharya-Chatterjee
- Department of Internal Medicine and the Barrett Cancer Center, University of Cincinnati, Cincinnati, OH USA
- The Vontz Center for Molecular Studies, University of Cincinnati, Room 1316, 3125 Eden Avenue, Cincinnati, OH 45267-0509 USA
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Critchley-Thorne RJ, Stagg AJ, Vassaux G. Recombinant Escherichia coli expressing invasin targets the Peyer's patches: the basis for a bacterial formulation for oral vaccination. Mol Ther 2006; 14:183-91. [PMID: 16581299 DOI: 10.1016/j.ymthe.2006.01.011] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2005] [Revised: 01/12/2006] [Accepted: 01/30/2006] [Indexed: 01/22/2023] Open
Abstract
We have investigated the tropism of nonpathogenic recombinant invasive Escherichia coli in the gastrointestinal tract and the efficacy of this invasive E. coli as an oral vaccine for cancer immunotherapy. E. coli expressing invasin from Yersinia pseudotuberculosis selectively invade nonphagocytic cells in which beta(1)-integrin is expressed and accessible. Following internalization the E. coli are degraded in the phagosome. Coexpression of listeriolysin O (LLO) mediates release of the content of the bacteria into the cytosol of the invaded cell. In vitro and in vivo experiments demonstrated that gut epithelial cells failed to be invaded by invasive E. coli, due to a basolateral localization of beta(1)-integrin. By contrast, selective uptake of invasive bacteria from the intestinal lumen into Peyer's patches was observed ex vivo. Once in this structure, invasive E. coli colocalized with dendritic cells and possibly B cells. Oral administration of invasive E. coli coexpressing the model antigen ovalbumin and LLO from Listeria monocytogenes was able to elicit systemic protection against a lethal challenge of B16 tumor cells expressing ovalbumin. These data demonstrate the selectivity of invasin-mediated invasion to the Peyer's patches and indicate the potential of nonpathogenic, invasive E. coli as an oral vaccine with applications in immunotherapy.
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Affiliation(s)
- Rebecca J Critchley-Thorne
- Centre for Molecular Oncology, Institute of Cancer and CR-UK Clinical Centre, Barts and The London, Queen Mary's School of Medicine and Dentistry, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
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Mager DL. Bacteria and cancer: cause, coincidence or cure? A review. J Transl Med 2006; 4:14. [PMID: 16566840 PMCID: PMC1479838 DOI: 10.1186/1479-5876-4-14] [Citation(s) in RCA: 176] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2006] [Accepted: 03/28/2006] [Indexed: 01/28/2023] Open
Abstract
Research has found that certain bacteria are associated with human cancers. Their role, however, is still unclear. Convincing evidence links some species to carcinogenesis while others appear promising in the diagnosis, prevention or treatment of cancers. The complex relationship between bacteria and humans is demonstrated by Helicobacter pylori and Salmonella typhi infections. Research has shown that H. pylori can cause gastric cancer or MALT lymphoma in some individuals. In contrast, exposure to H. pylori appears to reduce the risk of esophageal cancer in others. Salmonella typhi infection has been associated with the development of gallbladder cancer; however S. typhi is a promising carrier of therapeutic agents for melanoma, colon and bladder cancers. Thus bacterial species and their roles in particular cancers appear to differ among different individuals. Many species, however, share an important characteristic: highly site-specific colonization. This critical factor may lead to the development of non-invasive diagnostic tests, innovative treatments and cancer vaccines.
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Affiliation(s)
- D L Mager
- The Forsyth Institute, 140 The Fenway, Boston, MA, USA.
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18
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Salucci V, Mennuni C, Calvaruso F, Cerino R, Neuner P, Ciliberto G, La Monica N, Scarselli E. CD8+ T-cell tolerance can be broken by an adenoviral vaccine while CD4+ T-cell tolerance is broken by additional co-administration of a Toll-like receptor ligand. Scand J Immunol 2006; 63:35-41. [PMID: 16398699 DOI: 10.1111/j.1365-3083.2006.01706.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
T-cell tolerance to tumor antigens is a considerable challenge to cancer immunotherapy. The existence of a murine model transgenic for human carcinoembryonic antigen (CEA) allows CEA vaccination efficacy to be studied in a physiologically tolerant context. Immunization of CEA-transgenic mice with an adenoviral vector coding for CEA induced a significant CD8+ T-cell response specific to CEA but failed to induce CEA-specific CD4+ T cells and antibodies. To overcome CD4+ T-cell tolerance, we explored the effect of adjuvants inducing in vivo dendritic cell maturation. Two different Toll-like receptor ligands, monophosphoryl lipid A (MPL) and CpG motif-containing oligodeoxynucleotides (CpG-ODN), were tested. CD4+-mediated IFN-gamma production was induced in the CEA-transgenic mice only when the genetic immunization was performed in the presence of these adjuvants. Moreover, CpG-ODN had a greater effect than MPL in inducing CD4+ T-cell response and enabling anti-CEA antibody production.
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Affiliation(s)
- V Salucci
- Istituto di Ricerca di Biologia Molecolare, Pomezia, Italy
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19
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Thamm DH, Kurzman ID, King I, Li Z, Sznol M, Dubielzig RR, Vail DM, MacEwen EG. Systemic administration of an attenuated, tumor-targeting Salmonella typhimurium to dogs with spontaneous neoplasia: phase I evaluation. Clin Cancer Res 2005; 11:4827-34. [PMID: 16000580 DOI: 10.1158/1078-0432.ccr-04-2510] [Citation(s) in RCA: 130] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Genetically modified bacteria are a potentially powerful anticancer therapy due to their tumor targeting capacity, inherent antitumor activity, and ability to serve as efficient vectors for gene delivery. This study sought to characterize the acute and short-term toxicities and tumor colonization rates of a genetically modified Salmonella typhimurium (VNP20009) in dogs with spontaneous tumors, in the context of a phase I dose escalation trial. EXPERIMENTAL DESIGN Forty-one pet dogs with a variety of malignant tumors received weekly or biweekly i.v. infusions of VNP20009, at doses ranging from 1.5 x 10(5) to 1 x 10(8) cfu/kg. Vital signs and clinicopathologic variables were monitored regularly. Incisional biopsies were obtained before and 1 week following the first infusion for histopathology and bacterial culture. RESULTS The nominal maximum tolerated dose was 3 x 10(7) cfu/kg, with refractory fever and vomiting being the dose-limiting toxicities. One treatment-related acute death occurred. Bacteria were cultured from tumor tissue in 42% of cases. Thirty-five patients were evaluable for antitumor response. Major antitumor responses were seen in 15% (4 complete response and 2 partial response), and disease stabilization for at least 6 weeks in 10%. CONCLUSIONS Administration of VNP20009 at doses with acceptable toxicity results in detectable bacterial colonization of tumor tissue and significant antitumor activity in tumor-bearing dogs.
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Affiliation(s)
- Douglas H Thamm
- Department of Medical Sciences and Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, USA.
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20
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Huang Y, Fayad R, Smock A, Ullrich AM, Qiao L. Induction of mucosal and systemic immune responses against human carcinoembryonic antigen by an oral vaccine. Cancer Res 2005; 65:6990-9. [PMID: 16061685 DOI: 10.1158/0008-5472.can-04-3669] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Carcinoembryonic antigen (CEA) is a tumor-associated antigen targeted for the development of colorectal tumor vaccines. In this study, we developed papillomavirus pseudoviruses encoding the truncated CEA without NH2-terminal signal peptide (PV-CEA) as an oral vaccine to induce CEA-specific CTL responses. In CEA transgenic (CEA-Tg) mice orally immunized with PV-CEA, the immunologic tolerance to CEA as a "self-antigen" was overcome and both mucosal and systemic CEA-specific cytolytic activities were detected by in vitro 51Cr release assays. In a tumor prevention model, the growth rate of CEA+ tumors was significantly delayed in CEA-Tg mice orally immunized with PV-CEA when compared with the control vaccine. Further, the IFN-gamma enzyme-linked ImmunoSPOT and in vitro 51Cr release assay results showed that HLA-A2-restricted, CEA-specific CTL responses were induced in both mucosal and systemic lymphoid tissues in A2 transgenic mice after oral immunization with PV-CEA. Finally, we showed that coadministration of papillomavirus pseudoviruses encoding interleukin-2 with PV-CEA enhanced the generation of A2-restricted, CEA-specific CTLs in aged CEA/A2 double transgenic mice, which were more clinically relevant. Our data suggest that PV-CEA pseudovirus vaccine is a promising oral CEA vaccine for humans to induce CEA-specific CTLs at the site of colorectal tumors (i.e., intestinal mucosa), which might efficiently eliminate CEA+ colorectal tumor cells in the mucosa.
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Affiliation(s)
- Yujun Huang
- Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois 60153, USA
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21
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Salucci V, Lena AM, Ciliberto G, Scarselli E, La Monica N. Adenovirus Transduction and Culture Conditions Affect the Immunogenicity of Murine Dendritic Cells. Scand J Immunol 2005; 62:206-17. [PMID: 16179007 DOI: 10.1111/j.1365-3083.2005.01658.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Adenovirus vectors encoding carcinoembryonic antigen (Ad-CEA) or costimulatory molecules CD80, intercellular adhesion molecule-1 (ICAM-1) and leucocyte function-associated antigen-3 (LFA-3) (Ad-STIM) were used to transduce murine bone marrow-derived dendritic cells (BMDC). BMDC were characterized for expression of activation markers and for their ability to elicit protective immunity against MC38-CEA tumours in wildtype and CEA-transgenic (CEA-tg) mice. To determine optimal culture conditions, studies were conducted using BMDC cultured in heterologous bovine serum or autologous mouse serum. Transduction of cells grown in presence of heterologous serum increased the expression of costimulatory molecules, major histocompatibility complex class II, of IL-6 and IL-12. Upon vaccination, tumour protection was not specific and was observed also with untransduced cells. Transduced BMDC cultured in the presence of autologous serum showed low expression of the activation markers, did not express IL-6 and had reduced ability to stimulate T-cell proliferation. Nonetheless, CEA-specific CD8+ T-cell response was enhanced upon coinfection of Ad-STIM and Ad-CEA in both mouse strains, although this immune response was not sufficient to protect CEA-tg mice from tumour challenge. These studies support the use of BMDC transduced with Ad vectors encoding tumour antigens for cancer immunotherapy and demonstrate that culture conditions greatly affect the immunological properties of these cells.
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Affiliation(s)
- V Salucci
- Istituto di Ricerche di Biologia Molecolare (IRBM), Pomezia, Italy
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22
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Blumenthal RD, Osorio L, Hayes MK, Horak ID, Hansen HJ, Goldenberg DM. Carcinoembryonic antigen antibody inhibits lung metastasis and augments chemotherapy in a human colonic carcinoma xenograft. Cancer Immunol Immunother 2005; 54:315-27. [PMID: 15592930 PMCID: PMC11032782 DOI: 10.1007/s00262-004-0597-6] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2004] [Accepted: 07/13/2004] [Indexed: 11/28/2022]
Abstract
PURPOSE In addition to its use as a blood marker for many carcinomas, elevated expression of carcinoembryonic antigen (CEA, CD66e, CEACAM5) has been implicated in various biological aspects of neoplasia, especially tumor cell adhesion, metastasis, the blocking of cellular immune mechanisms, and having antiapoptosis functions. However, it is not known if treatment with anti-CEA antibodies can affect tumor metastasis or alter the effects of cytotoxic drugs. METHODS In vitro, human colon cancer cell lines were treated with anti-CEA MAb IgG1, hMN-14 (labetuzumab), to assess direct effects on proliferation, as well as antibody-dependent cellular cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). In vivo studies were undertaken in nude mice bearing s.c. (local growth) or i.v. (metastatic model) GW-39 and LS174T human colon cancer grafts, to evaluate the MAb alone and in combination with either CPT-11 or 5-fluorouracil (5FU). RESULTS In vitro, labetuzumab did not induce apoptosis, nor did it affect tumor cell proliferation directly or by CDC, but it did inhibit tumor cell proliferation by ADCC. In vivo, labetuzumab did not increase median survival in the GW-39 metastatic model unless the mice were pretreated with GM-CSF to increase their peripheral WBC counts; GM-CSF alone was ineffective. Also, if GW-39 tumors were pretreated with IFN-gamma to up-regulate CEA expression threefold prior to i.v. injection, labetuzumab significantly increased median survival of the mice. When nude mice received labetuzumab with CPT-11 or 5FU, median survival increased significantly as compared to the drug or antibody alone. CONCLUSIONS Labetuzumab, a CEA-specific MAb, induces effector-cell function in vitro against CEA-positive colonic tumor cells, and also inhibits growth of lung metastasis when CEA expression is up-regulated or if peripheral WBCs are increased. The MAb also shows chemosensitizing properties.
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Affiliation(s)
- Rosalyn D. Blumenthal
- Center for Molecular Medicine and Immunology, Garden State Cancer Center, 520 Belleville Avenue, Belleville, NJ 07109 USA
| | - Lou Osorio
- Center for Molecular Medicine and Immunology, Garden State Cancer Center, 520 Belleville Avenue, Belleville, NJ 07109 USA
| | | | | | | | - David M. Goldenberg
- Center for Molecular Medicine and Immunology, Garden State Cancer Center, 520 Belleville Avenue, Belleville, NJ 07109 USA
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23
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Mennuni C, Calvaruso F, Facciabene A, Aurisicchio L, Storto M, Scarselli E, Ciliberto G, La Monica N. Efficient induction of T-cell responses to carcinoembryonic antigen by a heterologous prime-boost regimen using DNA and adenovirus vectors carrying a codon usage optimized cDNA. Int J Cancer 2005; 117:444-55. [PMID: 15906358 DOI: 10.1002/ijc.21188] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The immunogenic properties of plasmid DNA and recombinant adenovirus (Ad) encoding the carcinoembryonic antigen (CEA) were examined in mice by measuring both the amplitude and type of immune response, and the immunogenicity of codon usage optimized cDNA encoding CEA (CEAopt) was assessed both in C57Bl/6 and CEA transgenic mice. Vectors were injected into quadriceps muscle either alone or in combination, and plasmid DNA was electroporated to enhance gene expression efficiency and immunogenicity. Injection of plasmid pVIJ/CEA followed by Ad-CEA boost elicited the highest amplitude of both CD4+ and CD8+ T-cell response to the target antigen, measured by both IFNgamma-ELIspot assay and intracellular staining. Vectors carrying cDNA of CEAopt expressed a greater amount of the CEA protein than their wild-type counterparts, and this enhanced expression was associated with greater immunogenicity. Both CD4+ and CD8+ T-cell epitopes were mapped in the C-terminal portion of the protein. In CEA transgenic mice, only immunization based on repeated injections of pVIJ/CEAopt followed by Ad-CEAopt was able to elicit a CEA-specific CD8+ T-cell response, whereas the wild-type vectors did not break tolerance to this target antigen. MC38-CEA tumor cells injected s.c. in CEA transgenic mice vaccinated with CEAopt vectors exhibited delayed growth kinetics. These studies demonstrate that this type of genetic vaccine is highly immunogenic and can break tolerance to CEA tumor antigen in CEA transgenic mice.
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Affiliation(s)
- Carmela Mennuni
- Istituto di Ricerche di Biologia Molecolare (IRBM), Pomezia, Italy
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24
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Abstract
DNA vaccines have been used to generate protective immunity against tumors in a variety of experimental models. The favorite target antigens have been those that are frequently expressed by human tumors, such as carcinoembryonic antigen (CEA), ErbB2/neu, and melanoma-associated antigens. DNA vaccines have the advantage of being simple to construct, produce and deliver. They can activate all arms of the immune system, and allow substantial flexibility in modifying the type of immune response generated through codelivery of cytokine genes. DNA vaccines can be applied by intramuscular, dermal/epidermal, oral, respiratory and other routes, and pose relatively few safety concerns. Compared to other nucleic acid vectors, they are usually devoid of viral or bacterial antigens and can be designed to deliver only the target tumor antigen(s). This is likely to be important when priming a response against weak tumor antigens. DNA vaccines have been more effective in rodents than in larger mammals or humans. However, a large number of methods that might be applied clinically have been shown to ameliorate these vaccines. This includes in vivo electroporation, and/or inclusion of various immunostimulatory molecules, xenoantigens (or their epitopes), antigen-cytokine fusion genes, agents that improve antigen uptake or presentation, and molecules that activate innate immunity mechanisms. In addition, CpG motifs carried by plasmids can overcome the negative effects of regulatory T cells. There have been few studies in humans, but recent clinical trials suggest that plasmid/virus, or plasmid/antigen-adjuvant, prime-boost strategies generate strong immune responses, and confirm the usefulness of plasmid-based vaccination.
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Affiliation(s)
- Gérald J Prud'homme
- Department of Laboratory Medicine and Pathobiology, St. Michael's Hospital and University of Toronto, Ontario M5B 1W8, Canada.
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25
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Niethammer AG, Wodrich H, Loeffler M, Lode HN, Emmerich K, Abdollahi A, Krempien R, Debus J, Huber PE, Reisfeld RA. Multidrug resistance-1 (MDR-1): a new target for T cell-based immunotherapy. FASEB J 2004; 19:158-9. [PMID: 15498893 DOI: 10.1096/fj.04-2355fje] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Acquired multidrug resistance (MDR) remains a major challenge in the treatment of cancer with chemotherapeutic drugs. It can be mediated by the up-regulated expression of different proteins within the tumor cell membrane. Here, we used murine multidrug resistance-1 (MDR-1) as a target-antigen for the immunotherapy of cancer. We successfully demonstrated that peripheral T cell tolerance can be broken by oral administration of a DNA vaccine encoding MDR-1 and carried by attenuated Salmonella typhimurium to secondary lymphoid organs. Thus, mice, immunized orally three times at 2-wk intervals and challenged 2 wk thereafter with either MDR-1 expressing CT-26 colon carcinoma cells or MDR-1 expressing Lewis lung carcinoma cells, revealed a significant increase in life span. This was evident, when compared with animals either vaccinated with the empty control vector or challenged with the parental cell lines lacking overexpression of MDR-1. The immune response induced was antigen-specific and CD8+ T cell-mediated. The presence of the target antigen led to up-regulation of activation markers on CD8+ T cells and resulted in a strong cytotoxic T cell response as well as lysis of tumor target cells in vitro. We furthermore established the vaccine to be an effective treatment for established multi-drug-resistant tumor metastases, resulting in a significantly increased life span of experimental animals. Absence of CD8+ T cells due to in vivo depletion led to abrogation of effectiveness. Taken together, our results demonstrate that T cell tolerance against the MDR-1 self-antigen can be broken. It is anticipated that the combination of such an approach with chemotherapy could lead to more effective treatments of cancer.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B, Member 1/biosynthesis
- ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics
- Animals
- CD8-Positive T-Lymphocytes/physiology
- Cancer Vaccines
- Cell Line, Tumor
- Colonic Neoplasms/genetics
- Colonic Neoplasms/metabolism
- Colonic Neoplasms/pathology
- Colonic Neoplasms/therapy
- Genes, MDR/genetics
- Genes, MDR/immunology
- Genetic Vectors/biosynthesis
- Genetic Vectors/genetics
- Immunity/physiology
- Immunization/methods
- Immunotherapy/methods
- Lung Neoplasms/genetics
- Lung Neoplasms/metabolism
- Lung Neoplasms/pathology
- Lung Neoplasms/therapy
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Subcutaneous Tissue/metabolism
- Subcutaneous Tissue/pathology
- T-Lymphocytes/metabolism
- T-Lymphocytes/pathology
- Transduction, Genetic/methods
- Vaccination/methods
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Affiliation(s)
- Andreas G Niethammer
- Department of Radiation Oncology, Heidelberg Medical School, Heidelberg, Germany
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26
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Stevenson FK, Ottensmeier CH, Johnson P, Zhu D, Buchan SL, McCann KJ, Roddick JS, King AT, McNicholl F, Savelyeva N, Rice J. DNA vaccines to attack cancer. Proc Natl Acad Sci U S A 2004; 101 Suppl 2:14646-52. [PMID: 15292504 PMCID: PMC521995 DOI: 10.1073/pnas.0404896101] [Citation(s) in RCA: 87] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Delivery of antigens by injection of the encoding DNA allows access to multiple antigen-presenting pathways. Knowledge of immunological processes can therefore be used to modify construct design to induce selected effector functions. Expression can be directed to specific intracellular sites, and additional genes can be fused or codelivered to amplify responses. Therapeutic vaccination against cancer adds a requirement to overcome tolerance and to activate a weakened immune repertoire. Induction of CD4(+) T helper cells is critical for both antibody and T cell effector responses. To activate immunity against tumor antigens, we fused the tumor-derived sequences to genes encoding microbial proteins. This strategy engages T helper cells from the large antimicrobial repertoire for linked help for inducing antibody against cell-surface tumor antigens. The principle of linked T cell help also holds for induction of epitope-specific antitumor CD8(+) T cells, but the microbial sequence has to be minimized to avoid competition with tumor antigens. Epitope-specific DNA vaccination leads to powerful antitumor attack and can activate immunity from a profoundly tolerized repertoire. Vaccine designs validated in preclinical models are now in clinical trial with immune responses detected against both tumor antigens and fused microbial antigens. DNA priming is highly efficient, but boosting may benefit from increased antigen expression. Physical methods including electroporation provide increased expression without introducing additional competing antigens. A wide range of cancers can be targeted, and objective assays of response will determine efficacy.
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Affiliation(s)
- Freda K Stevenson
- Molecular Immunology Group, Tenovus Laboratory, Cancer Sciences Division, Southampton University Hospitals Trust, Southampton SO16 6YD, UK.
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27
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Schoen C, Stritzker J, Goebel W, Pilgrim S. Bacteria as DNA vaccine carriers for genetic immunization. Int J Med Microbiol 2004; 294:319-35. [PMID: 15532991 DOI: 10.1016/j.ijmm.2004.03.001] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Genetic immunization with plasmid DNA vaccines has proven to be a promising tool in conferring protective immunity in various experimental animal models of infectious diseases or tumors. Recent research focuses on the use of bacteria, in particular enteroinvasive species, as effective carriers for DNA vaccines. Attenuated strains of Shigella flexneri, Salmonella spp., Yersinia enterocolitica or Listeria monocytogenes have shown to be attractive candidates to target DNA vaccines to immunological inductive sites at mucosal surfaces. This review summarizes recent progress in bacteria-mediated delivery of plasmid DNA vaccines in the field of infectious diseases and cancer.
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Affiliation(s)
- Christoph Schoen
- Department of Microbiology, Biocenter of the University, D-97074 Würzburg, Germany
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28
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Saha A, Chatterjee SK, Foon KA, Primus FJ, Sreedharan S, Mohanty K, Bhattacharya-Chatterjee M. Dendritic cells pulsed with an anti-idiotype antibody mimicking carcinoembryonic antigen (CEA) can reverse immunological tolerance to CEA and induce antitumor immunity in CEA transgenic mice. Cancer Res 2004; 64:4995-5003. [PMID: 15256474 DOI: 10.1158/0008-5472.can-04-0626] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
In this report, we have studied the immunogenicity of the nominal antigen, carcinoembryonic antigen (CEA), and that of an anti-idiotype antibody, 3H1, which mimics CEA and can be used as a surrogate for CEA. We have demonstrated that immunization of CEA transgenic mice with bone marrow-derived mature dendritic cells (DC) loaded with anti-idiotype 3H1 or CEA could reverse CEA unresponsiveness and result in the induction of CEA-specific immune responses and the rejection of CEA-transfected MC-38 colon carcinoma cells, C15. Immunized mice splenocytes proliferated in an antigen-specific manner by a mechanism dependent on the functions of CD4, MHC II, B7-2, CD40, CD28, and CD25. However, immune splenic lymphocytes isolated from 3H1-DC-vaccinated mice when stimulated in vitro with 3H1 or CEA secreted significantly higher levels of Th1 cytokines than did CEA-DC vaccinated mice. DC vaccination also induced antigen-specific effector CD8+ T cells capable of expressing interleukin-2, IFN-gamma, and tumor necrosis factor (TNF)-alpha and displayed cytotoxic activity against C15 cells in an MHC class I-restricted manner. 3H1-DC vaccination resulted in augmented CTL responses and the elevated expression of CD69, CD25, and CD28 on CD8(+) CTLs. The immune responses developed in 3H1-DC-immunized mice resulted in rejection of C15 tumor cells in nearly 100% of experimental mice, whereas only 40% of experimental mice immunized with CEA-DC were protected from C15 tumor growth. These findings suggest that under the experimental conditions used, 3H1-DC vaccination was better than CEA-DC vaccination in breaking immune tolerance to CEA and inducing protective antitumor immune responses in this murine model transgenic for human CEA.
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Affiliation(s)
- Asim Saha
- Department of Internal Medicine and the Barrett Cancer Center, University of Cincinnati, Cincinnati, OH 45267, USA
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29
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Reisfeld RA, Niethammer AG, Luo Y, Xiang R. DNA vaccines suppress tumor growth and metastases by the induction of anti-angiogenesis. Immunol Rev 2004; 199:181-90. [PMID: 15233734 DOI: 10.1111/j.0105-2896.2004.00137.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Four novel oral DNA vaccines provide long-lived protection against melanoma, colon, breast, and non-small cell lung carcinoma in mouse model systems. The vaccines are delivered by attenuated Salmonella typhimurium to secondary lymphoid organs and are directed against targets such as carcinoembryonic antigen, tyrosine-related protein, vascular endothelial growth factor receptor-2 [also called fetal liver kinase-1 (FLK-1)], and transcription factor Fos-related antigen-1 (Fra-1). The FLK-1 and Fra-1 vaccines are effective in suppressing angiogenesis in the tumor vasculature. All four vaccines are capable of inducing potent cell-mediated protective immunity, breaking peripheral T-cell tolerance against these self-antigens resulting in effective suppression of tumor growth and metastasis. It is anticipated that such research efforts will contribute toward the rational design of future DNA vaccines that will be effective for prevention and treatment of human cancer.
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30
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Zeytin HE, Patel AC, Rogers CJ, Canter D, Hursting SD, Schlom J, Greiner JW. Combination of a Poxvirus-Based Vaccine with a Cyclooxygenase-2 Inhibitor (Celecoxib) Elicits Antitumor Immunity and Long-Term Survival in CEA.Tg/MIN Mice. Cancer Res 2004; 64:3668-78. [PMID: 15150127 DOI: 10.1158/0008-5472.can-03-3878] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The present study was designed to determine whether: (a) chronic administration of dietary celecoxib (Celebrex), a potent nonsteroidal anti-inflammatory drug, which targets the cyclooxygenase-2 (COX-2) enzyme, negatively impacts host immunity; and (b) celecoxib can be coupled with a poxvirus-based vaccine to impact tumor burden in a murine tumor model of spontaneous adenomatous polyposis coli. Naive mice fed the celecoxib-supplemented diets developed eosinophilia with lowered plasma prostaglandin E(2) levels and reduced COX-2 mRNA expression levels in their splenic T cells. Responses of splenic T, B, and natural killer cells to broad-based and antigen-specific stimuli were, for the most part, unchanged in those mice as well as COX-2 knockout mice; exceptions included: (a) reduced IFN-gamma production by concanavalin A- or antigen-stimulated T cells; and (b) heightened lipopolysaccharide response of naive B cells from mice fed a diet supplemented with 1000 ppm of celecoxib. When transgenic mice that express the human carcinoembryonic antigen (CEA) gene (CEA transgenic) were bred with mice bearing a mutation in the Apc(Delta850) gene (multiple intestinal neoplasia mice), the progeny (CEA transgenic/multiple intestinal neoplasia) spontaneously develop multiple intestinal neoplasms that overexpress CEA and COX-2. Beginning at 30 days of age, the administration of a diversified prime/boost recombinant CEA-poxvirus-based vaccine regimen or celecoxib (1000 ppm)-supplemented diet reduced the number of intestinal neoplasms by 54% and 65%, respectively. Combining the CEA-based vaccine with the celecoxib-supplemented diet reduced tumor burden by 95% and significantly improved overall long-term survival. Both tumor reduction and improved overall survival were achieved without any evidence of autoimmunity directed at CEA-expressing or other normal tissues. Celecoxib is prescribed for the treatment of familial adenomatous polyposis in humans, and the CEA-based vaccines have been well tolerated and capable of eliciting anti-CEA host immune responses in early clinical studies. The results suggest that the administration of a recombinant poxvirus-based vaccine is compatible with celecoxib, and this combined chemoimmuno-based approach might lead to an additive therapeutic antitumor benefit not only in patients diagnosed with familial adenomatous polyposis but, perhaps, in other preventive settings in which COX-2 overexpression is associated with progression from premalignancy to neoplasia.
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Affiliation(s)
- Hasan E Zeytin
- Laboratories of Tumor Immunology and Biology, Division of Cancer Prevention, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA
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31
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Reisfeld RA, Niethammer AG, Luo Y, Xiang R. DNA vaccines designed to inhibit tumor growth by suppression of angiogenesis. Int Arch Allergy Immunol 2004; 133:295-304. [PMID: 14988601 DOI: 10.1159/000077009] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
The development of new blood vessels, i.e. angiogenesis, is a rate-limiting step in the development of tumors since tumor growth is generally limited to 1-2 mm3 in the absence of a blood supply. Thus, the inhibition of tumor growth by attacking the tumor's vascular supply offers a primary target for antiangiogenic intervention by DNA-based vaccines. Here, we describe two novel orally delivered DNA vaccines which suppress tumor angiogenesis and induce a robust cell-mediated immune response that provides for long-lived protection against melanoma, colon, breast and non-small-cell lung carcinoma in mouse model systems. These vaccines, which are delivered by attenuated Salmonella typhimurium to secondary lymphoid organs, are directed against such targets as vascular endothelial growth factor receptor 2 (FLK-1) and transcription factor Fos-related antigen 1 (Fra-1). Both vaccines break peripheral T cell tolerance against these self-antigens and induce a robust T cell-mediated immune response leading to suppression of tumor angiogenesis and resulting in effective suppression of tumor growth and metastases. Such research efforts may open up new possibilities for the rational design of future DNA vaccines effective for the prevention and treatment of cancer.
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Crawford NPS, Colliver DW, Galandiuk S. Tumor markers and colorectal cancer: utility in management. J Surg Oncol 2004; 84:239-48. [PMID: 14756436 DOI: 10.1002/jso.10325] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Colorectal cancer (CRC) is a leading cause of morbidity and mortality. Although genetic testing can screen for rare hereditary CRC syndromes, there is no ideal means of screening for sporadic forms of CRC. This review will focus on markers that are currently used in the management of sporadic CRC and their limitations, as well as possible future clinical applications.
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Affiliation(s)
- Nigel P S Crawford
- Price Institute of Surgical Research, Department of Surgery, University of Louisville, Kentucky 40292, USA
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Feng K, Zhao H, Chen J, Yao D, Jiang X, Zhou W. Anti-angiogenesis effect on glioma of attenuated Salmonella typhimurium vaccine strain with flk-1 gene. Curr Med Sci 2004; 24:389-91. [PMID: 15587406 DOI: 10.1007/bf02861875] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2004] [Indexed: 10/19/2022]
Abstract
To investigate the anti-vasculature effects and the anti-glioma effects of attenuated Salmonella typhimurium vaccine strain expressing VEGFR2 (flk-1) gene, plasmid pcDNA3.1-flk1 was constructed and electro-transfected into live attenuated Salmonella typhimurium strain SL7207. Mouse models of intracranial G1261 glioblastoma were treated with an orally administered attenuated Salmonella typhimurium expressing flk-1 gene. The survival period was recorded and vessel density was observed by immunofluorescence. CTLs activity was measured by MTT assay. Our results showed that attenuated Salmonella typhimurium vaccine strain expressing flk-1 gene could significantly inhibit glioblastoma growth, reduce vessel density, prolong the survival period and improve the survival rate in these mice. The flk-1 specific CTLs activity was increased obviously after the vaccination. Our study showed that attenuated Salmonella typhimurium vaccine strain expressing flk-1 gene could break peripheral immune tolerance a in glioma gainst this self-antigen and kill endothelial cells by the orally administered vaccine and can be used for both prophylactic and therapeutic purposes.
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Affiliation(s)
- Keke Feng
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and technology, Wuhan 430022, China
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Ohtsukasa S, Okabe S, Yamashita H, Iwai T, Sugihara K. Increased expression of CEA and MHC class I in colorectal cancer cell lines exposed to chemotherapy drugs. J Cancer Res Clin Oncol 2003; 129:719-26. [PMID: 14564514 DOI: 10.1007/s00432-003-0492-0] [Citation(s) in RCA: 62] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2003] [Accepted: 07/25/2003] [Indexed: 12/20/2022]
Abstract
PURPOSE Cancer-specific immunotherapy holds great promise as an emerging treatment for advanced colorectal cancer and may be combined with standard chemotherapy to provide a synergistic inhibitory action against tumor cells. To examine the interrelationship between the immune system and chemotherapy, we studied the induction of both CEA, a tumor-associated antigen, and MHC class I, a major component of the antigen presenting system, in response to a number of chemotherapeutic agents. METHODS The effect of a selection of standard chemotherapeutics on MHC class I and CEA expression in human colorectal cancer cell lines was determined by flow cytometry and semi-quantitative RT-PCR. In addition, studies using mice bearing tumors derived from an injected murine colon cancer cell line were performed to determine if alteration in MHC class I expression occurs in vivo following continuous infusion of chemotherapeutic agents into the peritoneal cavity, as well as to facilitate correlations between expression of this factor and therapeutic effectiveness. RESULTS All anti-cancer drugs examined, when given at IC50 values, induced expression of MHC class I protein in the human colon cancer cell line, COLO201. However, expression of CEA mRNA was only induced upon exposure to 5-FU, in contrast to obscure induction following CDDP and SN-38 treatment. Combined treatment with 5-FU and CDDP gave additional effect on CEA expression in COLO201 cells. Regarding the in vivo studies in mice, the size of the murine colon cancer cell-derived tumors was reduced only in response to treatment with CDDP, which also mediated the highest induction of MHC class I expression. CONCLUSION These results suggest that chemotherapeutic agents trigger the immune system and cancer-specific immunotherapy may be effective when used in combination with systemic chemotherapy.
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Affiliation(s)
- Shunroh Ohtsukasa
- Department of Surgery, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, 113-8519 Tokyo, Japan
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Guo CC, Ding J, Pan BR, Yu ZC, Han QL, Meng FP, Liu N, Fan DM. Development of an oral DNA vaccine against MG7-Ag of gastric cancer using attenuated salmonella typhimurium as carrier. World J Gastroenterol 2003; 9:1191-5. [PMID: 12800222 PMCID: PMC4611782 DOI: 10.3748/wjg.v9.i6.1191] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To develop an oral DNA vaccine against gastric cancer and evaluate its efficacy in mice.
METHODS: The genes of the MG7-Ag mimotope and a universal Th epitope (Pan-DR epitope, PADRE) were included in the PCR primers. By PCR, the fusion gene of the two epitopes was amplified. The fusion gene was confirmed by sequencing and was then cloned into pcDNA3.1 (+) plasmid. The pcDNA3.1 (+)-MG7/PADRE was used to transfect an attenuated Salmonella typhimurium. C57BL/6 mice were orally immunized with 1 × 108 cfu Salmonella transfectants. Salmonella harboring the empty pcDNA3.1 (+) plasmid and phosphate buffer saline (PBS) were used as negative controls. At the 6th week, serum titer of MG7-Ag specific antibody was detected by ELISA. At the 8th week cellular immunity was detected by an unprimed proliferation test of the spleenocytes by using a [3H]-thymidine incorporation assay. Ehrlich ascites carcinoma cells expressing MG7-Ag were used as a model in tumor challenge assay to evaluate the protective effect of the vaccine.
RESULTS: Serum titer of antibody against MG7-Ag was significantly higher in mice immunized with the vaccine than that in control groups (0.841 vs 0.347, P < 0.01; 0.841 vs 0.298, P < 0.01), while in vitro unprimed proliferation assay of the spleenocytes showed no statistical difference between those three groups. Two weeks after tumor challenge, 2 in 7 immunized mice were tumor free, while all the mice in the control groups showed tumor formation.
CONCLUSION: Oral DNA vaccine against the MG7-Ag momitope of gastric cancer is immunogenic. It can induce significant humoral immunity against tumor in mice, and the vaccine has partially protective effects.
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Affiliation(s)
- Chang-Cun Guo
- Institute of Digestive Disease, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China
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Zöller M. Immunotherapy of cancer by active vaccination: does allogeneic bone marrow transplantation after non-myeloablative conditioning provide a new option? Technol Cancer Res Treat 2003; 2:237-60. [PMID: 12779354 DOI: 10.1177/153303460300200307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
The critical role of antigen-specific T cells in cancer immunotherapy has been amply demonstrated in many model systems. Though success of clinical trials still remains far behind expectation, the continuous improvement in our understanding of the biology of the immune response will provide the basis of optimized cancer vaccines and allow for new modalities of cancer treatment. This review focuses on the current status of active therapeutic vaccination and future prospects. The latter will mainly be concerned with allogeneic bone marrow cell transplantation after non-myeloablative conditioning, because it is my belief that this approach could provide a major breakthrough in cancer immunotherapy. Concerning active vaccination protocols the following aspects will be addressed: i) the targets of immunotherapeutic approaches; ii) the response elements needed for raising a therapeutically successful immune reaction; iii) ways to achieve an optimal confrontation of the immune system with the tumor and iv) supportive regimen of immunomodulation. Hazards which one is most frequently confronted with in trials to attack tumors with the inherent weapon of immune defense will only be briefly mentioned. Many question remain to be answered in the field of allogeneic bone marrow transplantation after non-myeloablative conditioning to optimize the therapeutic setting for this likely very powerful tool of cancer therapy. Current considerations to improve engraftment and to reduce graft versus host disease while strengthening graft versus tumor reactivity will be briefly reviewed. Finally, I will discuss whether tumor-reactive T cells can be "naturally" maintained during the process of T cell maturation in the allogeneic host. Provided this hypothesis can be substantiated, a T cell vaccine will meet a pool of virgin T cells in the allogeneically reconstituted host, which are tolerant towards the host, but not anergised towards tumor antigens presented by MHC molecules of the host.
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Affiliation(s)
- Margot Zöller
- Dept. of Tumor Progression & Immune Defense, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
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Weiss S. Transfer of eukaryotic expression plasmids to mammalian hosts by attenuated Salmonella spp. Int J Med Microbiol 2003; 293:95-106. [PMID: 12755370 DOI: 10.1078/1438-4221-00248] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Transkingdom transfer of DNA from bacteria to other organisms, well established for bacteria, yeast and plants, was recently also extended to mammalian host cells. Attenuated intracellular bacteria or non-pathogenic bacteria equipped with adhesion and invasion properties have been demonstrated to transfer eukaryotic expression plasmids in vitro and in vivo. Here the mucosal application of attenuated Salmonella enterica spp. as DNA carrier for the induction of immune responses towards protein antigens encoded by expression plasmids, their use to complement genetic defects or deliver immunotherapeutic proteins is reviewed. Plasmid transfer has been reported for Salmonella typhimurium, S. typhi and S. choleraesuis so far but clearly other Salmonella strains should be able to transfer expression plasmids as well. Transfer of DNA is effected most likely by bacterial death within the host cell resulting from metabolic attenuation. Since these bacteria remain in the phagocytic vacuole it is unclear how the DNA from such dying bacteria is delivered to the nucleus of infected cells. Nevertheless, the efficiency that has been observed was astonishingly high, reaching close to 100% under certain conditions. Gene transfer in vivo was mainly directed towards vaccination strategies either as vaccination against infectious microorganisms or model tumors. Interestingly, in some cases tolerance against autologous antigens could be broken. In general, this type of immunization was more efficacious than either direct application of antigen, vaccination with naked DNA or using the same bacterium as a heterologous carrier expressing the antigen via a prokaryotic promoter. The ease of generating such vehicles for gene transfer combined with technology validated for mass vaccination programs and the efficacy of induction of protective immune responses makes Salmonella as carrier for mucosal DNA vaccination a highly attractive area for further research and development.
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Affiliation(s)
- Siegfried Weiss
- Molecular Immunology, GBF, German Research Centre for Biotechnology, Mascheroder Weg 1, D-38124 Braunschweig, Germany.
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DeBenedette M, Radvanyi L, Singh-Sandhu D, Berinstein NL. Anti-carcinoembryonic antigen immunity. CANCER CHEMOTHERAPY AND BIOLOGICAL RESPONSE MODIFIERS 2003; 21:299-325. [PMID: 15338752 DOI: 10.1016/s0921-4410(03)21015-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/30/2023]
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Niethammer AG, Xiang R, Becker JC, Wodrich H, Pertl U, Karsten G, Eliceiri BP, Reisfeld RA. A DNA vaccine against VEGF receptor 2 prevents effective angiogenesis and inhibits tumor growth. Nat Med 2002; 8:1369-75. [PMID: 12415261 DOI: 10.1038/nm1202-794] [Citation(s) in RCA: 249] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2002] [Accepted: 10/08/2002] [Indexed: 11/09/2022]
Abstract
Tumor cells are elusive targets for immunotherapy due to their heterogeneity and genetic instability. Here we describe a novel, oral DNA vaccine that targets stable, proliferating endothelial cells in the tumor vasculature rather than tumor cells. Targeting occurs through upregulated vascular-endothelial growth factor receptor 2 (FLK-1) of proliferating endothelial cells in the tumor vasculature. This vaccine effectively protected mice from lethal challenges with melanoma, colon carcinoma and lung carcinoma cells and reduced growth of established metastases in a therapeutic setting. CTL-mediated killing of endothelial cells indicated breaking of peripheral immune tolerance against this self antigen, resulting in markedly reduced dissemination of spontaneous and experimental pulmonary metastases. Angiogenesis in the tumor vasculature was suppressed without impairment of fertility, neuromuscular performance or hematopoiesis, albeit with a slight delay in wound healing. Our strategy circumvents problems in targeting of genetically unstable tumor cells. This approach may provide a new strategy for the rational design of cancer therapies.
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Chabalgoity JA, Dougan G, Mastroeni P, Aspinall RJ. Live bacteria as the basis for immunotherapies against cancer. Expert Rev Vaccines 2002; 1:495-505. [PMID: 12901588 DOI: 10.1586/14760584.1.4.495] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
For more than a century, bacteria and bacterial products have been used for the treatment of cancer. Starting from the practical observation of tumor regression in individuals with concomitant bacterial infection, the field has evolved into some standard clinical practices, such as the use of BCG for the treatment of superficial bladder cancer. However, in the last few years, new applications have started to emerge that may profoundly change the perspective of the field. BCG can be engineered to express cytokines to improve its efficacy. Bacteria such as Salmonella and Listeria can be attenuated by genetically-defined mutations and provide effective vehicles for DNA vaccines encoding tumor-associated antigens. Salmonella and nonpathogenic strains of Clostridium can selectively accumulate in tumors in vivo, providing attractive delivery systems to target immunomodulatory molecules and therapeutic agents to the tumor site. Many of these new developments have been attempted for prophylactic or therapeutic vaccination in several different experimental models of cancer and in many cases, results from clinical trials are now emerging. There is still some way to go before achieving products that could be in routine use, but the field has great promise for the development of more effective immunotherapies for several different cancers. In this paper, we will review the current state of such applications and highlight some of the directions that the field may take.
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Affiliation(s)
- José A Chabalgoity
- Department of Biochemistry, Instituto de Higiene, Facultad de Medicina, Montevideo, Uruguay.
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Garmory HS, Brown KA, Titball RW. Salmonella vaccines for use in humans: present and future perspectives. FEMS Microbiol Rev 2002; 26:339-53. [PMID: 12413664 DOI: 10.1111/j.1574-6976.2002.tb00619.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
In recent years there has been significant progress in the development of attenuated Salmonella enterica serovar Typhi strains as candidate typhoid fever vaccines. In clinical trials these vaccines have been shown to be well tolerated and immunogenic. For example, the attenuated S. enterica var. Typhi strains CVD 908-htrA (aroC aroD htrA), Ty800 (phoP phoQ) and chi4073 (cya crp cdt) are all promising candidate typhoid vaccines. In addition, clinical trials have demonstrated that S. enterica var. Typhi vaccines expressing heterologous antigens, such as the tetanus toxin fragment C, can induce immunity to the expressed antigens in human volunteers. In many cases, the problems associated with expression of antigens in Salmonella have been successfully addressed and the future of Salmonella vaccine development is very promising.
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Affiliation(s)
- Helen S Garmory
- Department of Biomedical Sciences, Dstl Chemical and Biological Sciences, Porton Down, Salisbury SP4 0JQ, UK.
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