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Zhang Y, Zuo B, Yu Z, Zhao K, Zhang Y, He K, Seow Y, Yin H. Complete remission of tumors in mice with neoantigen-painted exosomes and anti-PD-1 therapy. Mol Ther 2023; 31:3579-3593. [PMID: 37919900 PMCID: PMC10727972 DOI: 10.1016/j.ymthe.2023.10.021] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 09/14/2023] [Accepted: 10/31/2023] [Indexed: 11/04/2023] Open
Abstract
Neoantigen-based cancer vaccines are emerging as promising tumor therapies, but enhancement of immunogenicity can further improve therapeutic outcomes. Here, we demonstrate that anchoring different peptide neoantigens on subcutaneously administered serum exosomes promote lymph node homing and dendritic cell uptake, resulting in significantly enhanced antigenicity in vitro and in vivo. Exosomes anchoring of melanoma peptide neoantigens augmented the magnitude and breadth of T cell response in vitro and in vivo, to a greater extent with CD8+ T cell responses. Simultaneous decoration of different peptide neoantigens on serum exosomes induced potent tumor suppression and neoantigen-specific immune responses in mice with melanoma and colon cancer. Complete tumor eradication and sustainable immunological memory were achieved with neoantigen-painted serum exosome vaccines in combination with programmed cell death protein 1 (PD-1) antibodies in mice with colon cancer. Importantly, human serum exosomes loaded with peptide neoantigens elicited significant tumor growth retardation and immune responses in human colon cancer 3-dimensional (3D) multicellular spheroids. Our study demonstrates that serum exosomes direct in vivo localization, increase dendritic cell uptake, and enhance the immunogenicity of antigenic peptides and thus provides a general delivery tool for peptide antigen-based personalized immunotherapy.
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Affiliation(s)
- Yang Zhang
- State Key Laboratory of Experimental Hematology & The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics & Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) & School of Medical Technology & School of Basic Medical Sciences, Tianjin Medical University, Qixiangtai Road, Heping District, Tianjin 300070, China
| | - Bingfeng Zuo
- State Key Laboratory of Experimental Hematology & The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics & Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) & School of Medical Technology & School of Basic Medical Sciences, Tianjin Medical University, Qixiangtai Road, Heping District, Tianjin 300070, China
| | - Zezhen Yu
- State Key Laboratory of Experimental Hematology & The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics & Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) & School of Medical Technology & School of Basic Medical Sciences, Tianjin Medical University, Qixiangtai Road, Heping District, Tianjin 300070, China
| | - Kangjie Zhao
- State Key Laboratory of Experimental Hematology & The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics & Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) & School of Medical Technology & School of Basic Medical Sciences, Tianjin Medical University, Qixiangtai Road, Heping District, Tianjin 300070, China
| | - Yali Zhang
- State Key Laboratory of Experimental Hematology & The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics & Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) & School of Medical Technology & School of Basic Medical Sciences, Tianjin Medical University, Qixiangtai Road, Heping District, Tianjin 300070, China
| | - Kai He
- Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Yiqi Seow
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, Singapore 138672, Singapore; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - HaiFang Yin
- State Key Laboratory of Experimental Hematology & The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics & Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) & School of Medical Technology & School of Basic Medical Sciences, Tianjin Medical University, Qixiangtai Road, Heping District, Tianjin 300070, China; Department of Clinical Laboratory, Tianjin Medical University General Hospital, Tianjin 300052, China.
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Kumar A, Gautam V, Sandhu A, Rawat K, Sharma A, Saha L. Current and emerging therapeutic approaches for colorectal cancer: A comprehensive review. World J Gastrointest Surg 2023; 15:495-519. [PMID: 37206081 PMCID: PMC10190721 DOI: 10.4240/wjgs.v15.i4.495] [Citation(s) in RCA: 80] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 01/11/2023] [Accepted: 03/03/2023] [Indexed: 04/22/2023] Open
Abstract
Colorectal cancer (CRC) affects 1 in 23 males and 1 in 25 females, making it the third most common cancer. With roughly 608000 deaths worldwide, CRC accounts for 8% of all cancer-related deaths, making it the second most common cause of death due to cancer. Standard and conventional CRC treatments include surgical expurgation for resectable CRC and radiotherapy, chemotherapy, immunotherapy, and their combinational regimen for non-resectable CRC. Despite these tactics, nearly half of patients develop incurable recurring CRC. Cancer cells resist the effects of chemotherapeutic drugs in a variety of ways, including drug inactivation, drug influx and efflux modifications, and ATP-binding cassette transporter overexpression. These constraints necessitate the development of new target-specific therapeutic strategies. Emerging therapeutic approaches, such as targeted immune boosting therapies, non-coding RNA-based therapies, probiotics, natural products, oncolytic viral therapies, and biomarker-driven therapies, have shown promising results in preclinical and clinical studies. We tethered the entire evolutionary trends in the development of CRC treatments in this review and discussed the potential of new therapies and how they might be used in conjunction with conventional treatments as well as their advantages and drawbacks as future medicines.
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Affiliation(s)
- Anil Kumar
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Vipasha Gautam
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Arushi Sandhu
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Kajal Rawat
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Antika Sharma
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Lekha Saha
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
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Hu LF, Lan HR, Huang D, Li XM, Jin KT. Personalized Immunotherapy in Colorectal Cancers: Where Do We Stand? Front Oncol 2021; 11:769305. [PMID: 34888246 PMCID: PMC8649954 DOI: 10.3389/fonc.2021.769305] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 10/26/2021] [Indexed: 12/17/2022] Open
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer death in the world. Immunotherapy using monoclonal antibodies, immune-checkpoint inhibitors, adoptive cell therapy, and cancer vaccines has raised great hopes for treating poor prognosis metastatic CRCs that are resistant to the conventional therapies. However, high inter-tumor and intra-tumor heterogeneity hinder the success of immunotherapy in CRC. Patients with a similar tumor phenotype respond differently to the same immunotherapy regimen. Mutation-based classification, molecular subtyping, and immunoscoring of CRCs facilitated the multi-aspect grouping of CRC patients and improved immunotherapy. Personalized immunotherapy using tumor-specific neoantigens provides the opportunity to consider each patient as an independent group deserving of individualized immunotherapy. In the recent decade, the development of sequencing and multi-omics techniques has helped us classify patients more precisely. The expansion of such advanced techniques along with the neoantigen-based immunotherapy could herald a new era in treating heterogeneous tumors such as CRC. In this review article, we provided the latest findings in immunotherapy of CRC. We elaborated on the heterogeneity of CRC patients as a bottleneck of CRC immunotherapy and reviewed the latest advances in personalized immunotherapy to overcome CRC heterogeneity.
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Affiliation(s)
- Li-Feng Hu
- Department of Colorectal Surgery, Shaoxing People’s Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, China
| | - Huan-Rong Lan
- Department of Breast and Thyroid Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Dong Huang
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Xue-Min Li
- Department of Hepatobiliary Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Ke-Tao Jin
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
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4
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Shahnazari M, Samadi P, Pourjafar M, Jalali A. Therapeutic vaccines for colorectal cancer: The progress and future prospect. Int Immunopharmacol 2020; 88:106944. [PMID: 33182032 DOI: 10.1016/j.intimp.2020.106944] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 08/21/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023]
Abstract
Cancer vaccines are usually derived from the patient's tumor cells or the antigens found on their surface, which may help the immune system to identify and kill these malignant cells. Current focus of many researches is designing vaccines with the hope of triggering the immune system to attack cancer cells in a more effective, reliable and safe manner. Although colorectal cancer (CRC) is recognized as the third leading cause of death by cancer, but significant advances in therapy strategies have been made in recent years, including cancer vaccine. In this review, we present various vaccine platforms that have been used in the border battle against CRC, some of which have been approved for clinical use and some are in late-stage clinical trials. Until September 2020 there is approximately 1940 clinical trials of cancer vaccines on patients with different cancer types, and also many more trials are in the planning stages, which makes it the most important period of therapeutic cancer vaccines studies in the history of the immunotherapy. In cancer vaccines clinical trials, there are several considerations that must be taken into account including engineering of antigen-presenting cells, potential toxicity of antigenic areas, pharmacokinetics and pharmacodynamics of vaccines, and monitoring of the patients' immune response. Therefore, the need to overcome immunosuppression mechanisms/immune tolerance is a critical step for the success of introducing therapeutic vaccines into the widely used drugs on market. In this way, better understanding of neoantigens, tumor immune surveillance escape mechanisms and host-tumor interactions are required to develop more effective and safe cancer vaccines.
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Affiliation(s)
- Mina Shahnazari
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran; Student Research Committee, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Pouria Samadi
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran; Student Research Committee, Hamadan University of Medical Sciences, Hamadan, Iran.
| | - Mona Pourjafar
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran; Student Research Committee, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Akram Jalali
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
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Hager S, Fittler FJ, Wagner E, Bros M. Nucleic Acid-Based Approaches for Tumor Therapy. Cells 2020; 9:E2061. [PMID: 32917034 PMCID: PMC7564019 DOI: 10.3390/cells9092061] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 09/06/2020] [Accepted: 09/07/2020] [Indexed: 12/24/2022] Open
Abstract
Within the last decade, the introduction of checkpoint inhibitors proposed to boost the patients' anti-tumor immune response has proven the efficacy of immunotherapeutic approaches for tumor therapy. Furthermore, especially in the context of the development of biocompatible, cell type targeting nano-carriers, nucleic acid-based drugs aimed to initiate and to enhance anti-tumor responses have come of age. This review intends to provide a comprehensive overview of the current state of the therapeutic use of nucleic acids for cancer treatment on various levels, comprising (i) mRNA and DNA-based vaccines to be expressed by antigen presenting cells evoking sustained anti-tumor T cell responses, (ii) molecular adjuvants, (iii) strategies to inhibit/reprogram tumor-induced regulatory immune cells e.g., by RNA interference (RNAi), (iv) genetically tailored T cells and natural killer cells to directly recognize tumor antigens, and (v) killing of tumor cells, and reprograming of constituents of the tumor microenvironment by gene transfer and RNAi. Aside from further improvements of individual nucleic acid-based drugs, the major perspective for successful cancer therapy will be combination treatments employing conventional regimens as well as immunotherapeutics like checkpoint inhibitors and nucleic acid-based drugs, each acting on several levels to adequately counter-act tumor immune evasion.
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Affiliation(s)
- Simone Hager
- Department of Chemistry and Pharmacy, Ludwig-Maximilians-University (LMU), 81377 Munich, Germany;
| | | | - Ernst Wagner
- Department of Chemistry and Pharmacy, Ludwig-Maximilians-University (LMU), 81377 Munich, Germany;
| | - Matthias Bros
- Department of Dermatology, University Medical Center, 55131 Mainz, Germany;
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6
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Janssen E, Subtil B, de la Jara Ortiz F, Verheul HMW, Tauriello DVF. Combinatorial Immunotherapies for Metastatic Colorectal Cancer. Cancers (Basel) 2020; 12:cancers12071875. [PMID: 32664619 PMCID: PMC7408881 DOI: 10.3390/cancers12071875] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 07/06/2020] [Accepted: 07/09/2020] [Indexed: 12/11/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most frequent and deadly forms of cancer. About half of patients are affected by metastasis, with the cancer spreading to e.g., liver, lungs or the peritoneum. The majority of these patients cannot be cured despite steady advances in treatment options. Immunotherapies are currently not widely applicable for this disease, yet show potential in preclinical models and clinical translation. The tumour microenvironment (TME) has emerged as a key factor in CRC metastasis, including by means of immune evasion-forming a major barrier to effective immuno-oncology. Several approaches are in development that aim to overcome the immunosuppressive environment and boost anti-tumour immunity. Among them are vaccination strategies, cellular transplantation therapies, and targeted treatments. Given the complexity of the system, we argue for rational design of combinatorial therapies and consider the implications of precision medicine in this context.
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Affiliation(s)
- Eline Janssen
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands; (E.J.); (B.S.); (F.d.l.J.O.)
| | - Beatriz Subtil
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands; (E.J.); (B.S.); (F.d.l.J.O.)
| | - Fàtima de la Jara Ortiz
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands; (E.J.); (B.S.); (F.d.l.J.O.)
| | - Henk M. W. Verheul
- Department of Medical Oncology, Radboud University Medical Center, PO Box 9101, 6500 HBNijmegen, The Netherlands;
| | - Daniele V. F. Tauriello
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands; (E.J.); (B.S.); (F.d.l.J.O.)
- Correspondence:
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Leystra AA, Clapper ML. Gut Microbiota Influences Experimental Outcomes in Mouse Models of Colorectal Cancer. Genes (Basel) 2019; 10:genes10110900. [PMID: 31703321 PMCID: PMC6895921 DOI: 10.3390/genes10110900] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 10/31/2019] [Accepted: 11/05/2019] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Mouse models are a valuable resource for use throughout the development and testing of new therapeutic strategies for CRC. Tumorigenesis and response to therapy in humans and mouse models alike are influenced by the microbial communities that colonize the gut. Differences in the composition of the gut microbiota can confound experimental findings and reduce the replicability and translatability of the resulting data. Despite this, the contribution of resident microbiota to preclinical tumor models is often underappreciated. This review does the following: (1) summarizes evidence that the gut microbiota influence CRC disease phenotypes; (2) outlines factors that can influence the composition of the gut microbiota; and (3) provides strategies that can be incorporated into the experimental design, to account for the influence of the microbiota on intestinal phenotypes in mouse models of CRC. Through careful experimental design and documentation, mouse models can continue to rapidly advance efforts to prevent and treat colon cancer.
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Wagner S, Mullins CS, Linnebacher M. Colorectal cancer vaccines: Tumor-associated antigens vs neoantigens. World J Gastroenterol 2018; 24:5418-5432. [PMID: 30622371 PMCID: PMC6319136 DOI: 10.3748/wjg.v24.i48.5418] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Revised: 12/11/2018] [Accepted: 12/20/2018] [Indexed: 02/06/2023] Open
Abstract
Therapeutic options for the treatment of colorectal cancer (CRC) are diverse but still not always satisfying. Recent success of immune checkpoint inhibition treatment for the subgroup of CRC patients suffering from hyper-mutated tumors suggests a permanent role of immune therapy in the clinical management of CRC. Substantial improvement in treatment outcome could be achieved by development of efficient patient-individual CRC vaccination strategies. This mini-review summarizes the current knowledge on the two general classes of targets: tumor-associated antigens (TAAs) and tumor-specific antigens. TAAs like carcinoembryonic antigen and melanoma associated antigen are present in and shared by a subgroup of patients and a variety of clinical studies examined the efficacy of different TAA-derived peptide vaccines. Combinations of several TAAs as the next step and the development of personalized TAA-based peptide vaccines are discussed. Improvements of peptide-based vaccines achievable by adjuvants and immune-stimulatory chemotherapeutics are highlighted. Finally, we sum up clinical studies using tumor-specific antigens - in CRC almost exclusively neoantigens - which revealed promising results; particularly no severe adverse events were reported so far. Critical progress for clinical outcomes can be expected by individualizing neoantigen-based peptide vaccines and combining them with immune-stimulatory chemotherapeutics and immune checkpoint inhibitors. In light of these data and latest developments, truly personalized neoantigen-based peptide vaccines can be expected to fulfill modern precision medicine's requirements and will manifest as treatment pillar for routine clinical management of CRC.
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Affiliation(s)
- Sandra Wagner
- Section of Molecular Oncology and Immunotherapy, General Surgery, University Medical Center, Rostock D-18057, Germany
| | - Christina S Mullins
- Section of Molecular Oncology and Immunotherapy, General Surgery, University Medical Center, Rostock D-18057, Germany
| | - Michael Linnebacher
- Section of Molecular Oncology and Immunotherapy, General Surgery, University Medical Center, Rostock D-18057, Germany
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9
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Park BK, Park JY, Kim TH, Kim D, Wu G, Gautam A, Maharjan S, Lee SI, Lee Y, Kwon HJ, Choi KC. Production of an anti-TM4SF5 monoclonal antibody and its application in the detection of TM4SF5 as a possible marker of a poor prognosis in colorectal cancer. Int J Oncol 2018; 53:275-285. [PMID: 29749436 DOI: 10.3892/ijo.2018.4385] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 04/20/2018] [Indexed: 11/06/2022] Open
Abstract
The cell surface transmembrane 4 superfamily member 5 protein (TM4SF5) has been implicated in various human cancers. Immunization with a peptide vaccine targeting human TM4SF5 has been shown to exert prophylactic and therapeutic effects against the development of hepatocellular carcinoma and colon cancer in mouse models. In this study, we developed a novel monoclonal antibody (mEC2‑CF) targeting a cyclic epitope of TM4SF5 and evaluated its reactivity to TM4SF5 in colorectal cancer (CRC) cells and cancer tissues. The isotype of mEC2‑CF was IgG2a and the antibody specifically recognized the cyclic peptide, based on ELISA. The antibody recognized recombinant TM4SF5 overexpressed in 293F cells, irrespective of N‑glycosidase F treatment. The antibody was internalized into the cytosol after binding to the surface of TM4SF5‑expressing CRC cells, suggesting that this antibody may be useful in therapeutics. In addition, we evaluated TM4SF5 expression in the tissues of patients with CRC patients to determine its prognostic significance. TM4SF5 expression was assessed by immunohistochemistry using mEC2‑CF and tissue microarray blocks of 204 primary CRC samples. The overall rate of TM4SF5 overexpression in the samples (immunohistochemical score >4) was 27.0% (55 of 204). The increased expression of TM4SF5 was significantly associated with a shorter survival rate (P=0.0014) and a worse disease‑free survival (P=0.0483) of patients with CRC. No association was observed between TM4SF5 expression and clinicopathological characteristics, apart from tumor depth of invasion (P=0.027). These results suggest that our novel antibody can be used to detect endogenous and recombinant TM4SF5, and that TM4SF5 may be a possible marker for the poor prognosis of patients with CRC.
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Affiliation(s)
- Byoung Kwon Park
- Center for Medical Science Research, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea
| | - Jae-Young Park
- Department of Pathology, Hallym University Sacred Heart Hospital, Chuncheon 24253, Republic of Korea
| | - Te Ha Kim
- Department of Microbiology, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea
| | - Dongbum Kim
- Center for Medical Science Research, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea
| | - Guang Wu
- Center for Medical Science Research, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea
| | - Avishekh Gautam
- Department of Microbiology, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea
| | - Sony Maharjan
- Center for Medical Science Research, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea
| | - Su In Lee
- Center for Medical Science Research, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea
| | - Younghee Lee
- Department of Biochemistry, College of Natural Sciences, Chungbuk National University, Cheongju 28644, Republic of Korea
| | - Hyung-Joo Kwon
- Center for Medical Science Research, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea
| | - Kyung Chan Choi
- Center for Medical Science Research, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea
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Antitumor immunity of DNA vaccine based on CTLA-4 fused with HER2 against colon carcinoma. EUR J INFLAMM 2018. [DOI: 10.1177/2058739218768144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) negatively regulates the T cell activation and competes with CD28 in binding with B7.1/B7.2 molecules. Fusion of the extracellular region of CTLA-4 and a specific antigen is an effective method for improving the immune efficacy of DNA vaccines. This study aimed to investigate the effects of DNA vaccine of human epidermal growth factor receptor-2 (HER2) fused with CTLA-4 on the development of colon carcinoma in mice and to identify the potential immune mechanisms underlying its effects. We constructed recombinant plasmids corresponding to the control group, individual antigen group, and fusion antigen group. Then, mice were intramuscularly injected with the corresponding plasmids and exposed to electrical pulses. Immunogenicity was evaluated at 2 weeks after the last immunization. Furthermore, to investigate the antitumor immune effects of the recombinant plasmid, we established a mouse model of HER2 expression in transplanted tumors. Experimental results showed that the recombinant plasmids expressing fusion antigen induced a stronger cellular immune response. Inoculation of the HER2-CTLA-4 plasmid exerted the strongest inhibitory effect on HER2 expression-mediated tumor growth in mice. These results highlight the potential of the CTLA-4 fusion DNA vaccine as a therapeutic vaccine against colon cancer based on HER2 and CTLA-4.
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11
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Signorini L, Delbue S, Ferrante P, Bregni M. Review on the immunotherapy strategies against metastatic colorectal carcinoma. Immunotherapy 2017; 8:1245-61. [PMID: 27605072 DOI: 10.2217/imt-2016-0045] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignancies throughout the world and the leading cause of cancer-related mortality in Western countries. Recent progress in CRC treatment options, such as surgery, chemotherapy, radiotherapy and target therapy, has improved the prognosis, but advanced disease with recurrence or distant metastasis is usually incurable and has an unfavorable prognosis. The introduction of immunotherapy-associated strategies, both active and passive, to the treatment of CRC aims to overcome the limits of classical treatments. We review the state of the art for CRC with respect to different immunotherapeutic approaches, such as the use of cancer vaccines and/or adoptive cellular therapy, their most current advances and limitations and perspectives for further improvements.
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Affiliation(s)
- Lucia Signorini
- Department of Biomedical, Surgical & Dental Sciences, Via Pascal, 36, University of Milano, 20123 Milano, Italy
| | - Serena Delbue
- Department of Biomedical, Surgical & Dental Sciences, Via Pascal, 36, University of Milano, 20123 Milano, Italy
| | - Pasquale Ferrante
- Department of Biomedical, Surgical & Dental Sciences, Via Pascal, 36, University of Milano, 20123 Milano, Italy
| | - Marco Bregni
- Ospedale di Circolo di Busto Arsizio, Via A. Da Brescia, 1, 21052 Busto Arsizio VA, Italy
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12
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Hanagata N. CpG oligodeoxynucleotide nanomedicines for the prophylaxis or treatment of cancers, infectious diseases, and allergies. Int J Nanomedicine 2017; 12:515-531. [PMID: 28144136 PMCID: PMC5248940 DOI: 10.2147/ijn.s114477] [Citation(s) in RCA: 101] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Unmethylated cytosine-guanine dinucleotide-containing oligodeoxynucleotides (CpG ODNs), which are synthetic agonists of Toll-like receptor 9 (TLR9), activate humoral and cellular immunity and are being developed as vaccine adjuvants to prevent or treat cancers, infectious diseases, and allergies. Free CpG ODNs have been used in many clinical trials implemented to verify their effects. However, recent research has reported that self-assembled CpG ODNs, protein/peptide–CpG ODN conjugates, and nanomaterial–CpG ODN complexes demonstrate higher adjuvant effects than free CpG ODNs, owing to their improved uptake efficiency into cells expressing TLR9. Moreover, protein/peptide–CpG ODN conjugates and nanomaterial–CpG ODN complexes are able to deliver CpG ODNs and antigens (or allergens) to the same types of cells, which enables a higher degree of prophylaxis or therapeutic effect. In this review, the author describes recent trends in the research and development of CpG ODN nanomedicines containing self-assembled CpG ODNs, protein/peptide–CpG ODN conjugates, and nanomaterial–CpG ODN complexes, focusing mainly on the results of preclinical and clinical studies.
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Affiliation(s)
- Nobutaka Hanagata
- Nanotechnology Innovation Station, National Institute for Materials Science, Tsukuba, Ibaraki; Graduate School of Life Science, Hokkaido University, Sapporo, Hokkaido, Japan
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13
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Gao P, Zhang C, Bian X, Guo Y, Wei Y, Zhang L, Liu Z, Wang X, Huang S. The increasingly anti-tumor effect of a colonic carcinoma DNA vaccine carrying HER2 by the adjuvanticity of IL-12. Immunopharmacol Immunotoxicol 2016; 38:441-446. [PMID: 27660891 DOI: 10.1080/08923973.2016.1233426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
The present study aimed to determine the effect of recombinant DNA vaccine-based human epidermal growth factor receptor-2 (HER2) and Interleukin 12 (IL-12) on the development of colonic carcinoma in mice and the potential immune mechanisms involved. Recombinant plasmids pVAX1-HER2, pVAX1-IL-12 and pVAX1-HER2-IL-12 were constructed, and injected into female mice intramuscularly (i.m.) followed by an electric pulse. The humoral and cellular immune responses after immunization were examined by enzyme linked immunosorbent assay (ELISA) and enzyme-linked immunospot assay (ELISPOT), respectively. To evaluate the anti-tumor efficacy of the plasmids, a mouse model with a HER2-expressing tumor was designed. Mice vaccinated with the HER2-IL-12 plasmid generated the strongest inhibition efficacy on the growth of HER2-expressing tumors and prolonged mouse survival. These observations emphasized the potential of IL-12 as an adjuvant for DNA vaccines and of vaccines based on HER2 and IL-12 as a promising treatment for colonic carcinoma.
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Affiliation(s)
- Ping Gao
- a Department of Gastroenterology , General Hospital of Daqing Oil Field , Daqing , Heilongjiang , China
| | - Chunhua Zhang
- a Department of Gastroenterology , General Hospital of Daqing Oil Field , Daqing , Heilongjiang , China
| | - Xiaoxia Bian
- a Department of Gastroenterology , General Hospital of Daqing Oil Field , Daqing , Heilongjiang , China
| | - Yanjun Guo
- a Department of Gastroenterology , General Hospital of Daqing Oil Field , Daqing , Heilongjiang , China
| | - Yueguang Wei
- a Department of Gastroenterology , General Hospital of Daqing Oil Field , Daqing , Heilongjiang , China
| | - Li Zhang
- a Department of Gastroenterology , General Hospital of Daqing Oil Field , Daqing , Heilongjiang , China
| | - Zhaoyang Liu
- a Department of Gastroenterology , General Hospital of Daqing Oil Field , Daqing , Heilongjiang , China
| | - Xiuying Wang
- a Department of Gastroenterology , General Hospital of Daqing Oil Field , Daqing , Heilongjiang , China
| | - Shumin Huang
- a Department of Gastroenterology , General Hospital of Daqing Oil Field , Daqing , Heilongjiang , China
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Jang MS, Sahastrabuddhe S, Yun CH, Han SH, Yang JS. Serum bactericidal assay for the evaluation of typhoid vaccine using a semi-automated colony-counting method. Microb Pathog 2016; 97:19-26. [PMID: 27216239 PMCID: PMC4944902 DOI: 10.1016/j.micpath.2016.05.013] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Revised: 05/18/2016] [Accepted: 05/19/2016] [Indexed: 12/22/2022]
Abstract
Typhoid fever, mainly caused by Salmonella enterica serovar Typhi (S. Typhi), is a life-threatening disease, mostly in developing countries. Enzyme-linked immunosorbent assay (ELISA) is widely used to quantify antibodies against S. Typhi in serum but does not provide information about functional antibody titers. Although the serum bactericidal assay (SBA) using an agar plate is often used to measure functional antibody titers against various bacterial pathogens in clinical specimens, it has rarely been used for typhoid vaccines because it is time-consuming and labor-intensive. In the present study, we established an improved SBA against S. Typhi using a semi-automated colony-counting system with a square agar plate harboring 24 samples. The semi-automated SBA efficiently measured bactericidal titers of sera from individuals immunized with S. Typhi Vi polysaccharide vaccines. The assay specifically responded to S. Typhi Ty2 but not to other irrelevant enteric bacteria including Vibrio cholerae and Shigella flexneri. Baby rabbit complement was more appropriate source for the SBA against S. Typhi than complements from adult rabbit, guinea pig, and human. We also examined the correlation between SBA and ELISA for measuring antibody responses against S. Typhi using pre- and post-vaccination sera from 18 human volunteers. The SBA titer showed a good correlation with anti-Vi IgG quantity in the serum as determined by Spearman correlation coefficient of 0.737 (P < 0.001). Taken together, the semi-automated SBA might be efficient, accurate, sensitive, and specific enough to measure functional antibody titers against S. Typhi in sera from human subjects immunized with typhoid vaccines.
Improved SBA against S. Typhi was developed using a colony counting system. The improved SBA was specific to S. Typhi but not to other gram-negative bacteria. There was a good correlation between SBA and anti-Vi IgG titers in vaccinee’s sera. This SBA would be useful for the clinical immuno-monitoring of typhoid vaccines.
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Affiliation(s)
- Mi Seon Jang
- Clinical Immunology, Sciences Unit, International Vaccine Institute, Seoul, Republic of Korea; Department of Oral Microbiology and Immunology, DRI, and BK21 Plus Program, School of Dentistry, Seoul National University, Seoul, Republic of Korea
| | | | - Cheol-Heui Yun
- Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, Republic of Korea
| | - Seung Hyun Han
- Department of Oral Microbiology and Immunology, DRI, and BK21 Plus Program, School of Dentistry, Seoul National University, Seoul, Republic of Korea.
| | - Jae Seung Yang
- Clinical Immunology, Sciences Unit, International Vaccine Institute, Seoul, Republic of Korea.
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15
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Abstract
Transmembrane 4 superfamily member 5 protein (TM4SF5) is presumed to serve as a molecular target to prevent or treat hepatocellular carcinoma (HCC) and colon cancer in a mouse model. Previously, we reported the efficacy of anti-cancer peptide vaccine targeting TM4SF5. In addition, we reported an anti-proliferative effect of anti-TM4SF5 monoclonal antibody in HCC. Here, we investigated expression of TM4SF5 in 45 primary colon cancer tissues. Almost all of the colon cancer tissues expressed TM4SF5 based on immunohistochemistry using anti-TM4SF5 monoclonal antibody. The treatment of human colon cancer cells with anti-TM4SF5 antibody reduced growth of TM4SF5 expressing cells and enhanced expression of E-cadherin and β-catenin. Using mouse colon cancer models, we then evaluated the in vivo anti-cancer effect of anti-TM4SF5 antibody. Injection of the antibody significantly reduced growth of tumors priorly established by subcutaneous injection of human colon cancer cells HT-29 in a xenograft setting. We obtained similar results with mouse colon cancer cell line CT-26 in an allograft setting. Therefore, we suggest that the TM4SF5-specific monoclonal antibody has a therapeutic effect against colon cancer.
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Lee Y, Lee YS, Cho SY, Kwon HJ. Perspective of Peptide Vaccine Composed of Epitope Peptide, CpG-DNA, and Liposome Complex Without Carriers. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2015; 99:75-97. [PMID: 26067817 DOI: 10.1016/bs.apcsb.2015.03.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The magnitude and specificity of cell-mediated and humoral immunity are critically determined by peptide sequences; peptides corresponding to the B- or T-cell receptor epitopes are sufficient to induce an effective immune response if delivered properly. Therefore, studies on the screening and application of peptide-based epitopes have been done extensively for the development of therapeutic antibodies and prophylactic vaccines. However, the efficacy of immune response and antibody production by peptide-based immunization is too limited for human application at the present. To improve the efficacy of vaccines, researchers formulated adjuvants such as alum, water-in-oil emulsion, and Toll-like receptor agonists. They also employed liposomes as delivering vehicles to stimulate immune responses. Here, we review our recent studies providing a potent method of epitope screening and antibody production without conventional carriers. We adopted Lipoplex(O), comprising a natural phosphodiester bond CpG-DNA and a specific liposome complex, as an adjuvant. Lipoplex(O) induces potent stimulatory activity in humans as well as in mice, and immunization of mice with several peptides along with Lipoplex(O) without general carriers induces significant production of each peptide-specific IgG2a. Immunization of peptide vaccines against virus-associated antigens in mice has protective effects against the viral infection. A peptide vaccine against carcinoma-associated antigen and the peptide-specific monoclonal antibody has functional effects against cancer cells in mouse models. In conclusion, we improved the efficacy of peptide vaccines in mice. Our strategy can be applied in development of therapeutic antibodies or in defense against pandemic infectious diseases through rapid screening of potent B-cell epitopes.
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Affiliation(s)
- Younghee Lee
- Department of Biochemistry, College of Natural Sciences, Chungbuk National University, Cheongju, South Korea
| | - Young Seek Lee
- Division of Molecular and Life Sciences, College of Science and Technology, Hanyang University, Ansan, South Korea
| | - Soo Young Cho
- Laboratory of Developmental Biology and Genomics, College of Veterinary Medicine, Research Institute for Veterinary Science BK21, Program for Veterinary Science, Seoul National University, Seoul, South Korea
| | - Hyung-Joo Kwon
- Department of Microbiology, College of Medicine, Hallym University, Chuncheon, South Korea; Center for Medical Science Research, College of Medicine, Hallym University, Chuncheon, South Korea.
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