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Bacteria and bacterial derivatives as delivery carriers for immunotherapy. Adv Drug Deliv Rev 2022; 181:114085. [PMID: 34933064 DOI: 10.1016/j.addr.2021.114085] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 11/16/2021] [Accepted: 12/14/2021] [Indexed: 02/08/2023]
Abstract
There is growing interest in the role of microorganisms in human health and disease, with evidence showing that new types of biotherapy using engineered bacterial therapeutics, including bacterial derivatives, can address specific mechanisms of disease. The complex interactions between microorganisms and metabolic/immunologic pathways underlie many diseases with unmet medical needs, suggesting that targeting these interactions may improve patient treatment. Using tools from synthetic biology and chemical engineering, non-pathogenic bacteria or bacterial products can be programmed and designed to sense and respond to environmental signals to deliver therapeutic effectors. This review describes current progress in biotherapy using live bacteria and their derivatives to achieve therapeutic benefits against various diseases.
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Kodama Y, Tokunaga A, Hashizume J, Nakagawa H, Harasawa H, Kurosaki T, Nakamura T, Nishida K, Nakashima M, Hashida M, Kawakami S, Sasaki H. Evaluation of transgene expression characteristics and DNA vaccination against melanoma metastasis of an intravenously injected ternary complex with biodegradable dendrigraft poly-L-lysine in mice. Drug Deliv 2021; 28:542-549. [PMID: 33685317 PMCID: PMC7946064 DOI: 10.1080/10717544.2021.1895904] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
We developed a biocompatible splenic vector for a DNA vaccine against melanoma. The splenic vector is a ternary complex composed of plasmid DNA (pDNA), biodegradable dendrigraft poly-L-lysine (DGL), and γ-polyglutamic acid (γ-PGA), the selective uptake of which by the spleen has already been demonstrated. The ternary complex containing pDNA encoding luciferase (pCMV-Luc) exhibited stronger luciferase activity for RAW264.7 mouse macrophage-like cells than naked pCMV-Luc. Although the ternary complex exhibited strong luciferase activity in the spleen after its tail vein injection, luciferase activity in the liver and spleen was significantly decreased by a pretreatment with clodronate liposomes, which depleted macrophages in the liver and spleen. These results indicate that the ternary complex is mainly transfected in macrophages and is a suitable formulation for DNA vaccination. We applied the ternary complex to a pUb-M melanoma DNA vaccine. The ternary complex containing pUb-M suppressed the growth of melanoma and lung metastasis by B16-F10 mouse melanoma cells. We also examined the acute and liver toxicities of the pUb-M ternary complex at an excess pDNA dose in mice. All mice survived the injection of the excess amount of the ternary complex. Liver toxicity was negligible in mice injected with the excess amount of the ternary complex. In conclusion, we herein confirmed that the ternary complex was mainly transfected into macrophages in the spleen after its tail vein injection. We also showed the prevention of melanoma metastasis by the DNA vaccine and the safety of the ternary complex.
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Affiliation(s)
- Yukinobu Kodama
- Department of Hospital Pharmacy, Nagasaki University Hospital, Nagasaki, Japan
| | - Ayako Tokunaga
- Department of Hospital Pharmacy, Nagasaki University Hospital, Nagasaki, Japan
| | - Junya Hashizume
- Department of Hospital Pharmacy, Nagasaki University Hospital, Nagasaki, Japan
| | - Hiroo Nakagawa
- Department of Hospital Pharmacy, Nagasaki University Hospital, Nagasaki, Japan
| | - Hitomi Harasawa
- Department of Hospital Pharmacy, Nagasaki University Hospital, Nagasaki, Japan
| | - Tomoaki Kurosaki
- Department of Hospital Pharmacy, Nagasaki University Hospital, Nagasaki, Japan
| | - Tadahiro Nakamura
- Department of Hospital Pharmacy, Nagasaki University Hospital, Nagasaki, Japan.,Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Koyo Nishida
- Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Mikiro Nakashima
- Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Mitsuru Hashida
- Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Shigeru Kawakami
- Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Hitoshi Sasaki
- Department of Hospital Pharmacy, Nagasaki University Hospital, Nagasaki, Japan
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Kodama Y, Nakashima M, Nagahara T, Oyama N, Hashizume J, Nakagawa H, Harasawa H, Muro T, Kurosaki T, Yamashita C, Hashida M, Kitahara T, Sasaki H, Kawakami S, Nakamura T. Development of a DNA Vaccine for Melanoma Metastasis by Inhalation Based on an Analysis of Transgene Expression Characteristics of Naked pDNA and a Ternary Complex in Mouse Lung Tissues. Pharmaceutics 2020; 12:E540. [PMID: 32545209 PMCID: PMC7355686 DOI: 10.3390/pharmaceutics12060540] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 06/07/2020] [Accepted: 06/09/2020] [Indexed: 12/22/2022] Open
Abstract
The present study investigated a pulmonary delivery system of plasmid DNA (pDNA) and its application to melanoma DNA vaccines. pCMV-Luc, pEGFP-C1, and pZsGreen were used as a model pDNA to evaluate transfection efficacy after inhalation in mice. Naked pDNA and a ternary complex, consisting of pDNA, dendrigraft poly-l-lysine (DGL), and γ-polyglutamic acid (γ-PGA), both showed strong gene expression in the lungs after inhalation. The transgene expression was detected in alveolar macrophage-rich sites by observation using multi-color deep imaging. On the basis of these results, we used pUb-M, which expresses melanoma-related antigens (ubiquitinated murine melanoma gp100 and tyrosinase-related protein 2 (TRP2) peptide epitopes), as DNA vaccine for melanoma. The inhalation of naked pUb-M and its ternary complex significantly inhibited the metastasis of B16-F10 cells, a melanoma cell line, in mice. The levels of the inflammatory cytokines, such as TNF-α, IFN-γ, and IL-6, which enhance Th1 responses, were higher with the pUb-M ternary complex than with naked pUb-M and pEGFP-C1 ternary complex as control. In conclusion, we clarified that the inhalation of naked pDNA as well as its ternary complex are a useful technique for cancer vaccination.
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Affiliation(s)
- Yukinobu Kodama
- Department of Hospital Pharmacy, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan; (Y.K.); (J.H.); (H.N.); (H.H.); (T.M.); (T.K.); (H.S.)
| | - Mikiro Nakashima
- Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan; (M.N.); (T.N.); (N.O.); (S.K.)
| | - Tadayuki Nagahara
- Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan; (M.N.); (T.N.); (N.O.); (S.K.)
| | - Natsuko Oyama
- Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan; (M.N.); (T.N.); (N.O.); (S.K.)
| | - Junya Hashizume
- Department of Hospital Pharmacy, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan; (Y.K.); (J.H.); (H.N.); (H.H.); (T.M.); (T.K.); (H.S.)
| | - Hiroo Nakagawa
- Department of Hospital Pharmacy, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan; (Y.K.); (J.H.); (H.N.); (H.H.); (T.M.); (T.K.); (H.S.)
| | - Hitomi Harasawa
- Department of Hospital Pharmacy, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan; (Y.K.); (J.H.); (H.N.); (H.H.); (T.M.); (T.K.); (H.S.)
| | - Takahiro Muro
- Department of Hospital Pharmacy, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan; (Y.K.); (J.H.); (H.N.); (H.H.); (T.M.); (T.K.); (H.S.)
| | - Tomoaki Kurosaki
- Department of Hospital Pharmacy, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan; (Y.K.); (J.H.); (H.N.); (H.H.); (T.M.); (T.K.); (H.S.)
| | - Chikamasa Yamashita
- Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan;
| | - Mitsuru Hashida
- Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimo-Adachi-cho, Sakyo-ku, Kyoto 606-8501, Japan;
| | - Takashi Kitahara
- Department of Pharmacy, Yamaguchi University Hospital, 1-1-1 MinamiKogushi, Ube, Yamaguchi 755-8505, Japan;
| | - Hitoshi Sasaki
- Department of Hospital Pharmacy, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan; (Y.K.); (J.H.); (H.N.); (H.H.); (T.M.); (T.K.); (H.S.)
| | - Shigeru Kawakami
- Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan; (M.N.); (T.N.); (N.O.); (S.K.)
| | - Tadahiro Nakamura
- Department of Hospital Pharmacy, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan; (Y.K.); (J.H.); (H.N.); (H.H.); (T.M.); (T.K.); (H.S.)
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Kurosaki T. [Development of Vaccines with Self-assembled Carriers That Deliver Drugs to Target Organs]. YAKUGAKU ZASSHI 2020; 140:363-368. [PMID: 32115553 DOI: 10.1248/yakushi.19-00174] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
I have developed novel ternary complexes of various vaccines with cationic materials and anionic polymers. Plasmid DNA (pDNA) encoding firefly luciferase was used as a model drug to form adequate ternary complexes. Cationic binary complexes were constructed using pDNA and polyethylenimine, and these binary complexes were coated with various anionic polymers to form ternary complexes. These ternary complexes significantly improved cytotoxicity and aggregation with erythrocytes in comparison to the binary complexes. On the other hand, most of those ternary complexes showed little in vitro transgene efficiency because of their anionic surface charge. γ-Polyglutamic acid (γ-PGA)-ternary complexes, however, demonstrated high in vitro transgene efficiency. After the intravenous administration of γ-PGA-ternary complexes to mice, extremely high gene expression was detected in the marginal zone of the spleen, which is rich in antigen-presenting cells. This spleen-specific phenomenon of γ-PGA-ternary complexes appeared to be suited to DNA vaccines against cancer. I therefore examined the preventive effect of γ-PGA-ternary complexes containing pUb-M, a pDNA encoding melanoma surface antigen, against melanoma-bearing mice. Vaccinations of γ-PGA-ternary complexes into mice significantly suppressed the tumor growth of B16-F10 melanoma cells subcutaneously injected into the mice. In the same manner, vaccinations of γ-PGA-ternary complexes containing ovalbumin (OVA) completely suppressed the growth of E.G7-OVA cells expressing OVA. These results strongly suggest that γ-PGA-ternary complexes are useful in the manufacture of specific tumor vaccines.
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Effective oral delivery of gp100 plasmid vaccine against metastatic melanoma through multi-faceted blending-by-blending nanogels. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2019; 22:102114. [DOI: 10.1016/j.nano.2019.102114] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Revised: 09/29/2019] [Accepted: 10/11/2019] [Indexed: 12/31/2022]
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Abstract
Recent advances in targeted therapy and immunotherapy have once again raised the hope that a cure might be within reach for many cancer types. Yet, most late-stage cancers are either insensitive to the therapies to begin with or develop resistance later. Therapy with live tumour-targeting bacteria provides a unique option to meet these challenges. Compared with most other therapeutics, the effectiveness of tumour-targeting bacteria is not directly affected by the 'genetic makeup' of a tumour. Bacteria initiate their direct antitumour effects from deep within the tumour, followed by innate and adaptive antitumour immune responses. As microscopic 'robotic factories', bacterial vectors can be reprogrammed following simple genetic rules or sophisticated synthetic bioengineering principles to produce and deliver anticancer agents on the basis of clinical needs. Therapeutic approaches using live tumour-targeting bacteria can either be applied as a monotherapy or complement other anticancer therapies to achieve better clinical outcomes. In this Review, we summarize the potential benefits and challenges of this approach. We discuss how live bacteria selectively induce tumour regression and provide examples to illustrate different ways to engineer bacteria for improved safety and efficacy. Finally, we share our experience and insights on oncology clinical trials with tumour-targeting bacteria, including a discussion of the regulatory issues.
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Affiliation(s)
- Shibin Zhou
- Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - Claudia Gravekamp
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - David Bermudes
- Department of Biology, California State University, Northridge, CA, USA
| | - Ke Liu
- Oncology Branch, Division of Clinical Evaluation, Pharmacology and Toxicology; Office of Tissues and Advanced Therapies, CBER, FDA, Silver Spring, MD, USA
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Zhou C, Yu C, Guo L, Wang X, Li H, Cao Q, Li F. In Vivo Study of the Effects of ER β on Apoptosis and Proliferation of Hormone-Independent Prostate Cancer Cell Lines PC-3M. BIOMED RESEARCH INTERNATIONAL 2018; 2018:1439712. [PMID: 30018975 PMCID: PMC6029510 DOI: 10.1155/2018/1439712] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/02/2017] [Revised: 04/09/2018] [Accepted: 04/19/2018] [Indexed: 11/18/2022]
Abstract
OBJECTIVE To evaluate the in vivo therapeutic effects of attenuated Salmonella carrying PCDNA3.1-ERβ plasmid in hormone-independent prostatic cancer in nude mice and to clarify the mechanism by which estrogen receptor β (ERβ) induces apoptosis and proliferation in prostatic cancer cells in mice. METHODS The orthotopic prostatic cancer models of mice were randomly divided as follows: MOCK group, treated with PBS, PQ group, treated with attenuated Salmonella alone, PQ-PCDNA3.1 group, treated with attenuated Salmonella carrying PCDNA3.1 plasmid, and PQ-PCDNA3.1-ERβ group, treated with the attenuated Salmonella carrying PCDNA3.1-ERβ plasmid. Then, 10 μl of the plasmid-containing solution, comprising 1 × 107 cfu of the bacteria, was administered via intranasal delivery to each group except the MOCK group. The experimental methods included flow cytometry and terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling (TUNEL) assay, immunohistochemistry, and western blotting. RESULTS Compared with the MOCK, PQ, and PQ-PCDNA3.1 groups, the weights of tumors in the PQ-PCDNA3.1-ERβ group were significantly reduced. The results of flow cytometry and TUNEL assay revealed that the number of apoptotic cells in the PQ-PCDNA3.1-ERβ group significantly increased. Compared with PQ-PCDNA3.1 group, the protein expression levels of ERβ, Bad, p-caspase 9, p-caspase 3, and cleaved PARP in the PQ-PCDNA3.1-ERβ group were significantly increased, while the expression levels of Akt, p-Akt, and Bcl-xl were decreased (P < 0.05). CONCLUSION The attenuated Salmonella carrying PCDNA3.1-ERβ plasmid could inhibit the growth of orthotopic prostatic cancer in mice by increasing the expression of ERβ.
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Affiliation(s)
- Changli Zhou
- School of Nursing, Jilin University, 965 Xinjiang Street, Changchun, Jilin 130020, China
| | - Chunyu Yu
- Basic Medical School, Jilin University, 126 Xinmin Street, Changchun, Jilin 130020, China
| | - Lirong Guo
- School of Nursing, Jilin University, 965 Xinjiang Street, Changchun, Jilin 130020, China
| | - Xige Wang
- School of Nursing, Jilin University, 965 Xinjiang Street, Changchun, Jilin 130020, China
| | - Huimin Li
- School of Nursing, Jilin University, 965 Xinjiang Street, Changchun, Jilin 130020, China
| | - Qinqin Cao
- School of Nursing, Jilin University, 965 Xinjiang Street, Changchun, Jilin 130020, China
| | - Feng Li
- School of Nursing, Jilin University, 965 Xinjiang Street, Changchun, Jilin 130020, China
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Expression, Polyubiquitination, and Therapeutic Potential of Recombinant E6E7 from HPV16 Antigens Fused to Ubiquitin. Mol Biotechnol 2017; 59:46-56. [PMID: 28025776 DOI: 10.1007/s12033-016-9990-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Ubiquitin-proteasome system plays an essential role in the immune response due to its involvement in the antigen generation and presentation to CD8+ T cells. Hereby, ubiquitin fused to antigens has been explored as an immunotherapeutic strategy that requires the activation of cytotoxic T lymphocytes. Here we propose to apply this ubiquitin fusion approach to a recombinant vaccine against human papillomavirus 16-infected cells. E6E7 multi-epitope antigen was fused genetically at its N- or C-terminal end to ubiquitin and expressed in Escherichia coli as inclusion bodies. The antigens were solubilized using urea and purified by nickel affinity chromatography in denatured condition. Fusion of ubiquitin to E6E7 resulted in marked polyubiquitination in vitro mainly when fused to the E6E7 N-terminal. When tested in a therapeutic scenario, the fusion of ubiquitin to E6E7 reinforced the anti-tumor protection and increased the E6/E7-specific cellular immune responses. Present results encourage the investigation of the adjuvant potential of the ubiquitin fusion to recombinant vaccines requiring CD8+ T cells.
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Fang J, Hu B, Li S, Zhang C, Liu Y, Wang P. A multi-antigen vaccine in combination with an immunotoxin targeting tumor-associated fibroblast for treating murine melanoma. MOLECULAR THERAPY-ONCOLYTICS 2016; 3:16007. [PMID: 27119119 PMCID: PMC4824564 DOI: 10.1038/mto.2016.7] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Accepted: 01/25/2016] [Indexed: 02/08/2023]
Abstract
A therapeutically effective cancer vaccine must generate potent antitumor immune responses and be able to overcome tolerance mechanisms mediated by the progressing tumor itself. Previous studies showed that glycoprotein 100 (gp100), tyrosinase-related protein 1 (TRP1), and tyrosinase-related protein 2 (TRP2) are promising immunogens for melanoma immunotherapy. In this study, we administered these three melanoma-associated antigens via lentiviral vectors (termed LV-3Ag) and found that this multi-antigen vaccine strategy markedly increased functional T-cell infiltration into tumors and generated protective and therapeutic antitumor immunity. We also engineered a novel immunotoxin, αFAP-PE38, capable of targeting fibroblast activation protein (FAP)-expressing fibroblasts within the tumor stroma. When combined with αFAP-PE38, LV-3Ag exhibited greatly enhanced antitumor effects on tumor growth in an established B16 melanoma model. The mechanism of action underlying this combination treatment likely modulates the immune suppressive tumor microenvironment and, consequently, activates cytotoxic CD8+ T cells capable of specifically recognizing and destroying tumor cells. Taken together, these results provide a strong rationale for combining an immunotoxin with cancer vaccines for the treatment of patients with advanced cancer.
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Affiliation(s)
- Jinxu Fang
- Mork Family Department of Chemical Engineering and Materials Science, University of Southern California , Los Angeles, California, USA
| | - Biliang Hu
- Mork Family Department of Chemical Engineering and Materials Science, University of Southern California , Los Angeles, California, USA
| | - Si Li
- Department of Pharmacology and Pharmaceutical Sciences, University of Southern California , Los Angeles, California, USA
| | - Chupei Zhang
- Mork Family Department of Chemical Engineering and Materials Science, University of Southern California , Los Angeles, California, USA
| | - Yarong Liu
- Mork Family Department of Chemical Engineering and Materials Science, University of Southern California , Los Angeles, California, USA
| | - Pin Wang
- Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, California, USA; Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, California, USA; Department of Biomedical Engineering, University of Southern California, Los Angeles, California, USA
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Hu Q, Wu M, Fang C, Cheng C, Zhao M, Fang W, Chu PK, Ping Y, Tang G. Engineering nanoparticle-coated bacteria as oral DNA vaccines for cancer immunotherapy. NANO LETTERS 2015; 15:2732-9. [PMID: 25806599 DOI: 10.1021/acs.nanolett.5b00570] [Citation(s) in RCA: 206] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/19/2023]
Abstract
Live attenuated bacteria are of increasing importance in biotechnology and medicine in the emerging field of cancer immunotherapy. Oral DNA vaccination mediated by live attenuated bacteria often suffers from low infection efficiency due to various biological barriers during the infection process. To this end, we herein report, for the first time, a new strategy to engineer cationic nanoparticle-coated bacterial vectors that can efficiently deliver oral DNA vaccine for efficacious cancer immunotherapy. By coating live attenuated bacteria with synthetic nanoparticles self-assembled from cationic polymers and plasmid DNA, the protective nanoparticle coating layer is able to facilitate bacteria to effectively escape phagosomes, significantly enhance the acid tolerance of bacteria in stomach and intestines, and greatly promote dissemination of bacteria into blood circulation after oral administration. Most importantly, oral delivery of DNA vaccines encoding autologous vascular endothelial growth factor receptor 2 (VEGFR2) by this hybrid vector showed remarkable T cell activation and cytokine production. Successful inhibition of tumor growth was also achieved by efficient oral delivery of VEGFR2 with nanoparticle-coated bacterial vectors due to angiogenesis suppression in the tumor vasculature and tumor necrosis. This proof-of-concept work demonstrates that coating live bacterial cells with synthetic nanoparticles represents a promising strategy to engineer efficient and versatile DNA vaccines for the era of immunotherapy.
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MESH Headings
- Administration, Oral
- Cancer Vaccines/administration & dosage
- Cancer Vaccines/chemistry
- Cell Line, Tumor
- Coated Materials, Biocompatible/chemical synthesis
- Humans
- Immunotherapy, Active/methods
- Nanocapsules/administration & dosage
- Nanocapsules/chemistry
- Nanocapsules/ultrastructure
- Neoplasms, Experimental/genetics
- Neoplasms, Experimental/microbiology
- Neoplasms, Experimental/pathology
- Salmonella/physiology
- Transformation, Bacterial
- Treatment Outcome
- Vaccines, DNA/administration & dosage
- Vaccines, DNA/chemistry
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Affiliation(s)
- Qinglian Hu
- †Institute of Chemical Biology and Pharmaceutical Chemistry, Zhejiang University, Hangzhou 310028, China
| | - Min Wu
- †Institute of Chemical Biology and Pharmaceutical Chemistry, Zhejiang University, Hangzhou 310028, China
| | - Chun Fang
- ‡College of Animal Science, Zhejiang University, Hangzhou 310028, China
| | - Changyong Cheng
- ‡College of Animal Science, Zhejiang University, Hangzhou 310028, China
| | - Mengmeng Zhao
- †Institute of Chemical Biology and Pharmaceutical Chemistry, Zhejiang University, Hangzhou 310028, China
| | - Weihuan Fang
- ‡College of Animal Science, Zhejiang University, Hangzhou 310028, China
| | - Paul K Chu
- §Department of Physics and Materials Science, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, China
| | - Yuan Ping
- ∥School of Materials Science and Engineering, Nanyang Technological University, Singapore 639798, Singapore
| | - Guping Tang
- †Institute of Chemical Biology and Pharmaceutical Chemistry, Zhejiang University, Hangzhou 310028, China
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Zhang C, Li HZ, Qian BJ, Liu CM, Guo F, Lin MC. MTDH/AEG-1-based DNA vaccine suppresses metastasis and enhances chemosensitivity to paclitaxel in pelvic lymph node metastasis. Biomed Pharmacother 2015; 70:217-26. [PMID: 25776504 DOI: 10.1016/j.biopha.2015.01.028] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2015] [Accepted: 01/23/2015] [Indexed: 01/03/2023] Open
Abstract
OBJECTIVE MTDH/AEG-1 could act as an oncogene by regulating cellular transformation, proliferation, invasion, metastasis, and angiogenesis. This study aims to explore the mechanism by which MTDH/AEG-1 inhibits cancer growth and metastasis and enhances chemosensitivity. METHODS Mouse model was established using orally immunized mice exposed to attenuated Salmonella containing vectors carrying full length MTDH/AEG-1 gene, and we were able to enhance the immune response and inhibit the growth and metastasis of prostate cancer through activation of cellular and humoral immunities and induction of CD8+ T cells. Immunohistochemistry and TUNEL assay, CD4+ and CD8+ T cell analysis by flow cytometry, HE staining, RT-PCR analysis, Western-blot analysis and quantitative polymerase chain reaction were performed. RESULTS The MTDH/AEG-1 gene vaccine induced the anti-tumor function of cytotoxic T lymphocytes and CD8+ T cells and inhibited tumor growth and metastasis of prostate cancer. In the therapy model, the MTDH/AEG-1 gene vaccine significantly enhanced chemosensitivity to paclitaxel, inhibited tumor growth, promoted tumor cell apoptosis, and prolonged the survival time of tumor-bearing mice without any apparent side effects. CONCLUSIONS Our results demonstrated that MTDH/AEG-1-based DNA vaccines could used for the treatment of prostate cancer in terms of the inhibition of tumor growth, the lifespan of tumor-bearing animals. Combined with chemotherapy, MTDH/AEG-1-based DNA vaccines may produce highly favorable outcomes in the prevention and treatment of prostate cancer, suggesting the immune efficacy of MTDH/AEG-1-based DNA should be further analyzed in other cancers.
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Affiliation(s)
- Chun Zhang
- Institute of Ningde Urological Research and Department of Urology, Affiliated Mindong Hospital of Fujian Medical University, No. 89, Heshan Road, Fu'an, Fujian 355000, China
| | - Hui-Zhang Li
- Institute of Ningde Urological Research and Department of Urology, Affiliated Mindong Hospital of Fujian Medical University, No. 89, Heshan Road, Fu'an, Fujian 355000, China.
| | - Ben-Jiang Qian
- Institute of Ningde Urological Research and Department of Urology, Affiliated Mindong Hospital of Fujian Medical University, No. 89, Heshan Road, Fu'an, Fujian 355000, China
| | - Chang-Ming Liu
- Institute of Ningde Urological Research and Department of Urology, Affiliated Mindong Hospital of Fujian Medical University, No. 89, Heshan Road, Fu'an, Fujian 355000, China
| | - Fang Guo
- Institute of Health Sciences, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences-Shanghai Jiao-Tong University School of Medicine (SJTU-SM), No. 225, South Chongqing Road, Shanghai 200025, China
| | - Miao-Chun Lin
- Institute of Ningde Urological Research and Department of Urology, Affiliated Mindong Hospital of Fujian Medical University, No. 89, Heshan Road, Fu'an, Fujian 355000, China
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Yoshida M, Kawakami S, Kono Y, Un K, Higuchi Y, Maruyama K, Yamashita F, Hashida M. Enhancement of the anti-tumor effect of DNA vaccination using an ultrasound-responsive mannose-modified gene carrier in combination with doxorubicin-encapsulated PEGylated liposomes. Int J Pharm 2014; 475:401-7. [PMID: 25218184 DOI: 10.1016/j.ijpharm.2014.09.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Revised: 08/25/2014] [Accepted: 09/06/2014] [Indexed: 10/24/2022]
Abstract
A method involving the use of doxorubicin-loaded polyethylene-glycol-modified liposomes and transfection using mannose-modified bubble lipoplexes in combination with ultrasound irradiation may be a promising approach to cancer treatment; it could not only suppress early-stage tumor growth but also enhance transfection efficacy in antigen-presenting cells, thus enhancing the therapeutic potential of a DNA vaccine. However, to date only limited research has been carried out regarding this combination DNA vaccination method for use in cancer therapy. In this study, we examined the anti-tumor effect of DNA vaccination using an ultrasound-responsive mannose-modified gene carrier combined with doxorubicin-encapsulated polyethylene-glycol-modified liposomes. Doxorubicin-encapsulated PEGylated liposomes activated transcriptional factors, such as nuclear factor-κB and AP-1 in the spleen; subsequently pUb-M, ubiquitylated melanoma-related antigen encoding plasmid DNA expression in splenic cells was significantly enhanced. Moreover, effective cytotoxic T-lymphocyte activities were stimulated by DNA vaccination combined with the administration of doxorubicin-encapsulated polyethylene-glycol-modified liposomes. Furthermore, potent DNA vaccine effects against established solid tumor and metastatic tumor derived from B16BL6 melanoma were observed. These results suggest that the combined use of DNA vaccination with doxorubicin-encapsulated polyethylene-glycol-modified liposomes could be an effective method for the treatment of melanoma using immunotherapy.
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Affiliation(s)
- Mitsuru Yoshida
- Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Shigeru Kawakami
- Division of Analytical Research for Pharmacoinformatics, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
| | - Yusuke Kono
- Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
| | - Keita Un
- Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Yuriko Higuchi
- Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Kazuo Maruyama
- Department of Biopharmaceutics, School of Pharmaceutical Science, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan
| | - Fumiyoshi Yamashita
- Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Mitsuru Hashida
- Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan; Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Yoshida-Ushinomiya-cho, Sakyo-ku, Kyoto 606-8302, Japan
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13
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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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14
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Lowe DB, Bose A, Taylor JL, Tawbi H, Lin Y, Kirkwood JM, Storkus WJ. Dasatinib promotes the expansion of a therapeutically superior T-cell repertoire in response to dendritic cell vaccination against melanoma. Oncoimmunology 2014; 3:e27589. [PMID: 24734217 PMCID: PMC3984268 DOI: 10.4161/onci.27589] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Revised: 12/18/2013] [Accepted: 12/18/2013] [Indexed: 12/16/2022] Open
Abstract
Dasatinib (DAS) is a potent inhibitor of the BCR-ABL, SRC, c-KIT, PDGFR, and ephrin tyrosine kinases that has demonstrated only modest clinical efficacy in melanoma patients. Given reports suggesting that DAS enhances T cell infiltration into the tumor microenvironment, we analyzed whether therapy employing the combination of DAS plus dendritic cell (DC) vaccination would promote superior immunotherapeutic benefit against melanoma. Using a M05 (B16.OVA) melanoma mouse model, we observed that a 7-day course of orally-administered DAS (0.1 mg/day) combined with a DC-based vaccine (VAC) against the OVA257–264 peptide epitope more potently inhibited tumor growth and extended overall survival as compared with treatment with either single modality. The superior efficacy of the combinatorial treatment regimen included a reduction in hypoxic-signaling associated with reduced levels of immunosuppressive CD11b+Gr1+ myeloid-derived suppressor cells (MDSC) and CD4+Foxp3+ regulatory T (Treg) populations in the melanoma microenvironment. Furthermore, DAS + VAC combined therapy upregulated expression of Type-1 T cell recruiting CXCR3 ligand chemokines in the tumor stroma correlating with activation and recruitment of Type-1, vaccine-induced CXCR3+CD8+ tumor-infiltrating lymphocytes (TILs) and CD11c+ DC into the tumor microenvironment. The culmination of this bimodal approach was a profound “spreading” in the repertoire of tumor-associated antigens recognized by CD8+ TILs, in support of the therapeutic superiority of combined DAS + VAC immunotherapy in the melanoma setting.
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Affiliation(s)
- Devin B Lowe
- Department of Dermatology; University of Pittsburgh School of Medicine; Pittsburgh, PA USA
| | - Anamika Bose
- Department of Dermatology; University of Pittsburgh School of Medicine; Pittsburgh, PA USA
| | - Jennifer L Taylor
- Department of Dermatology; University of Pittsburgh School of Medicine; Pittsburgh, PA USA
| | - Hussein Tawbi
- Department of Medicine; University of Pittsburgh School of Medicine; Pittsburgh, PA USA ; University of Pittsburgh Cancer Institute; Pittsburgh, PA USA
| | - Yan Lin
- Department of Biostatistics; University of Pittsburgh School of Medicine; Pittsburgh, PA USA ; University of Pittsburgh Cancer Institute; Pittsburgh, PA USA
| | - John M Kirkwood
- Department of Medicine; University of Pittsburgh School of Medicine; Pittsburgh, PA USA ; University of Pittsburgh Cancer Institute; Pittsburgh, PA USA
| | - Walter J Storkus
- Department of Dermatology; University of Pittsburgh School of Medicine; Pittsburgh, PA USA ; Department of Immunology; University of Pittsburgh School of Medicine; Pittsburgh, PA USA ; University of Pittsburgh Cancer Institute; Pittsburgh, PA USA
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15
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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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16
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Systemically administered gp100 encoding DNA vaccine for melanoma using water-in-oil-in-water multiple emulsion delivery systems. Int J Pharm 2013; 453:400-7. [DOI: 10.1016/j.ijpharm.2013.05.028] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2012] [Revised: 04/19/2013] [Accepted: 05/14/2013] [Indexed: 12/15/2022]
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17
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Multi-Compartmental Vaccine Delivery System for Enhanced Immune Response to gp100 Peptide Antigen in Melanoma Immunotherapy. Pharm Res 2012; 29:3393-403. [DOI: 10.1007/s11095-012-0834-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2012] [Accepted: 07/09/2012] [Indexed: 12/28/2022]
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18
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Stable antigen is most effective for eliciting CD8+ T-cell responses after DNA vaccination and infection with recombinant vaccinia virus in vivo. J Virol 2012; 86:9782-93. [PMID: 22761378 DOI: 10.1128/jvi.00694-12] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The induction of strong CD8(+) T-cell responses against infectious diseases and cancer has remained a major challenge. Depending on the source of antigen and the infectious agent, priming of CD8(+) T cells requires direct and/or cross-presentation of antigenic peptides on major histocompatibility complex (MHC) class I molecules by professional antigen-presenting cells (APCs). However, both pathways show distinct preferences concerning antigen stability. Whereas direct presentation was shown to efficiently present peptides derived from rapidly degraded proteins, cross-presentation is dependent on long-lived antigen species. In this report, we analyzed the role of antigen stability on DNA vaccination and recombinant vaccinia virus (VV) infection using altered versions of the same antigen. The long-lived nucleoprotein (NP) of lymphocytic choriomeningitis virus (LCMV) can be targeted for degradation by N-terminal fusion to ubiquitin or, as we show here, to the ubiquitin-like modifier FAT10. Direct presentation by cells either transfected with NP-encoding plasmids or infected with recombinant VV in vitro was enhanced in the presence of short-lived antigens. In vivo, however, the highest induction of NP-specific CD8(+) T-cell responses was achieved in the presence of long-lived NP. Our experiments provide evidence that targeting antigens for proteasomal degradation does not improve the immunogenicity of DNA vaccines and recombinant VVs. Rather, it is the long-lived antigen that is superior for the efficient activation of MHC class I-restricted immune responses in vivo. Hence, our results suggest a dominant role for antigen cross-priming in DNA vaccination and recombinant VV infection.
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19
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Morozov AV, Morozov VA, Astakhova TM, Timofeev AV, Karpov VL. DNA vaccine encoding α-fetoprotein fused with the ornithine decarboxylase degradation signal significantly suppresses the hepatocellular carcinoma growth in mice. Mol Biol 2012. [DOI: 10.1134/s0026893312030089] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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20
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Yu H. Bacteria-mediated disease therapy. Appl Microbiol Biotechnol 2011; 92:1107-13. [DOI: 10.1007/s00253-011-3648-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2011] [Revised: 09/29/2011] [Accepted: 10/16/2011] [Indexed: 12/19/2022]
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21
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Qian BJ, Yan F, Li N, Liu QL, Lin YH, Liu CM, Luo YP, Guo F, Li HZ. MTDH/AEG-1-based DNA vaccine suppresses lung metastasis and enhances chemosensitivity to doxorubicin in breast cancer. Cancer Immunol Immunother 2011; 60:883-93. [PMID: 21400023 PMCID: PMC11028919 DOI: 10.1007/s00262-011-0997-3] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2010] [Accepted: 02/14/2011] [Indexed: 01/22/2023]
Abstract
The gene MTDH/AEG-1 is overexpressed in more than 40% of breast cancer patients, and it is associated with poor clinical outcomes. Previous studies have indicated that MTDH/AEG-1 could promote metastatic lung-seeding and enhance chemoresistance. Therefore, MTDH/AEG-1 could be a candidate target against breast cancer lung metastasis. We demonstrated that MTDH/AEG-1-based DNA vaccine, delivered by attenuated Salmonella typhimurium, could evoke strong CD8(+) cytotoxic-T-cell mediated immune responses against breast cancer. This vaccine showed anti-tumor growth and metastasis efficacy in a prophylactic setting. Importantly, in a therapeutic model, MTDH/AEG-1 vaccine was proved to increase chemosensitivity to doxorubicin and inhibit breast cancer lung metastasis. This vaccine could also prolong the life span of tumor-bearing mice without significant side effects in vivo. These results suggested that this novel DNA vaccine was effective in the inhibition of breast cancer growth and metastasis, and this vaccine in combination with chemotherapies offered new strategies for the clinical therapeutics of breast cancer metastasis.
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MESH Headings
- Animals
- Cancer Vaccines/genetics
- Cancer Vaccines/immunology
- Cancer Vaccines/pharmacology
- Cell Adhesion Molecules/genetics
- Cell Adhesion Molecules/immunology
- Cell Line, Tumor
- Disease Models, Animal
- Doxorubicin/pharmacology
- Gene Expression Profiling
- Immunohistochemistry
- Lung Neoplasms/immunology
- Lung Neoplasms/secondary
- Lung Neoplasms/therapy
- Mammary Neoplasms, Experimental/genetics
- Mammary Neoplasms, Experimental/immunology
- Mammary Neoplasms, Experimental/pathology
- Mammary Neoplasms, Experimental/therapy
- Membrane Proteins
- Mice
- Mice, Inbred BALB C
- RNA-Binding Proteins
- Vaccines, DNA/genetics
- Vaccines, DNA/immunology
- Vaccines, DNA/pharmacology
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Affiliation(s)
- Ben-Jiang Qian
- Institute of Ningde Urological Research and Department of Urology, Affiliated Mindong Hospital of Fujian Medical University, No. 89, Heshan Road, Fu’an, Fujian, 355000 China
| | - Fei Yan
- Institute of Health Sciences, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences-Shanghai Jiao-Tong University School of Medicine (SJTU-SM), No. 225, South Chongqing Road, Shanghai, 200025 China
| | - Na Li
- Institute of Health Sciences, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences-Shanghai Jiao-Tong University School of Medicine (SJTU-SM), No. 225, South Chongqing Road, Shanghai, 200025 China
| | - Qiao-Ling Liu
- Center for Nanomedicine, Shanghai Advanced Research Institute of Chinese Academy of Sciences, Shanghai, China
| | - Yi-Hui Lin
- Institute of Health Sciences, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences-Shanghai Jiao-Tong University School of Medicine (SJTU-SM), No. 225, South Chongqing Road, Shanghai, 200025 China
| | - Chang-Ming Liu
- Institute of Ningde Urological Research and Department of Urology, Affiliated Mindong Hospital of Fujian Medical University, No. 89, Heshan Road, Fu’an, Fujian, 355000 China
| | - Yun-Ping Luo
- Department of Immunology, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Fang Guo
- Institute of Health Sciences, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences-Shanghai Jiao-Tong University School of Medicine (SJTU-SM), No. 225, South Chongqing Road, Shanghai, 200025 China
- Center for Nanomedicine, Shanghai Advanced Research Institute of Chinese Academy of Sciences, Shanghai, China
| | - Hui-Zhang Li
- Institute of Ningde Urological Research and Department of Urology, Affiliated Mindong Hospital of Fujian Medical University, No. 89, Heshan Road, Fu’an, Fujian, 355000 China
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22
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Hahn S, Setz C, Wild J, Schubert U. The PTAP sequence within the p6 domain of human immunodeficiency virus type 1 Gag regulates its ubiquitination and MHC class I antigen presentation. THE JOURNAL OF IMMUNOLOGY 2011; 186:5706-18. [PMID: 21482733 DOI: 10.4049/jimmunol.1003764] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Endogenous peptides presented by MHC class I (MHC-I) molecules are mostly derived from de novo synthesized, erroneous proteins, so-called defective ribosomal products (DRiPs), which are rapidly degraded via the ubiquitin-proteasome pathway. We have previously shown that the HIV-1 Gag protein represents a bona fide substrate for the DRiP pathway and that the amount of Gag-DRiPs can be enhanced by the introduction of an N-end rule degradation signal, leading to increased MHC-I presentation and immunogenicity of Gag. Based on these findings, we sought to identify a naturally occurring sequence motif within Gag that regulates its entry into the DRiP pathway. As the PTAP late assembly domain motif in the C-terminal p6 domain of Gag has been shown to negatively regulate the ubiquitination of Gag, we analyzed the correlation between ubiquitination and MHC-I presentation of PTAP-deficient Gag. Intriguingly, mutation of PTAP not only reduces the release of virus-like particles, but also increases ubiquitination of Gag and, consistently, enhances MHC-I presentation of a Gag-derived epitope. Although the half-life of the PTAP mutant was only mildly reduced, the entry into the DRiP pathway was significantly increased, as demonstrated by short-term pulse-chase analyses under proteasome inhibition. Collectively, these results indicate that, besides driving virus release, the PTAP motif regulates the entry of Gag into the DRiP pathway and, thus, into the MHC-I pathway. Although there are no naturally occurring PTAP mutants of HIV-1, mutations of PTAP might enhance the immunogenicity of Gag and, thus, be considered for the improvement of vaccine development.
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Affiliation(s)
- Sabine Hahn
- Institute of Clinical and Molecular Virology, Friedrich Alexander University, 91054 Erlangen, Germany
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23
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Dendritic cell-directed lentivector vaccine induces antigen-specific immune responses against murine melanoma. Cancer Gene Ther 2011; 18:370-80. [PMID: 21372855 DOI: 10.1038/cgt.2011.13] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Lentivectors are potential vaccine delivery vehicles because they can efficiently transduce a variety of non-dividing cells, including antigen-presenting cells, and do not cause expression of extra viral proteins. To improve safety while retaining efficiency, a dendritic cell (DC)-specific lentivector was constructed by pseudotyping the vector with an engineered viral glycoprotein derived from Sindbis virus. We assessed the level of anti-tumor immunity conferred by this engineered lentivector encoding the melanoma antigen gp100 in a mouse model. Footpad injection of the engineered lentivectors results in the best antigen-specific immune response as compared with subcutaneous and intraperitoneal injections. A single prime vaccination of the engineered lentivectors can elicit a high frequency (up to 10%) of gp100-specific CD8(+) T cells in peripheral blood 3 weeks after the vaccination and this response will be maintained at around 5% for up to 8 weeks. We found that these engineered lentivectors elicited relatively low levels of anti-vector neutralizing antibody responses. Importantly, direct injection of this engineered lentivector inhibited the growth of aggressive B16 murine melanoma. These data suggest that DC-specific lentivectors can be a novel and alternative vaccine carrier with the potential to deliver effective anti-tumor immunity for cancer immunotherapy.
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24
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Un K, Kawakami S, Suzuki R, Maruyama K, Yamashita F, Hashida M. Suppression of Melanoma Growth and Metastasis by DNA Vaccination Using an Ultrasound-Responsive and Mannose-Modified Gene Carrier. Mol Pharm 2011; 8:543-54. [DOI: 10.1021/mp100369n] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Keita Un
- Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan
- The Japan Society for the Promotion of Science (JSPS), Chiyoda-ku, Tokyo 102-8471, Japan
| | - Shigeru Kawakami
- Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Ryo Suzuki
- Department of Biopharmaceutics, School of Pharmaceutical Sciences, Teikyo University, 1091-1 Suwarashi, Midori-ku, Sagamihara, Kanagawa 252-5195, Japan
| | - Kazuo Maruyama
- Department of Biopharmaceutics, School of Pharmaceutical Sciences, Teikyo University, 1091-1 Suwarashi, Midori-ku, Sagamihara, Kanagawa 252-5195, Japan
| | - Fumiyoshi Yamashita
- Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Mitsuru Hashida
- Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan
- Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Yoshida-ushinomiya-cho, Sakyo-ku, Kyoto 606-8302, Japan
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25
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Abstract
Several bacterial species have inherent ability to colonize solid tumors in vivo. However, their natural anti-tumor activity can be enhanced by genetic engineering that enables these bacteria express or transfer therapeutic molecules into target cells. In this review, we summarize latest research on cancer therapy using genetically modified bacteria with particular emphasis on blocking tumor angiogenesis. Despite recent progress, only a few recent studies on bacterial tumor therapy have focused on anti-angiogenesis. Bacteria-mediated anti-angiogenesis therapy for cancer, however, is an attractive approach given that solid tumors are often characterized by increased vascularization. Here, we discuss four different approaches for using modified bacteria as anti-cancer therapeutics--bactofection, DNA vaccination, alternative gene therapy and transkingdom RNA interference--with a specific focus on angiogenesis suppression. Critical areas and future directions for this field are also outlined.
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26
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Paterson Y, Guirnalda PD, Wood LM. Listeria and Salmonella bacterial vectors of tumor-associated antigens for cancer immunotherapy. Semin Immunol 2010; 22:183-9. [PMID: 20299242 PMCID: PMC4411241 DOI: 10.1016/j.smim.2010.02.002] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2009] [Accepted: 02/15/2010] [Indexed: 01/30/2023]
Abstract
This review covers the use of the facultative intracellular bacteria, Listeriamonocytogenes and Salmonella enterica serovar typhimurium as delivery systems for tumor-associated antigens in tumor immunotherapy. Because of their ability to infect and survive in antigen presenting cells, these bacteria have been harnessed to deliver tumor antigens to the immune system both as bacterially expressed proteins and encoded on eukaryotic plasmids. They do this in the context of strong innate immunity, which provides the required stimulus to the immune response to break tolerance against those tumor-associated antigens that bear homology to self. Here we describe differences in the properties of these bacteria as vaccine vectors, a summary of the major therapies they have been applied to and their advancement towards the clinic.
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Affiliation(s)
- Yvonne Paterson
- University of Pennsylvania, Department of Microbiology, 323 Johnson Pavilion, 36th St. and Hamilton Walk, Philadelphia, PA 19104-6076, United States.
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27
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Fest S, Huebener N, Bleeke M, Durmus T, Stermann A, Woehler A, Baykan B, Zenclussen AC, Michalsky E, Jaeger IS, Preissner R, Hohn O, Weixler S, Gaedicke G, Lode HN. Survivin minigene DNA vaccination is effective against neuroblastoma. Int J Cancer 2009; 125:104-14. [DOI: 10.1002/ijc.24291] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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28
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Xiang R, Luo Y, Niethammer AG, Reisfeld RA. Oral DNA vaccines target the tumor vasculature and microenvironment and suppress tumor growth and metastasis. Immunol Rev 2009; 222:117-28. [PMID: 18363997 DOI: 10.1111/j.1600-065x.2008.00613.x] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Four novel oral DNA vaccines provide protection against melanoma, colon, breast, and lung carcinoma in mouse models. Vaccines are delivered by attenuated Salmonella typhimurium to secondary lymphoid organs and respectively target vascular endothelial growth factor receptor-2, transcription factor Fos-related antigen-1, anti-apoptosis protein survivin and Legumain, an asparaginyl endopeptidase specifically overexpressed on tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). These vaccines are all capable of inducing potent cell-mediated protective immunity against self-antigens, resulting in marked suppression of tumor growth and dissemination. Key mechanisms induced by these DNA vaccines include efficient suppression of angiogenesis in the tumor vasculature and marked activation of cytotoxic T cells, natural killer cells, and antigen-presenting dendritic cells. The vaccine targeting Legumain establishes the new paradigm whereby a reduction in the density of TAMs in the TME decreases the release of factors potentiating tumor growth and angiogenesis. This, in turn, remodels the TME and decreases its immunosuppressive milieu and thereby potentiates the DNA vaccine's ability to effectively suppress tumor cell proliferation, vascularization, and metastasis. It is anticipated that such research efforts will lead to novel DNA-based vaccines that will be effective for the treatment of cancer.
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Affiliation(s)
- Rong Xiang
- Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA
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29
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Hu H, Huang X, Tao L, Huang Y, Cui BA, Wang H. Comparative analysis of the immunogenicity of SARS-CoV nucleocapsid DNA vaccine administrated with different routes in mouse model. Vaccine 2009; 27:1758-63. [PMID: 19186202 PMCID: PMC7115532 DOI: 10.1016/j.vaccine.2009.01.021] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2008] [Revised: 01/03/2009] [Accepted: 01/11/2009] [Indexed: 01/14/2023]
Abstract
The development of strategies to augment the immunogenicity of DNA vaccines is critical for improving their clinical utility. One such strategy involves using the different immune routes with DNA vaccines. In the present study, the immunogenicity of SARS-CoV nucleocapsid DNA vaccine, induced by using the current routine vaccination routes (intramuscularly, by electroporation, or orally using live-attenuated Salmonella typhimurium), was compared in mouse model. The comparison between the three vaccination routes indicated that immunization intramuscularly induced a moderate T cell response and antibody response. Mice administrated by electroporation induced the highest antibody response among the three immunization groups and a mid-level of cellular response. In contrast, the orally DNA vaccine evoked vigorous T cell response and a weak antibody production. These results indicated that the distinct types of immune responses were generated by the different routes of DNA immunization. In addition, our results also show that the delivery of DNA vaccines by electroporation and orally using live-attenuated Salmonella in vivo is an effective method to increase the immune responses. Further studies could be carried out using a combination strategy of both oral and electroporation immunizations to stimulate higher cellular and humoral immune responses.
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MESH Headings
- Administration, Oral
- Animals
- Antibodies, Viral/analysis
- Antibodies, Viral/biosynthesis
- Antibody Formation/immunology
- Capsid/immunology
- Cell Proliferation
- DNA, Viral/genetics
- DNA, Viral/immunology
- Electroporation
- Female
- Immunity, Cellular/immunology
- Injections, Intramuscular
- Interferon-gamma/biosynthesis
- Interleukin-4/biosynthesis
- Lymphocytes/immunology
- Mice
- Mice, Inbred BALB C
- Plasmids/immunology
- Severe acute respiratory syndrome-related coronavirus/immunology
- Salmonella typhimurium/immunology
- Severe Acute Respiratory Syndrome/immunology
- Vaccines, Attenuated/immunology
- Vaccines, DNA/administration & dosage
- Vaccines, DNA/immunology
- Viral Vaccines/administration & dosage
- Viral Vaccines/immunology
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Affiliation(s)
- Hui Hu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Science, Wuhan 430071, PR China.
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30
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Durántez M, López-Vázquez AB, de Cerio ALD, Huarte E, Casares N, Prieto J, Borrás-Cuesta F, Lasarte JJ, Sarobe P. Induction of multiepitopic and long-lasting immune responses against tumour antigens by immunization with peptides, DNA and recombinant adenoviruses expressing minigenes. Scand J Immunol 2008; 69:80-9. [PMID: 19144076 DOI: 10.1111/j.1365-3083.2008.02202.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The development of immunization strategies to induce strong and multiepitopic T-cell responses against tumour antigens is needed for anti-tumour immunotherapy. However, a common finding after immunization with complex antigens is the preferential induction of immune responses against immunodominant epitopes. In this study, with the aim of inducing multiepitopic responses against several common tumour antigens, we have designed a minigene construct encoding four human leucocyte antigen (HLA)-A2-restricted epitopes belonging to tumour antigens CEA (CEA-691 and CEA-571), MAGE2 (MAGE2-157) and MAGE3 (MAGE3-112), as well as the universal PADRE epitope recognized by T helper lymphocytes. To optimize the activation of immune responses against these epitopes, we have used different antigen formats (short peptides encompassing individual epitopes and DNA plasmids or adenoviral constructs expressing the minigene) in single or combined immunization schedules. A single immunization with either DNA plasmid or recombinant adenovirus induced a monospecific immune response against the immunodominant epitope CEA-571, whereas immunization with the peptide pool induced responses against all epitopes. Combination of peptide priming followed by a boost with the plasmid and the recombinant adenovirus expressing the minigene induced stronger, multi-specific and long-lasting immune responses, overcoming the immunodominance imposed by the main T-cell epitope. Moreover, these combined immunization strategies were able to induce responses that were able to recognize Mel624 HLA-A2+ tumour cells expressing MAGE2. These results suggest that heterologous immunization strategies combining peptides and DNA or recombinant adenoviruses can be useful to broaden the specificity and enhance the efficacy of subunit vaccines.
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Affiliation(s)
- M Durántez
- Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
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31
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Abstract
The use and optimisation of plasmid DNA delivery systems for the purposes of eliciting transgene specific immune responses to orally administered DNA encoded antigen represents a significant challenge. Here, we have outlined a multicomponent polymer modified liposomal delivery system that offers potential for oral administration of plasmid DNA. It is shown that the polymer/liposome formulated DNA is able to elicit markedly enhanced transgene specific cytokine production following in vitro restimulation of splenocytes with recombinant antigen. This is discussed with reference to recent publications and the potential of plasmid DNA delivery systems for the purposes of genetic immunisation, as reported in selected literature, is assessed.
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Affiliation(s)
- S Somavarapu
- Centre for Drug Delivery Research, School of Pharmacy, University of London, UK
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32
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Abstract
The discovery that genes can be functionally transferred from bacteria to mammalian cells has suggested the possible use of bacterial vectors as gene delivery vehicles for vaccines. Attenuated invasive human intestinal bacteria, such as Salmonella and Shigella, have been used as plasmid DNA vaccine carriers and their potency has been evaluated in several animal models. This delivery system allows the administration of DNA vaccines together with associated bacterial immunostimulators directly to professional antigen presenting cells via human mucosal surfaces. Various strategies have been taken to improve the use of this delivery system to achieve robust immune responses at both mucosal and systemic sites of the immunized animals.
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Affiliation(s)
- F Xu
- Vaccine Research Department, Chiron Corporation, Emeryville, CA 94608, USA.
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33
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Huebener N, Fest S, Strandsby A, Michalsky E, Preissner R, Zeng Y, Gaedicke G, Lode HN. A rationally designed tyrosine hydroxylase DNA vaccine induces specific antineuroblastoma immunity. Mol Cancer Ther 2008; 7:2241-51. [DOI: 10.1158/1535-7163.mct-08-0109] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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34
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Lewēn S, Zhou H, Hu HD, Cheng T, Markowitz D, Reisfeld RA, Xiang R, Luo Y. A Legumain-based minigene vaccine targets the tumor stroma and suppresses breast cancer growth and angiogenesis. Cancer Immunol Immunother 2008; 57:507-15. [PMID: 17786443 PMCID: PMC11030723 DOI: 10.1007/s00262-007-0389-x] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2007] [Accepted: 08/08/2007] [Indexed: 12/31/2022]
Abstract
Tumor associated macrophages (TAMs) are well known to play a very important role in tumor angiogenesis and metastasis. The suppression of TAMs in the tumor-microenvironment (TME) provides a novel strategy to inhibit tumor growth and dissemination by remodeling the tumor's stroma. Here, we tested our hypothesis that suppression of TAMs can be achieved in syngeneic BALB/c mice with oral minigene vaccines against murine MHC class I antigen epitopes of Legumain, an asparaginyl endopeptidase and a member of the C13 family of cystine proteases which is overexpressed on TAMs in the tumor stroma. Vaccine vectors were constructed and transformed into attenuated Salmonella typhimurium (Dam ( - ) , AroA ( - )) for oral delivery. Groups of mice received either the expression vectors encoding the Legumain H-2D or 2K epitopes or the control empty vector by gavage. The efficacy of the minigene vaccines was determined by their ability to protect mice from lethal tumor cell challenges, the induction of a specific CTL response as well as IFN-gamma release, and inhibition of tumor angiogenesis. We demonstrated that the Legumain minigene vaccine provided effective protection against tumor cell challenge by inducing a specific CD8+ T-cell response against Legumain+ TAMs in our breast tumor model. The protection, induced by this T-cell response, mediated by the Legumain Kd minigene, is also responsible for lysing D2F2 breast carcinoma cells in syngeneic BALB/c mice and for suppressing tumor angiogenesis. Importantly, in a prophylactic setting, the minigene vaccine proved to be of similar anti-tumor efficacy as a vaccine encoding the entire Legumain gene. Together, our findings establish proof of concept that a Legumain minigene vaccine provides a more flexible alternative to the whole gene vaccine, which may facilitate the future design and clinical applications of such a vaccine for cancer prevention.
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Affiliation(s)
- Susanna Lewēn
- 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
| | - Huai-dong Hu
- Key Laboratory of Molecular Biology for Infectious Disease, Ministry of Education, Institute for Viral Hepatitis, Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010 China
| | - Tingmei Cheng
- Key Laboratory of Molecular Biology for Infectious Disease, Ministry of Education, Institute for Viral Hepatitis, Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010 China
| | - Dorothy Markowitz
- 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
| | - Rong Xiang
- Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 USA
- Key Laboratory of Molecular Biology for Infectious Disease, Ministry of Education, Institute for Viral Hepatitis, Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010 China
| | - Yunping Luo
- Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 USA
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35
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Two oral HBx vaccines delivered by live attenuated Salmonella: both eliciting effective anti-tumor immunity. Cancer Lett 2008; 263:67-76. [PMID: 18226855 DOI: 10.1016/j.canlet.2007.12.022] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2007] [Revised: 12/11/2007] [Accepted: 12/14/2007] [Indexed: 12/29/2022]
Abstract
Live attenuated bacteria have great potential for use in vaccine development due to several unique advantages, including stable antigen expression, effective antigen presentation, convenient and inexpensive delivery, and low cost of vaccine production. In this study, we expressed hepatitis B virus x gene (HBx) on mouse melanoma cells as the target antigen and constructed Salmonella-based HBx vaccines by two strategies, i.e., recombinant eukaryotic plasmid encoding HBx and a recombinant prokaryotic plasmid encoding Type III secretion system effector-HBx fusion protein. Both HBx constructs elicited significant levels of CTL reaction and IFN-gamma secreting T cells. When mice were challenged with melanoma cells expressing HBx, tumor growth rates in immunized animals were significantly slower than controls. Tumor sizes and tumor weight indices of immunized mice were also significantly lower than controls. We conclude that both strategies described in this study may lead to novel approaches of tumor vaccines.
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36
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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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37
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Wang JX, Zheng L, Song SX, Zhang X, Li LM, Wang F, Liu YF, Sun SH. Augmented Humoral and Cellular Immune Responses Induced by Canine Adenovirus Type 1 DNA Vaccine in BALB/c Mice. Viral Immunol 2007; 20:461-8. [DOI: 10.1089/vim.2007.0018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Jun-Xia Wang
- Department of Molecular Biology, Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Long Zheng
- Department of Molecular Biology, Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Shu-Xia Song
- Department of Medical Genetics, College of Basic Medical Sciences, Second Military Medical University, Shanghai, People's Republic of China
| | - Xia Zhang
- Department of Molecular Biology, Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Li-Min Li
- Department of Molecular Biology, Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Fang Wang
- Department of Medical Genetics, College of Basic Medical Sciences, Second Military Medical University, Shanghai, People's Republic of China
| | - Ying Fu Liu
- Department of Molecular Biology, Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Shu-Han Sun
- Department of Medical Genetics, College of Basic Medical Sciences, Second Military Medical University, Shanghai, People's Republic of China
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38
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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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39
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Lu Y, Kawakami S, Yamashita F, Hashida M. Development of an antigen-presenting cell-targeted DNA vaccine against melanoma by mannosylated liposomes. Biomaterials 2007; 28:3255-62. [PMID: 17449093 DOI: 10.1016/j.biomaterials.2007.03.028] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2007] [Accepted: 03/27/2007] [Indexed: 10/23/2022]
Abstract
As part of our research involving the targeted delivery of plasmid DNA (pDNA) to antigen-presenting cells (APCs), we developed mannosylated cationic liposomes: N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA)/cholesten-5-yloxy-N-(4-((1-imino-2-D-thiomannosyl-ethyl)amino)butyl)formamide (Man-C4-Chol)/Chol (Man liposomes). In this study, we used melanoma-associated antigen expressing pDNA; pUb-M and Man liposomes to create a novel APC-targeted DNA vaccine against melanoma and examined its potency by measuring the Ub-M mRNA expression in splenic dendritic cells and macrophages, the cytotoxic T lymphocyte (CTL) activity against melanoma B16BL6 cells and the melanoma B16BL6-specific anti-tumor effect after intraperitoneal (i.p.) administration. We verified that Man lipoplex induces significantly higher pUb-M gene transfection into dendritic cells and macrophages than unmodified lipoplex and naked DNA and it also strongly induces CTL activity against melanoma, inhibits its growth and prolongs the survival after tumor challenge compared with unmodified liposomes and the standard method (naked pDNA, intramuscular (i.m.)). These results demonstrate that Man liposomes are a potent APCs-targeted vector that induce strong immunopotency of DNA vaccine against melanoma.
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MESH Headings
- Animals
- Antigen-Presenting Cells/immunology
- Cell Line, Tumor
- Cells, Cultured
- Cytotoxicity Tests, Immunologic
- Female
- Liposomes/administration & dosage
- Liposomes/chemistry
- Macrophages, Peritoneal/cytology
- Macrophages, Peritoneal/immunology
- Mannose-Binding Lectins
- Melanoma, Experimental/immunology
- Melanoma, Experimental/prevention & control
- Mice
- Mice, Inbred C57BL
- Neoplasm Transplantation
- RNA, Messenger/analysis
- T-Lymphocytes, Cytotoxic/immunology
- Transfection
- Vaccines, DNA/administration & dosage
- Vaccines, DNA/genetics
- Vaccines, DNA/immunology
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Affiliation(s)
- Yan Lu
- Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
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40
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Parsa S, Pfeifer B. Engineering bacterial vectors for delivery of genes and proteins to antigen-presenting cells. Mol Pharm 2007; 4:4-17. [PMID: 17233543 DOI: 10.1021/mp0600889] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Bacterial vectors offer a biological route to gene and protein delivery with this article featuring delivery to antigen-presenting cells (APCs). Primarily in the context of immune stimulation against infectious disease or cancer, the goal of bacterially mediated delivery is to overcome the hurdles to effective macromolecule delivery. This review will present several bacterial vectors as macromolecule (protein or gene) delivery devices with both innate and acquirable (or engineered) biological features to facilitate delivery to APCs. The review will also present topics related to large-scale manufacture, storage, and distribution that must be considered if the bacterial delivery devices are ever to be used in a global market.
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Affiliation(s)
- Saba Parsa
- Department of Chemical and Biological Engineering, Tufts University, Medford, Massachusetts 02155, USA
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41
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Agorio C, Schreiber F, Sheppard M, Mastroeni P, Fernandez M, Martinez MA, Chabalgoity JA. Live attenuatedSalmonella as a vector for oral cytokine gene therapy in melanoma. J Gene Med 2007; 9:416-23. [PMID: 17410612 DOI: 10.1002/jgm.1023] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Systemic administration of cytokines has shown therapeutic benefits in cancer patients; however, serious adverse effects associated with direct protein administration prevent the wide use of this approach. We have assessed the capacity of live attenuated Salmonella to act as a vector for oral cytokine-gene therapy. Salmonella orally administered to melanoma-bearing mice was found to accumulate within the tumor, reaching up to 10(5) bacteria per gram of tumor by day 21 after bacterial inoculation. Numbers of bacteria recovered from tumor did not differ from those recovered from liver or spleen at any time point. Recombinant bacteria carrying eukaryotic expression vectors encoding the murine IL-4 or IL-18 genes were administered to groups of mice with established subcutaneous melanoma tumors. We found that a single oral dose of Salmonella carrying any of the cytokine-encoding plasmids resulted in significantly increased survival time, as compared with mice that received Salmonella carrying the parental plasmid or PBS. Increased levels of IFNgamma were found in sera of animals receiving either of the cytokine-encoding bacteria, but not in mice receiving Salmonella alone or PBS. Co-administration of both recombinant bacteria maximized the production of IFNgamma. Overall these results suggest that cytokine-encoding Salmonella can be an effective and safer alternative to systemic administration of cytokines for immunotherapy of cancer.
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Affiliation(s)
- Caroline Agorio
- Laboratory for Vaccine Research, Departamento de Desarrollo Biotecnológico, Instituto de Higiene, Facultad de Medicina, Av. Navarro 3051, Montevideo, Uruguay
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42
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Luo Y, Markowitz D, Xiang R, Zhou H, Reisfeld RA. FLK-1-based minigene vaccines induce T cell-mediated suppression of angiogenesis and tumor protective immunity in syngeneic BALB/c mice. Vaccine 2006; 25:1409-15. [PMID: 17113202 PMCID: PMC1995657 DOI: 10.1016/j.vaccine.2006.10.043] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2006] [Revised: 10/17/2006] [Accepted: 10/24/2006] [Indexed: 11/23/2022]
Abstract
Angiogenesis is a rate-limiting step in the development of tumors. Here, we demonstrate that oral minigene DNA vaccines against murine vascular endothelial growth factor receptor-2 (FLK-1), a self-antigen overexpressed on proliferating endothelial cells in the tumor vasculature, induced protection against tumors of different origin in syngeneic BALB/c mice. This protection is mediated by CD8 T cells, which specifically kill FLK-1(+) endothelial cells, resulting in marked suppression of tumor angiogenesis. More importantly, the minigene vaccine proved to be of similar efficacy as a vaccine encoding the whole FLK-1 gene. These data suggest a FLK-1 minigene vaccine provides a more flexible alternative to the whole gene vaccine and will facilitate their future design and clinical applications in cancer therapy and prevention.
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MESH Headings
- Administration, Oral
- Animals
- CD8-Positive T-Lymphocytes/immunology
- Cancer Vaccines/genetics
- Cancer Vaccines/immunology
- Cancer Vaccines/pharmacology
- Cell Line, Tumor
- Colonic Neoplasms/blood supply
- Colonic Neoplasms/immunology
- Colonic Neoplasms/prevention & control
- Colonic Neoplasms/therapy
- Endothelial Cells/cytology
- Endothelial Cells/immunology
- Female
- Mammary Neoplasms, Experimental/blood supply
- Mammary Neoplasms, Experimental/immunology
- Mammary Neoplasms, Experimental/prevention & control
- Mammary Neoplasms, Experimental/therapy
- Mice
- Mice, Inbred BALB C
- Neoplasms, Experimental/blood supply
- Neoplasms, Experimental/immunology
- Neoplasms, Experimental/prevention & control
- Neoplasms, Experimental/therapy
- Neovascularization, Pathologic/immunology
- Neovascularization, Pathologic/therapy
- Vaccines, DNA/genetics
- Vaccines, DNA/immunology
- Vaccines, DNA/pharmacology
- Vascular Endothelial Growth Factor Receptor-2/genetics
- Vascular Endothelial Growth Factor Receptor-2/immunology
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43
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Fernandez-Borges N, Brun A, Whitton JL, Parra B, Diaz-San Segundo F, Salguero FJ, Torres JM, Rodriguez F. DNA vaccination can break immunological tolerance to PrP in wild-type mice and attenuates prion disease after intracerebral challenge. J Virol 2006; 80:9970-6. [PMID: 17005675 PMCID: PMC1617305 DOI: 10.1128/jvi.01210-06] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2006] [Accepted: 08/01/2006] [Indexed: 11/20/2022] Open
Abstract
Transmissible spongiform encephalopathies (TSEs) can be ameliorated by prion protein (PrP)-specific antibodies, but active immunization is complicated by immune tolerance to the normal cellular host protein (PrP(C)). Here, we show that DNA immunization of wild-type mice can break immune tolerance against the prion protein, resulting in the induction of PrP-specific antibody and T-cell responses. PrP immunogenicity was increased by fusion to the lysosomal targeting signal from LIMPII (lysosomal integral membrane protein type II). Although mice immunized with a PrP-LIMPII DNA vaccine showed a dramatic delay in the onset of early disease signs after intracerebral challenge, immunization against PrP also had some deleterious effects. These results clearly confirm the feasibility of using active immunization to protect against TSEs and, in the absence of effective treatments, indicate a suitable alternative for combating the spread of these diseases.
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Affiliation(s)
- Natalia Fernandez-Borges
- Edifici Centre de Recerca en Sanitat Animal, Campus de la UAB, Bellaterra, Cerdanyola del Valles, Barcelona 08193, Spain.
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44
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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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45
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McWilliams JA, McGurran SM, Dow SW, Slansky JE, Kedl RM. A modified tyrosinase-related protein 2 epitope generates high-affinity tumor-specific T cells but does not mediate therapeutic efficacy in an intradermal tumor model. THE JOURNAL OF IMMUNOLOGY 2006; 177:155-61. [PMID: 16785510 DOI: 10.4049/jimmunol.177.1.155] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The generation of tumor-specific T cells is hampered by the presentation of poorly immunogenic tumor-specific epitopes by the tumor. Here, we demonstrate that, although CD8+ T cells specific for the self/tumor Ag tyrosinase-related protein 2 (TRP2) are readily detected in tumor-bearing hosts, vaccination of either tumor-bearing or naive mice with an epitope derived from TRP2 fails to generate significant numbers of tetramer-staining TRP2-specific T cells or antitumor immunity. We identified an altered peptide epitope, called deltaV, which elicits T cell responses that are cross-reactive to the wild-type TRP2 epitope. Immunization with deltaV generates T cells with increased affinity for TRP2 compared with immunization with the wild-type TRP2 epitope, although TRP2 immunization often generates a greater number of TRP2-specific T cells based on intracellular IFN-gamma analysis. Despite generating higher affinity responses, deltaV immunization alone fails to provide any greater therapeutic efficacy against tumor growth than TRP2 immunization. This lack of tumor protection is most likely a result of both the deletion of high affinity and functional tolerance induction of lower affinity TRP2-specific T cells. Our data contribute to a growing literature demonstrating the ability of variant peptide epitopes to generate higher affinity T cell responses against tumor-specific Ags. However, consistent with most clinical data, simple generation of higher affinity T cells is insufficient to mediate tumor immunity.
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MESH Headings
- Animals
- Antigens, Neoplasm/metabolism
- Antigens, Neoplasm/physiology
- Antigens, Neoplasm/therapeutic use
- Cancer Vaccines/administration & dosage
- Cancer Vaccines/immunology
- Cell Adhesion/immunology
- Cell Line, Tumor
- Epitopes, T-Lymphocyte/administration & dosage
- Epitopes, T-Lymphocyte/metabolism
- Epitopes, T-Lymphocyte/therapeutic use
- Female
- H-2 Antigens/metabolism
- Injections, Intradermal
- Intramolecular Oxidoreductases/administration & dosage
- Intramolecular Oxidoreductases/metabolism
- Intramolecular Oxidoreductases/therapeutic use
- Lymphocyte Activation/immunology
- Melanoma, Experimental/immunology
- Melanoma, Experimental/mortality
- Melanoma, Experimental/therapy
- Mice
- Mice, Inbred C57BL
- Neoplasm Transplantation
- Peptides/administration & dosage
- Peptides/metabolism
- Peptides/therapeutic use
- Protein Binding/immunology
- Skin Neoplasms/immunology
- Skin Neoplasms/mortality
- Skin Neoplasms/therapy
- T-Lymphocyte Subsets/immunology
- T-Lymphocyte Subsets/metabolism
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46
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Luo Y, Zhou H, Krueger J, Kaplan C, Lee SH, Dolman C, Markowitz D, Wu W, Liu C, Reisfeld RA, Xiang R. Targeting tumor-associated macrophages as a novel strategy against breast cancer. J Clin Invest 2006; 116:2132-2141. [PMID: 16862213 PMCID: PMC1513049 DOI: 10.1172/jci27648] [Citation(s) in RCA: 431] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2005] [Accepted: 05/23/2006] [Indexed: 11/17/2022] Open
Abstract
Tumor-associated macrophages (TAMs) are associated with tumor progression and metastasis. Here, we demonstrate for the first time that legumain, a member of the asparaginyl endopeptidase family functioning as a stress protein, overexpressed by TAMs, provides an ideal target molecule. In fact, a legumain-based DNA vaccine served as a tool to prove this point, as it induced a robust CD8+ T cell response against TAMs, which dramatically reduced their density in tumor tissues and resulted in a marked decrease in proangiogenic factors released by TAMs such as TGF-beta, TNF-alpha, MMP-9, and VEGF. This, in turn, led to a suppression of both tumor angiogenesis and tumor growth and metastasis. Importantly, the success of this strategy was demonstrated in murine models of metastatic breast, colon, and non-small cell lung cancers, where 75% of vaccinated mice survived lethal tumor cell challenges and 62% were completely free of metastases. In conclusion, decreasing the number of TAMs in the tumor stroma effectively altered the tumor microenvironment involved in tumor angiogenesis and progression to markedly suppress tumor growth and metastasis. Gaining better insights into the mechanisms required for an effective intervention in tumor growth and metastasis may ultimately lead to new therapeutic targets and better anticancer strategies.
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Affiliation(s)
- Yunping Luo
- Department of Immunology, The Scripps Research Institute, La Jolla, California, USA.
Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Chongqing University of Medical Sciences, Chongqing, China
| | - He Zhou
- Department of Immunology, The Scripps Research Institute, La Jolla, California, USA.
Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Chongqing University of Medical Sciences, Chongqing, China
| | - Jörg Krueger
- Department of Immunology, The Scripps Research Institute, La Jolla, California, USA.
Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Chongqing University of Medical Sciences, Chongqing, China
| | - Charles Kaplan
- Department of Immunology, The Scripps Research Institute, La Jolla, California, USA.
Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Chongqing University of Medical Sciences, Chongqing, China
| | - Sung-Hyung Lee
- Department of Immunology, The Scripps Research Institute, La Jolla, California, USA.
Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Chongqing University of Medical Sciences, Chongqing, China
| | - Carrie Dolman
- Department of Immunology, The Scripps Research Institute, La Jolla, California, USA.
Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Chongqing University of Medical Sciences, Chongqing, China
| | - Dorothy Markowitz
- Department of Immunology, The Scripps Research Institute, La Jolla, California, USA.
Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Chongqing University of Medical Sciences, Chongqing, China
| | - Wenyuan Wu
- Department of Immunology, The Scripps Research Institute, La Jolla, California, USA.
Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Chongqing University of Medical Sciences, Chongqing, China
| | - Cheng Liu
- Department of Immunology, The Scripps Research Institute, La Jolla, California, USA.
Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Chongqing University of Medical Sciences, Chongqing, China
| | - Ralph A. Reisfeld
- Department of Immunology, The Scripps Research Institute, La Jolla, California, USA.
Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Chongqing University of Medical Sciences, Chongqing, China
| | - Rong Xiang
- Department of Immunology, The Scripps Research Institute, La Jolla, California, USA.
Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Chongqing University of Medical Sciences, Chongqing, China
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47
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Souders NC, Verch T, Paterson Y. In vivo bactofection: listeria can function as a DNA-cancer vaccine. DNA Cell Biol 2006; 25:142-51. [PMID: 16569193 DOI: 10.1089/dna.2006.25.142] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The development of an effective therapeutic vaccine to induce cancer-specific immunity remains an unsolved yet pressing priority requiring novel vaccine strategies. Here we have generated a series of vaccines in which bacteria deliver a plasmid encoding a tumor antigen under the control of a mammalian promoter in an attempt to induce an antitumor immune response. Utilizing a plasmid release mechanism involving the suicide of the carrier bacteria, we were able to engineer Listeria monocytogenes to induce antitumor immunity to a physiologically relevant tumor antigen, the cervical cancer oncoprotein E7. In a mouse model of cervical cancer, we were able to slow tumor growth and induce an effector CD8(+) T-cell response against the immunodominant epitope for E7. The CD8(+) T cells generated could both home to and penetrate the tumor. This is the first demonstration of in vivo efficacy of bactofection vectors in treating solid tumors. However, although this delivery system was more effective than administering plasmid alone, it was not as effective as L. monocytogenes engineered to deliver the E7 protein in impacting on established tumor growth.
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MESH Headings
- Animals
- Antigens, Neoplasm/immunology
- Bacterial Vaccines/genetics
- Bacterial Vaccines/immunology
- CD8-Positive T-Lymphocytes/immunology
- Cancer Vaccines/genetics
- Cancer Vaccines/immunology
- Cell Line
- Cell Line, Transformed
- Cell Transformation, Viral
- Disease Models, Animal
- Epitopes, T-Lymphocyte/immunology
- Female
- Flow Cytometry
- Genetic Vectors
- Interferon-gamma/analysis
- Listeria monocytogenes/genetics
- Listeria monocytogenes/immunology
- Listeriosis/immunology
- Mice
- Mice, Inbred C57BL
- Neoplasms, Experimental/immunology
- Neoplasms, Experimental/therapy
- Neoplasms, Experimental/virology
- Plasmids
- Uterine Cervical Neoplasms/immunology
- Uterine Cervical Neoplasms/therapy
- Uterine Cervical Neoplasms/virology
- Vaccines, DNA/genetics
- Vaccines, DNA/immunology
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Affiliation(s)
- N C Souders
- Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
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48
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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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49
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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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50
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Duan X, Hisaeda H, Shen J, Tu L, Imai T, Chou B, Murata S, Chiba T, Tanaka K, Fehling HJ, Koga T, Sueishi K, Himeno K. The ubiquitin-proteasome system plays essential roles in presenting an 8-mer CTL epitope expressed in APC to corresponding CD8+ T cells. Int Immunol 2006; 18:679-87. [PMID: 16569681 DOI: 10.1093/intimm/dxl005] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
MUT1 is an H-2Kb-restricted 8-mer CTL epitope expressed in Lewis lung carcinoma (3LL) tumor cells derived from C57BL/6 (B6) mice. We constructed a chimeric gene encoding ubiquitin-fused MUT1 (pUB-MUT1). By using a gene gun, B6 mice were immunized with the gene prior to challenge with 3LL tumor cells. Tumor growth and lung metastasis were prominently suppressed in mice immunized with pUB-MUT1 but only slightly in those immunized with the MUT1 gene (pMUT) alone. CD8+ T cells were confirmed to be the final effector by in vitro experiments and in vivo removal of the cells with a corresponding antibody. Anti-tumor immunity was profoundly suppressed in mice deficient in an immuno-subunit of proteasome, LMP7. Furthermore, mice deficient in a proteasome regulator, PA28alpha/beta, failed to acquire protective immunity. Thus, application of the ubiquitin-fusion degradation pathway was useful even in immunization with genes encoding a single CTL epitope for induction of specific and active CD8+ T cells.
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MESH Headings
- Animals
- Antigen Presentation/immunology
- Antigen-Presenting Cells/immunology
- Biolistics
- COS Cells
- Carcinoma, Lewis Lung/immunology
- Carcinoma, Lewis Lung/prevention & control
- Chlorocebus aethiops
- Epitopes, T-Lymphocyte/biosynthesis
- Epitopes, T-Lymphocyte/immunology
- Female
- Interferon-gamma/immunology
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Multienzyme Complexes/deficiency
- Multienzyme Complexes/immunology
- Oligopeptides/genetics
- Oligopeptides/immunology
- Proteasome Endopeptidase Complex/immunology
- Proteasome Endopeptidase Complex/metabolism
- Proteins/immunology
- Proteins/metabolism
- T-Lymphocytes, Cytotoxic/enzymology
- T-Lymphocytes, Cytotoxic/immunology
- T-Lymphocytes, Cytotoxic/metabolism
- Tumor Cells, Cultured
- Ubiquitin/immunology
- Ubiquitin/metabolism
- Vaccines, DNA/genetics
- Vaccines, DNA/immunology
- Vaccines, DNA/pharmacology
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Affiliation(s)
- Xuefeng Duan
- Department of Microbiology and Immunology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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